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Institute
- Theodor-Boveri-Institut für Biowissenschaften (78)
- Physikalisches Institut (41)
- Graduate School of Life Sciences (31)
- Institut für Psychologie (25)
- Institut für Theoretische Physik und Astrophysik (24)
- Fakultät für Physik und Astronomie (21)
- Medizinische Klinik und Poliklinik I (19)
- Rudolf-Virchow-Zentrum (19)
- Neurologische Klinik und Poliklinik (18)
- Institut für Molekulare Infektionsbiologie (17)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine, Baltimore, MD, U.S. (4)
- Institut für Optik und Atomare Physik, Technische Universität Berlin, 10623 Berlin, Germany (2)
- Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan (2)
- CERN (Geneva, Switzerland) (1)
- Fraunhofer-Institut für Silicatforschung ISC (1)
- GEOMAR Helmholtz-Zentrum für Ozeanforschung Kiel (1)
- Hospital Augsburg, Augsburg, Germany (1)
- Institute for Sustainable Chemistry & Catalysis with Boron (1)
- Johns Hopkins University School of Medicine, Baltimore, MD, U.S. (1)
- Johns Hopkis School of Medicine (1)
ResearcherID
- M-1240-2017 (1)
This work is concerned with the syntheses and photophysical properties of para-xylylene bridged macrocycles nPBI with ring sizes from two to nine PBI units, as well as the complexation of polycyclic aromatic guest compounds.
With a reduced but substantial fluorescence quantum yield of 21% (in CHCl3) the free host 2PBI(4-tBu)4 can be used as a dual fluorescence probe. Upon encapsulation of rather electron-poor guests the fluorescence quenching interactions between the chromophores are prevented, leading to a significant fluorescence enhancement to > 90% (“turn-on”). On the other hand, the addition of electron-rich guest molecules induces an electron transfer from the guest to the electron-poor PBI chromophores and thus quenches the fluorescence entirely (“turn-off”). The photophysical properties of the host-guest complexes were studied by transient absorption spectroscopy. These measurements revealed that the charge transfer between guest and 2PBI(4-tBu)4 occurs in the “normal region” of the Marcus-parabola with the fastest charge separation rate for perylene. In contrast, the charge recombination back to the PBI ground state lies far in the “inverted region” of the Marcus-parabola.
Beside complexation of planar aromatic hydrocarbons into the cavity of the cyclophanes an encapsulation of fullerene into the cyclic trimer 3PBI(4-tBu)4 was observed. 3PBI(4-tBu)4 provides a tube-like structure in which the PBI subunits represent the walls of those tubes. The cavity has the optimal size for hosting fullerenes, with C70 fitting better than C60 and a binding constant that is higher by a factor of 10. TA spectroscopy in toluene that was performed on the C60@3PBI(4-tBu)4 complex revealed two energy transfer processes. The first one comes from the excited PBI to the fullerene, which subsequently populates the triplet state. From the fullerene triplet state a second energy transfer occurs back to the PBI to generate the PBI triplet state.
In all cycles that were studied by TA spectroscopy, symmetry-breaking charge separation (SB-CS) was observed in dichloromethane. This process is fastest within the PBI cyclophane 2PBI(4-tBu)4 and slows down for larger cycles, suggesting that the charge separation takes place through space and not through bonds. The charges then recombine to the PBI triplet state via a radical pair intersystem crossing (RP-ISC) mechanism, which could be used to generate singlet oxygen in yields of ~20%.
By changing the solvent to toluene an intramolecular folding of the even-numbered larger cycles was observed that quenches the fluorescence and increases the 0-1 transition band in the absorption spectra. Force field calculations of 4PBI(4-tBu)4 suggested a folding into pairs of dimers, which explains the remarkable odd-even effect with respect to the number of connected PBI chromophores and the resulting alternation in the absorption and fluorescence properties. Thus, the even-numbered macrocycles can fold in a way that all chromophores are in a paired arrangement, while the odd-numbered cycles have open conformations (3PBI(4-tBu)4, 5PBI(4-tBu)4, 7PBI(4-tBu)4) or at least additional unpaired PBI unit (9PBI(4-tBu)4).
With these experiments we could for the first time give insights in the interactions between cyclic PBI hosts and aromatic guest molecules. Associated with the encapsulation of guest molecules a variety of possible applications can be envisioned, like fluorescence sensing, chiral recognition and photodynamic therapy by singlet oxygen generation. Particularly, these macrocycles provide photophysical relaxation pathways of PBIs, like charge separation and recombination and triplet state formation that are hardly feasible in monomeric PBI dyes. Furthermore, diverse compound specific features were found, like the odd-even effect in the folding process or the transition of superficial nanostructures of the tetrameric cycle influenced by the AFM tip. The comprehensive properties of these macrocycles provide the basis for further oncoming studies and can serve as an inspiration for the synthesis of new macrocyclic compounds.
Background
Herpesviruses can infect a wide range of animal species. Herpes simplex virus 1 (HSV-1) is one of the eight herpesviruses that can infect humans and is prevalent worldwide. Herpesviruses have evolved multiple ways to adapt the infected cells to their needs, but knowledge about these transcriptional and post-transcriptional modifications is sparse.
Results
Here, we show that HSV-1 induces the expression of about 1000 antisense transcripts from the human host cell genome. A subset of these is also activated by the closely related varicella zoster virus. Antisense transcripts originate either at gene promoters or within the gene body, and they show different susceptibility to the inhibition of early and immediate early viral gene expression. Overexpression of the major viral transcription factor ICP4 is sufficient to turn on a subset of antisense transcripts. Histone marks around transcription start sites of HSV-1-induced and constitutively transcribed antisense transcripts are highly similar, indicating that the genetic loci are already poised to transcribe these novel RNAs. Furthermore, an antisense transcript overlapping with the BBC3 gene (also known as PUMA) transcriptionally silences this potent inducer of apoptosis in cis.
Conclusions
We show for the first time that a virus induces widespread antisense transcription of the host cell genome. We provide evidence that HSV-1 uses this to downregulate a strong inducer of apoptosis. Our findings open new perspectives on global and specific alterations of host cell transcription by viruses.
Spinal muscular atrophy and amyotrophic lateral sclerosis are the two most common devastating motoneuron diseases. The mechanisms leading to motoneuron degeneration are not resolved so far, although different hypotheses have been built on existing data. One possible mechanism is disturbed axonal transport of RNAs in the affected motoneurons. The underlying question of this study was therefore to characterize changes in transcript levels of distinct RNAs in cell culture models of spinal muscular atrophy and amyotrophic lateral sclerosis, especially in the axonal compartment of primary motoneurons.
To investigate this in detail we first established compartmentalized cultures of Primary mouse motoneurons. Subsequently, total RNA of both compartments was extracted
separately and either linearly amplified and subjected to microarray profiling or whole transcriptome amplification followed by RNA-Sequencing was performed. To make
the whole transcriptome amplification method suitable for compartmentalized cultures, we adapted a double-random priming strategy. First, we applied this method
for initial optimization onto serial dilutions of spinal cord RNA and later on to the compartmentalized motoneurons.
Analysis of the data obtained from wildtype cultures already revealed interesting results. First, the RNA composition of axons turned out to be highly similar to the somatodendritic compartment. Second, axons seem to be particularly enriched for transcripts related to protein synthesis and energy production. In a next step we
repeated the experiments by using knockdown cultures. The proteins depleted hereby are Smn, Tdp-43 and hnRNP R. Another experiment was performed by knocking down the non-coding RNA 7SK, the main interacting RNA of hnRNP R.
Depletion of Smn led to a vast number of deregulated transcripts in the axonal and somatodendritic compartment. Transcripts downregulated in the axons upon Smn depletion were especially enriched for GOterms related to RNA processing and encode proteins located in neuron projections including axons and growth cones.
Strinkingly, among the upregulated transcripts in the somatodendritic compartment we mainly found MHC class I transcripts suggesting a potential neuroprotective role.
In contrast, although knockdown of Tdp-43 also revealed a large number of downregulated transcripts in the axonal compartment, these transcripts were mainly
associated with functions in transcriptional regulation and RNA splicing. For the hnRNP R knockdown our results were again different. Here, we observed
downregulated transcripts in the axonal compartment mainly associated with regulation of synaptic transmission and nerve impulses. Interestingly, a comparison between deregulated transcripts in the axonal compartment of both hnRNP R and 7SK knockdown presented a significant overlap of several transcripts suggesting
some common mechanism for both knockdowns.
Thus, our data indicate that a loss of disease-associated proteins involved in axonal RNA transport causes distinct transcriptome alterations in motor axons.
Background:
Sit-to-stand height-adjustable desks (HAD) may promote workplace standing, as long as workers use them on a regular basis. The aim of this study was to investigate (i) how common HAD in German desk-based workers are, and how frequently HADs are used, (ii) to identify sociodemographic, health-related, and psycho-social variables of workday sitting including having a HAD, and (iii) to analyse sociodemographic, health-related, and psycho-social variables of users and non-users of HADs.
Methods:
A cross-sectional sample of 680 participants (51.9% men; 41.0 ± 13.1 years) in a desk-based occupation was interviewed by telephone about their occupational sitting and standing proportions, having and usage of a HAD, and answered questions concerning psycho-social variables of occupational sitting. The proportion of workday sitting was calculated for participants having an HAD (n = 108) and not-having an HAD (n = 573), as well as for regular users of HAD (n = 54), and irregular/non-users of HAD (n = 54). Linear regressions were conducted to calculate associations between socio-demographic, health-related, psychosocial variables and having/not having an HAD, and the proportion of workday sitting. Logistic regressions were executed to examine the association of mentioned variables and participants’ usage of HADs.
Results:
Sixteen percent report that they have an HAD, and 50% of these report regular use of HAD. Having an HAD is not a correlate of the proportion of workday sitting. Further analysis restricted to participants having available a HAD highlights that only the ‘perceived advantages of sitting less’ was significantly associated with HAD use in the fully adjusted model (OR 1.75 [1.09; 2.81], p < 0.05).
Conclusions:
The present findings indicate that accompanying behavioral action while providing an HAD is promising to increase the regular usage of HAD. Hence, future research needs to address the specificity of behavioral actions in order to enhance regular HAD use, and needs to give more fundamental insights into these associations.
Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.
When More Is Better – Consumption Priming Decreases Responders’ Rejections in the Ultimatum Game
(2017)
During the past decades, economic theories of rational choice have been exposed to outcomes that were severe challenges to their claim of universal validity. For example, traditional theories cannot account for refusals to cooperate if cooperation would result in higher payoffs. A prominent illustration are responders’ rejections of positive but unequal payoffs in the Ultimatum Game. To accommodate this anomaly in a rational framework one needs to assume both a preference for higher payoffs and a preference for equal payoffs. The current set of studies shows that the relative weight of these preference components depends on external conditions and that consumption priming may decrease responders’ rejections of unequal payoffs. Specifically, we demonstrate that increasing the accessibility of consumption-related information accentuates the preference for higher payoffs. Furthermore, consumption priming increased responders’ reaction times for unequal payoffs which suggests an increased conflict between both preference components. While these results may also be integrated into existing social preference models, we try to identify some basic psychological processes underlying economic decision making. Going beyond the Ultimatum Game, we propose that a distinction between comparative and deductive evaluations may provide a more general framework to account for various anomalies in behavioral economics.
Eclosion in flies and other insects is a circadian-gated behaviour under control of a central and a peripheral clock. It is not influenced by the motivational state of an animal, and thus presents an ideal paradigm to study the relation and signalling pathways between central and peripheral clocks, and downstream peptidergic regulatory systems. Little is known, however, about eclosion rhythmicity under natural conditions, and research into this direction is hampered by the physically closed design of current eclosion monitoring systems.
We describe a novel open eclosion monitoring system (WEclMon) that allows the puparia to come into direct contact with light, temperature and humidity. We demonstrate that the system can be used both in the laboratory and outdoors, and shows a performance similar to commercial closed funnel-type monitors. Data analysis is semi-automated based on a macro toolset for the open imaging software Fiji. Due to its open design, the WEclMon is also well suited for optogenetic experiments. A small screen to identify putative neuroendocrine signals mediating time from the central clock to initiate eclosion showed that optogenetic activation of ETH-, EH and myosuppressin neurons can induce precocious eclosion. Genetic ablation of myosuppressin-expressing neurons did, however, not affect eclosion rhythmicity.
The three-dimensional cuneiform script is one of the oldest known writing systems and a central object of research in Ancient Near Eastern Studies and Hittitology. An important step towards the understanding of the cuneiform script is the provision of opportunities and tools for joint analysis. This paper presents an approach that contributes to this challenge: a collaborative compatible web-based scientific exploration and analysis of 3D scanned cuneiform fragments. The WebGL -based concept incorporates methods for compressed web-based content delivery of large 3D datasets and high quality visualization. To maximize accessibility and to promote acceptance of 3D techniques in the field of Hittitology, the introduced concept is integrated into the Hethitologie-Portal Mainz, an established leading online research resource in the field of Hittitology, which until now exclusively included 2D content. The paper shows that increasing the availability of 3D scanned archaeological data through a web-based interface can provide significant scientific value while at the same time finding a trade-off between copyright induced restrictions and scientific usability.
Chromium dioxide CrO\(_2\) belongs to a class of materials called ferromagnetic half-metals, whose peculiar aspect is that they act as a metal in one spin orientation and as a semiconductor or insulator in the opposite one. Despite numerous experimental and theoretical studies motivated by technologically important applications of this material in spintronics, its fundamental properties such as momentumresolved electron dispersions and the Fermi surface have so far remained experimentally inaccessible because of metastability of its surface, which instantly reduces to amorphous Cr\(_2\)O\(_3\). In this work, we demonstrate that direct access to the native electronic structure of CrO\(_2\) can be achieved with soft-x-ray angle-resolved photoemission spectroscopy whose large probing depth penetrates through the Cr\(_2\)O\(_3\) layer. For the first time, the electronic dispersions and Fermi surface of CrO\(_2\) are measured, which are fundamental prerequisites to solve the long debate on the nature of electronic correlations in this material. Since density functional theory augmented by a relatively weak local Coulomb repulsion gives an exhaustive description of our spectroscopic data, we rule out strong-coupling theories of CrO\(_2\). Crucial for the correct interpretation of our experimental data in terms of the valence-band dispersions is the understanding of a nontrivial spectral response of CrO\(_2\) caused by interference effects in the photoemission process originating from the nonsymmorphic space group of the rutile crystal structure of CrO\(_2\).
In this work fluorescence-based single molecule detection at low concetration is investigated, with an emphasis on the usage of active transport and waveguides.
Active transport allows to overcome the limits of diffusion-based systems in terms of the lowest detectable threshold of concentration.
The effect of flow in single molecule experiments is investigated and a theoretical model is derived for laminar flow.
Waveguides on the other hand promise compact detection schemes and show great potential for their possible integration into lab-on-a-chip applications. Their properties in single molecule experiments are analyzed with help of a method based on the reciprocity theorem of electromagnetic theory.
Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.
Background:
Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation.
Methods:
Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4.
Results:
Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05).
Conclusion:
Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.
We develop the formalism of holographic renormalization to compute two-point functions in a holographic Kondo model. The model describes a (0 + 1)-dimensional impurity spin of a gauged SU(N ) interacting with a (1 + 1)-dimensional, large-N , strongly-coupled Conformal Field Theory (CFT). We describe the impurity using Abrikosov pseudo-fermions, and define an SU(N )-invariant scalar operator O built from a pseudo-fermion and a CFT fermion. At large N the Kondo interaction is of the form O\(^{†}\)O, which is marginally relevant, and generates a Renormalization Group (RG) flow at the impurity. A second-order mean-field phase transition occurs in which O condenses below a critical temperature, leading to the Kondo effect, including screening of the impurity. Via holography, the phase transition is dual to holographic superconductivity in (1 + 1)-dimensional Anti-de Sitter space. At all temperatures, spectral functions of O exhibit a Fano resonance, characteristic of a continuum of states interacting with an isolated resonance. In contrast to Fano resonances observed for example in quantum dots, our continuum and resonance arise from a (0 + 1)-dimensional UV fixed point and RG flow, respectively. In the low-temperature phase, the resonance comes from a pole in the Green’s function of the form −i〈O〉\(^{2}\), which is characteristic of a Kondo resonance.
The prediction and the experimental discovery of topological insulators has set the stage for a novel type of electronic devices. In contrast to conventional metals or semiconductors, this new class of materials exhibits peculiar transport properties at the sample surface, as conduction channels emerge at the topological boundaries of the system.
In specific materials with strong spin-orbit coupling, a particular form of a two-dimensional topological insulator, the quantum spin Hall state, can be observed.
Here, the respective one-dimensional edge channels are helical in nature, meaning that there is a locking of the spin orientation of an electron and its direction of motion.
Due to the symmetry of time-reversal, elastic backscattering off interspersed impurities is suppressed in such a helical system, and transport is approximately ballistic.
This allows in principle for the realization of novel energy-efficient devices, ``spintronic`` applications, or the formation of exotic bound states with non-Abelian statistics, which could be used for quantum computing.
The present work is concerned with the general transport properties of one-dimensional helical states. Beyond the topological protection mentioned above, inelastic backscattering can arise from various microscopic sources, of which the most prominent ones will be discussed in this Thesis. As it is characteristic for one-dimensional systems, the role of electron-electron interactions can be of major importance in this context.
First, we review well-established techniques of many-body physics in one dimension such as perturbative renormalization group analysis, (Abelian) bosonization, and Luttinger liquid theory. The latter allow us to treat electron interactions in an exact way.
Those methods then are employed to derive the corrections to the conductance in a helical transport channel, that arise from various types of perturbations.
Particularly, we focus on the interplay of Rashba spin-orbit coupling and electron interactions as a source of inelastic single-particle and two-particle backscattering. It is demonstrated, that microscopic details of the system, such as the existence of a momentum cutoff, that restricts the energy spectrum, or the presence of non-interacting leads attached to the system, can fundamentally alter the transport signature.
By comparison of the predicted corrections to the conductance to a transport experiment, one can gain insight about the microscopic processes and the structure of a quantum spin Hall sample.
Another important mechanism we analyze is backscattering induced by magnetic moments. Those findings provide an alternative interpretation of recent transport measurements in InAs/GaSb quantum wells.
Oligopeptides incorporating \(N3\)-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against \(Candida\) \(albicans\), with minimal inhibitory concentration values in the 0.05–50 μg mL\(^{-1}\) range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3) were transported by Ptr2p/Ptr22p peptide transporters (PTR) and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11) were taken up by the oligopeptide transporters (OPT) oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of \(C. albicans\) to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP-oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98%) of those colonies did not originate from truly resistant cells. The true resistance of 2% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of \(PTR2\), \(PTR22\), or \(OPT1–3\) genes, but mutations in the \(PTR2\) gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found.
Background
Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.
Methods and results
We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.
Conclusion
Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.
Background:
Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.
Results:
Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.
Conclusions:
Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.
Bacteriophage AR9 is a recently sequenced jumbo phage that encodes two multisubunit RNA polymerases. Here we investigated the AR9 transcription strategy and the effect of AR9 infection on the transcription of its host, Bacillus subtilis. Analysis of whole-genome transcription revealed early, late, and continuously expressed AR9 genes. Alignment of sequences upstream of the 5′ ends of AR9 transcripts revealed consensus sequences that define early and late phage promoters. Continuously expressed AR9 genes have both early and late promoters in front of them. Early AR9 transcription is independent of protein synthesis and must be determined by virion RNA polymerase injected together with viral DNA. During infection, the overall amount of host mRNAs is significantly decreased. Analysis of relative amounts of host transcripts revealed notable differences in the levels of some mRNAs. The physiological significance of up- or downregulation of host genes for AR9 phage infection remains to be established. AR9 infection is significantly affected by rifampin, an inhibitor of host RNA polymerase transcription. The effect is likely caused by the antibiotic-induced killing of host cells, while phage genome transcription is solely performed by viral RNA polymerases.
TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87%), but this rate dropped to 26% for stages II–IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.
This thesis reports a successful fabrication and characterisation of ferromagnetic/superconductor junction (F/S) on graphene. The thesis preposes a fabrication method to produce F/S junctions on graphene which make use of ALD grown Al2O3 as the tunnel barrier for the ferromagnetic contacts. Measurements done on F/G/S/G/F suggests that by injecting spin polarised current into the superconductor, a spin imbalance is created in the quasiparticle density of states of the superconductor which then diffuses through the graphene channel. The observed characteristic curves are similar to the ones which are already reported on metallic ferromagnet/superconductor junctions where the spin imbalance is created using Zeeman splitting. Further measurements also show that the curves loose their characteristic shapes when the temperature is increased above the critical temperature (Tc) or when the external magnetic field is higher then the critical field (Hc) of the superconducting contact. But to prove conclusively and doubtlessly the existence of spin imbalance in ferromagnet/superconductor junctions on graphene, more devices have to be made and characterised preferably in a dilution refrigerator.
Dementia is a complex neurodegenerative syndrome that by 2050 could affect about 135 Million people worldwide. People with dementia experience a progressive decline in their cognitive abilities and have serious problems coping with activities of daily living, including
orientation and wayfinding tasks. They even experience difficulties in finding their way in a familiar environment. Being lost or fear of getting lost may consequently develop into other psychological deficits such as anxiety, suspicions, illusions, and aggression. Frequent results are social isolation and a reduced quality of life. Moreover, the lives of relatives and
caregivers of people with dementia are also negatively affected.
Regarding navigation and orientation, most existing approaches focus on outdoor environment and people with mild dementia, who have the capability to use mobile devices. However, Rasquin (2007) observe that even a device with three buttons may be too complicated for
people with moderate to severe dementia. In addition, people who are living in care homes mainly perform indoor activities. Given this background, we decided to focus on designing a system for indoor environments for people with moderate to severe dementia, who are unable
or reluctant to use smartphone technology.
Adopting user-centered design approach, context and requirements of people with dementia were gathered as a first step to understand needs and difficulties (especially in spatial disorientation and wayfinding problems) experienced in dementia care facilities. Then, an "Implicit Interactive Intelligent (III) Environment" for people with dementia was proposed emphasizing implicit interaction and natural interface. The backbone of this III Environment is based on supporting orientation and navigation tasks with three systems: a Monitoring system, an intelligent system, and a guiding system. The monitoring system and intelligent system automatically detect and interpret the locations and activities performed by the users i.e. people with dementia. This approach (implicit input) reduces cognitive workload as well as physical workload on the user to provide input. The intelligent system is also aware of context, predicts next situations (location, activity), and decides when to provide an appropriate service to the users. The guiding system with intuitive and dynamic environmental cues (lighting with color) has the responsibility for guiding the users to the places they need to be.
Overall, three types of a monitoring system with Ultra-Wideband and iBeacon technologies, different techniques and algorithms were implemented for different contexts of use.
They showed a high user acceptance with a reasonable price as well as decent accuracy and precision. In the intelligent system, models were built to recognize the users’ current activity, detect the erroneous activity, predict the next location and activity, and analyze the
history data, detect issues, notify them and suggest solutions to caregivers via visualized web interfaces. About the guiding systems, five studies were conducted to test and evaluate the effect of lighting with color on people with dementia. The results were promising. Although
several components of III Environment in general and three systems, in particular, are in place (implemented and tested separately), integrating them all together and employing this in the dementia context as a fully properly evaluation with formal stakeholders (people with
dementia and caregivers) are needed for the future step.
Tourism in Würzburg: Suggestions on how to enhance the travel experience for Chinese tourists
(2017)
This report provides suggestions on how to enhance the travel experience for Chinese tourists in the German city of Würzburg. Based on a user experience survey and a market research, this work includes a quantitative and competitive analysis. It further provides concrete and hands-on measurements for the city council to improve the experience of Chinese visitors coming to Würzburg.
The top-quark mass is measured in the all-hadronic top-antitop quark decay channel using proton-proton collisions at a centre-of-mass energy of \(\sqrt{s}=8\) TeV with the ATLAS detector at the CERN Large Hadron Collider. The data set used in the analysis corresponds to an integrated luminosity of 20.2 fb\(^{−1}\). The large multi-jet background is modelled using a data-driven method. The top-quark mass is obtained from template fits to the ratio of the three-jet to the dijet mass. The three-jet mass is obtained from the three jets assigned to the top quark decay. From these three jets the dijet mass is obtained using the two jets assigned to the W boson decay. The top-quark mass is measured to be 173.72 ± 0.55 (stat.) ± 1.01 (syst.) GeV.
Visual saliency maps reflecting locations that stand out from the background in terms of their low-level physical features have proven to be very useful for empirical research on attentional exploration and reliably predict gaze behavior. In the present study we tested these predictions for socially relevant stimuli occurring in naturalistic scenes using eye tracking. We hypothesized that social features (i.e. human faces or bodies) would be processed preferentially over non-social features (i.e. objects, animals) regardless of their low-level saliency. To challenge this notion, we included three tasks that deliberately addressed non-social attributes. In agreement with our hypothesis, social information, especially heads, was preferentially attended compared to highly salient image regions across all tasks. Social information was never required to solve a task but was regarded nevertheless. More so, after completing the task requirements, viewing behavior reverted back to that of free-viewing with heavy prioritization of social features. Additionally, initial eye movements reflecting potentially automatic shifts of attention, were predominantly directed towards heads irrespective of top-down task demands. On these grounds, we suggest that social stimuli may provide exclusive access to the priority map, enabling social attention to override reflexive and controlled attentional processes. Furthermore, our results challenge the generalizability of saliency-based attention models.
Background/Aims:
Acute kidney injury (AKI) is a postoperative complication after cardiac surgery with a high impact on mortality and morbidity. Nephrocheck® [TIMP-2*IGFBP7] determines markers of tubular stress, which occurs prior to tubular damage. It is unknown at which time-point [TIMP-2*IGFBP7] measurement should be performed to ideally predict AKI. We investigated the association of [TIMP-2*IGFBP7] at various time-points with the incidence of AKI in patients undergoing elective cardiac surgery including cardio-pulmonary bypass.
Methods: In a prospective cohort study, serial blood and urine samples were collected from 150 patients: pre-operative, at ICU-admission, 24h and 48h post-surgery. AKI was defined as Serum-Creatinine rise >0.3 mg/dl within 48hrs. Urinary [TIMP-2*IGFBP7] was measured at pre-operative, ICU-admission and 24h post-surgery; medical staff was kept blinded to these results.
Results: A total of 35 patients (23.5%) experienced AKI, with a higher incidence in those with high [TIMP-2*IGFBP7] values at ICU admission (57.1% vs. 10.1%, p<0.001). In logistic regression [TIMP-2*IGFBP7] at ICU admission was independently associated with the occurrence of AKI (Odds Ratio 11.83; p<0.001, C-statistic= 0.74) after adjustment for EuroSCORE II and CBP-time.
Conclusions: Early detection of elevated [TIMP-2*IGFBP7] at ICU admission was strongly predictive for postoperative AKI and appeared to be more precise as compared to subsequent measurements.
Endogenous clocks help animals to anticipate the daily environmental changes. These
internal clocks rely on environmental cues, called Zeitgeber, for synchronization. The
molecular clock consists of transcription-translation feedback loops and is located in
about 150 neurons (Helfrich-Förster and Homberg, 1993; Helfrich-Förster, 2005). The
core clock has the proteins Clock (CLK) and Cycle (CYC) that together act as a
transcription activator for period (per) and timeless (tim) which then, via PER and TIM
block their own transcription by inhibiting CLK/CYC activity (Darlington et al., 1998;
Hardin, 2005; Dubruille and Emery, 2008). Light signals trigger the degradation of TIM
through a blue-light sensing protein Cryptochrome (CRY) and thus, allows CLK/CYC to
resume per and tim transcription (Emery et al., 1998; Stanewsky et al., 1998).
Therefore, light acts as an important Zeitgeber for the clock entrainment. The
mammalian clock consists of similarly intertwined feedback loops.
Endogenous clocks facilitate appropriate alterations in a variety of behaviors
according to the time of day. Also, these clocks can provide the phase information to the
memory centers of the brain to form the time of day related associations (TOD). TOD
memories promote appropriate usage of resources and concurrently better the survival
success of an animal. For instance, animals can form time-place associations related to
the availability of a biologically significant stimulus like food or mate. Such memories will
help the animal to obtain resources at different locations at the appropriate time of day.
The significance of these memories is supported by the fact that many organisms
including bees, ants, rats and mice demonstrate time-place learning (Biebach et al.
1991; Mistlberger et al. 1997; Van der Zee et al. 2008; Wenger et al. 1991). Previous
studies have shown that TOD related memories rely on an internal clock, but the identity
of the clock and the underlying mechanism remain less well understood. The present
study demonstrates that flies can also form TOD associated odor memories and further
seeks to identify the appropriate mechanism.
Hungry flies were trained in the morning to associate odor A with the sucrose
reward and subsequently were exposed to odor B without reward. The same flies were
exposed in the afternoon to odor B with and odor A without reward. Two cycles of the
65
reversal training on two subsequent days resulted in the significant retrieval of specific
odor memories in the morning and afternoon tests. Therefore, flies were able to
modulate their odor preference according to the time of day. In contrast, flies trained in
a non-reversal manner were unable to form TOD related memories. The study also
demonstrates that flies are only able to form time-odor memories when the two
reciprocal training cycles occur at a minimum 6 h interval.
This work also highlights the role of the internal state of flies in establishing timeodor
memories. Prolonged starvation motivates flies to appropriate their search for the
food. It increases the cost associated with a wrong choice in the T-maze test as it
precludes the food discovery. Accordingly, an extended starvation promotes the TOD
related changes in the odor preference in flies already with a single cycle of reversal
training. Intriguingly, prolonged starvation is required for the time-odor memory
acquisition but is dispensable during the memory retrieval.
Endogenous oscillators promote time-odor associations in flies. Flies in constant
darkness have functional rhythms and can form time-odor memories. In contrast, flies
kept in constant light become arrhythmic and demonstrated no change in their odor
preference through the day. Also, clock mutant flies per01 and clkAR, show compromised
performance compared to CS flies when trained in the time-odor conditioning assay.
These results suggest that flies need a per and clk dependent oscillator for establishing
TOD related memories. Also, the clock governed rhythms are necessary for the timeodor
memory acquisition but not for the retrieval.
Pigment-Dispersing Factor (PDF) neuropeptide is a clock output factor (Park and
Hall, 1998; Park et al., 2000; Helfrich-Förster, 2009). pdf01 mutant flies are unable to
form significant time-odor memories. PDF is released by 8 neurons per hemisphere in
the fly brain. This cluster includes the small (s-LNvs) and large (l-LNvs) ventral lateral
neurons. Restoring PDF in these 16 neurons in the pdf01 mutant background rescues
the time-odor learning defect. The PDF neuropeptide activates a seven transmembrane
G-protein coupled receptor (PDFR) which is broadly expressed in the fly brain (Hyun et
al., 2005). The present study shows that the expression of PDFR in about 10 dorsal
neurons (DN1p) is sufficient for robust time-odor associations in flies.
66
In conclusion, flies use distinct endogenous oscillators to acquire and retrieve
time-odor memories. The first oscillator is light dependent and likely signals through the
PDF neuropeptide to promote the usage of the time as an associative cue during
appetitive conditioning. In contrast, the second clock is light independent and
specifically signals the time information for the memory retrieval. The identity of this
clock and the underlying mechanism are open to investigation.
Zinc oxide nanoparticles (ZnO-NP) are widely spread in consumer products. Data about the toxicological characteristics of ZnO-NP is still under controversial discussion. The human skin is the most important organ concerning ZnO-NP exposure. Intact skin was demonstrated to be a sufficient barrier against NPs; however, defect skin may allow NP contact to proliferating cells. Within these cells, stem cells are the most important toxicological target for NPs. The aim of this study was to evaluate the genotoxic and cytotoxic effects of ZnO-NP at low-dose concentrations after long-term and repetitive exposure to human mesenchymal stem cells (hMSC). Cytotoxic effects of ZnO-NP were measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Furthermore, genotoxicity was evaluated by the comet assay. For long-term observation over 6 weeks, transmission electron microscopy (TEM) was applied. The results of the study indicated cytotoxic effects of ZnO-NP beginning at high concentrations of 50 μg/mL and genotoxic effects in hMSC exposed to 1 and 10 μg/mL ZnO-NP. Repetitive exposure enhanced cyto- but not genotoxicity. Intracellular NP accumulation was observed up to 6 weeks. The results suggest cytotoxic and genotoxic potential of ZnO-NP. Even low doses of ZnO-NP may induce toxic effects as a result of repetitive exposure and long-term cellular accumulation. This data should be considered before using ZnO-NP on damaged skin.
Within gauge/gravity duality, we consider the local quench-like time evolution obtained by joining two 1+1-dimensional heat baths at different temperatures at time \(t\) = 0. A steady state forms and expands in space. For the 2+1-dimensional gravity dual, we find that the “shockwaves” expanding the steady-state region are of spacelike nature in the bulk despite being null at the boundary. However, they do not transport information. Moreover, by adapting the time-dependent Hubeny-Rangamani-Takayanagi prescription, we holographically calculate the entanglement entropy and also the mutual information for different entangling regions. For general temperatures, we find that the entanglement entropy increase rate satisfies the same bound as in the ‘entanglement tsunami’ setups. For small temperatures of the two baths, we derive an analytical formula for the time dependence of the entanglement entropy. This replaces the entanglement tsunami-like behaviour seen for high temperatures. Finally, we check that strong subadditivity holds in this time-dependent system, as well as further more general entanglement inequalities for five or more regions recently derived for the static case.
In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts.
The topic of this thesis is the theoretical and numerical analysis of optimal control problems, whose differential constraints are given by Fokker-Planck models related to jump-diffusion processes. We tackle the issue of controlling a stochastic process by formulating a deterministic optimization problem. The
key idea of our approach is to focus on the probability density function of the process,
whose time evolution is modeled by the Fokker-Planck equation. Our control framework is advantageous since it allows to model the action of the control over the entire range of the process, whose statistics are characterized by the shape of its probability density function.
We first investigate jump-diffusion processes, illustrating their main properties. We define stochastic initial-value problems and present results on the existence and uniqueness of their solutions. We then discuss how numerical solutions of stochastic problems are computed, focusing on the Euler-Maruyama method.
We put our attention to jump-diffusion models with time- and space-dependent coefficients and jumps given by a compound Poisson process. We derive the related Fokker-Planck equations, which take the form of partial integro-differential equations. Their differential term is governed by a parabolic operator, while the nonlocal integral operator is due to the presence of the jumps. The derivation is carried out in two cases. On the one hand, we consider a process with unbounded range. On the other hand, we confine the dynamic of the sample paths to a bounded domain, and thus the behavior of the process in proximity of the boundaries has to be specified. Throughout this thesis, we set the barriers of the domain to be reflecting.
The Fokker-Planck equation, endowed with initial and boundary conditions, gives rise to Fokker-Planck problems. Their solvability is discussed in suitable functional spaces. The properties of their solutions are examined, namely their regularity, positivity and probability mass conservation. Since closed-form solutions to Fokker-Planck problems are usually not available, one has to resort to numerical methods.
The first main achievement of this thesis is the definition and analysis of conservative and positive-preserving numerical methods for Fokker-Planck problems. Our SIMEX1 and SIMEX2 (Splitting-Implicit-Explicit) schemes are defined within the framework given by the method of lines. The differential operator is discretized by a finite volume scheme given by the Chang-Cooper method, while the integral operator is approximated by a mid-point rule. This leads to a large system of ordinary differential equations, that we approximate with the Strang-Marchuk splitting method. This technique decomposes the original problem in a
sequence of different subproblems with simpler structure, which are separately solved and linked to each other through initial conditions and final solutions. After performing the splitting step, we carry out the time integration with first- and second-order time-differencing methods. These steps give rise to the SIMEX1 and SIMEX2 methods, respectively.
A full convergence and stability analysis of our schemes is included. Moreover, we are able to prove that the positivity and the mass conservation of the solution to Fokker-Planck problems are satisfied at the discrete level by the numerical solutions computed with the SIMEX schemes.
The second main achievement of this thesis is the theoretical analysis and the numerical solution of optimal control problems governed by Fokker-Planck models. The field of optimal control deals with finding control functions in such a way that given cost functionals are minimized. Our framework aims at the minimization of the difference between a known sequence of values and the first moment of a jump-diffusion process; therefore, this formulation can also be considered as a parameter estimation problem for stochastic processes. Two cases are discussed, in which the form of the cost functional is continuous-in-time and discrete-in-time, respectively.
The control variable enters the state equation as a coefficient of the Fokker-Planck partial integro-differential operator. We also include in the cost functional a $L^1$-penalization term, which enhances the sparsity of the solution. Therefore, the resulting optimization problem is nonconvex and nonsmooth. We derive the first-order optimality systems satisfied by the optimal solution. The computation of the optimal solution is carried out by means of proximal iterative schemes in an infinite-dimensional framework.
The yeast form of the fungus Candida albicans promotes persistence in the gut of gnotobiotic mice
(2017)
Many microorganisms that cause systemic, life-threatening infections in humans reside as harmless commensals in our digestive tract. Yet little is known about the biology of these microbes in the gut. Here, we visualize the interface between the human commensal and pathogenic fungus Candida albicans and the intestine of mice, a surrogate host. Because the indigenous mouse microbiota restricts C. albicans settlement, we compared the patterns of colonization in the gut of germ free and antibiotic-treated conventionally raised mice. In contrast to the heterogeneous morphologies found in the latter, we establish that in germ free animals the fungus almost uniformly adopts the yeast cell form, a proxy of its commensal state. By screening a collection of C. albicans transcription regulator deletion mutants in gnotobiotic mice, we identify several genes previously unknown to contribute to in vivo fitness. We investigate three of these regulators—ZCF8, ZFU2 and TRY4—and show that indeed they favor the yeast form over other morphologies. Consistent with this finding, we demonstrate that genetically inducing non-yeast cell morphologies is detrimental to the fitness of C. albicans in the gut. Furthermore, the identified regulators promote adherence of the fungus to a surface covered with mucin and to mucus-producing intestinal epithelial cells. In agreement with this result, histology sections indicate that C. albicans dwells in the murine gut in close proximity to the mucus layer. Thus, our findings reveal a set of regulators that endows C. albicans with the ability to endure in the intestine through multiple mechanisms.
Work is seen by many thinkers as the fundamental dimension of man`s existence on earth. Through work, he provides his basic necessities on earth and co-operate with God in the work of creation.
He received this mandate to work from the very beginning of creation by God. In carrying out this mandate, man every human being reflects the very action of the creator of the Universe.
God worked and intended that man who is created in His image and likeness continues the work of creation by working.
Even though Man suffers and sweats through work and yet, in spite of all this toil-perhaps in a sense because of it – work is a good thing for man. It is not only good in the sense that it is useful or something to enjoy; it is also good as being something worthy, that is to say something that corresponds to man's dignity that expresses this dignity and increases it.
This project examines man as a creature called to work and born into work. It is true that through work, man provides himself and his family with the basic necessities of life and everyday needs for the reason he charges wages for his sweat. Work goes beyond and should exceed the boundaries of the material benefit that comes out of it to the satisfaction and fulfilment for the very purpose we should work. The modern society has attached so much importance to money and material possession, the question then is how do we go along working in the spirit of improvement and renewal of the earth? The modern man understands work only as a means of making his daily bread. For this reason, he engages himself in an occupation that he has little or no interest in. He ends up quarrelling everyday with the people that he or she is supposed to serve through work. The result is low work output and waste of talents and the society loses an opportunity for improvement as every creature is supposed to contribute uniquely.
A good example is Nigeria, Africa’s most populous nation with a population estimate of about over 170,000,000 people and the sixth Oil producing Nation.
Starting from conception till death, man as a being relates with others. In this relationship he often encounters lots of problems that threaten his existence. One of them is the threat to his dignity. This experience is vivid in many countries particularly in Africa. But my work is limited to an ethnic group in Nigeria, namely Igbo people. The work discloses the extent 'displacement of value' in Igboland has contributed to the devaluation of human dignity and the attempts made to combat it. This displacement resulted in what we can call "value crisis". Some elements, like Igbo culture and cultural communication with foreign cultures that have tentacles in modernized orientation, are discussed as 'transmission carriers'. In order to x-ray properly the heart of this research and communicate the necessary messages, the work is presented in six chapters. However, this summary will not be presented in chapters.
Thus the need for a research on the reason for the failings and crisis of approach regarding this aspect of Igbo life that deals with the value of human dignity. This comes to term with the question which asked has the interest in the enhancement of the dignity of man waned because the effort towards this goal seem futile and unnecessary…Or is human dignity something we care about but take for granted as a cultural inheritance that no longer needs defence?” This question arouses thoughts on the value of HD. The entire work tried to justify the view that the protection of HD is for all times a true assignment of all. This must neither be considered to be relevant only for a time nor only for a portion or a group of individuals. Thus a special attention on this regard is demanded especially in modern day Igbo society.
RecQ4 is a member of the RecQ helicase family, an evolutionarily conserved class of enzymes, dedicated to preserving genomic integrity by operating in telomere maintenance, DNA repair and replication. While reduced RecQ4 activity is associated with cancer predisposition and premature aging, RecQ4 upregulation is related to carcinogenesis and metastasis. Within the RecQ family, RecQ4 assumes an exceptional position, lacking several characteristic RecQ domains. Here we present the crystal structure of human RecQ4, encompassing the conserved ATPase core and a novel C-terminal domain that lacks resemblance to the RQC domain observed in other RecQ helicases. The new domain features a zinc-binding site and two distinct types of winged-helix domains, which are not involved in canonical DNA binding or helicase activity. Based on our structural and functional analysis, we propose that RecQ4 exerts a helicase mechanism, which may be more closely related to bacterial RecQ helicases than to its human family members.
A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein–protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein–protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/.
Osteocytes and their cell processes reside in a large, interconnected network of voids pervading the mineralized bone matrix of most vertebrates. This osteocyte lacuno-canalicular network (OLCN) is believed to play important roles in mechanosensing, mineral homeostasis, and for the mechanical properties of bone. While the extracellular matrix structure of bone is extensively studied on ultrastructural and macroscopic scales, there is a lack of quantitative knowledge on how the cellular network is organized. Using a recently introduced imaging and quantification approach, we analyze the OLCN in different bone types from mouse and sheep that exhibit different degrees of structural organization not only of the cell network but also of the fibrous matrix deposited by the cells. We define a number of robust, quantitative measures that are derived from the theory of complex networks. These measures enable us to gain insights into how efficient the network is organized with regard to intercellular transport and communication. Our analysis shows that the cell network in regularly organized, slow-growing bone tissue from sheep is less connected, but more efficiently organized compared to irregular and fast-growing bone tissue from mice. On the level of statistical topological properties (edges per node, edge length and degree distribution), both network types are indistinguishable, highlighting that despite pronounced differences at the tissue level, the topological architecture of the osteocyte canalicular network at the subcellular level may be independent of species and bone type. Our results suggest a universal mechanism underlying the self-organization of individual cells into a large, interconnected network during bone formation and mineralization.
In daily life, olfactory stimuli are potential generators of affective states, but also have a strong influence on social interaction. Pleasant odors have been shown to increase perceived attractiveness and pro-social behavior, whereas unpleasant body odors are often associated with negative personality traits. Since both pleasant odors and positive affective state facilitate pro-social behavior, it is conceivable that the influence of the odors on social interaction is mediated by the induced affective state elicited by the odor itself. The present thesis aims at exploring the impact of hedonic, i.e., pleasant or unpleasant, odors on the processing and evaluation of social stimuli as assessed by verbal, physiological, and behavioral indices. First, I investigate the effects of initially neutral odors which gained threatening value through an aversive conditioning procedure on social stimuli (Study 1). Second, I study the influence of naturally hedonic odors on social interaction. Third, this thesis aims at disentangling differences in the effects of an odor attributed to either a social interaction partner or the environment where the social encounter takes place (Study 2, 3, and 4).
In the first study, a context conditioning procedure was applied, during which one out of two long-lasting neutral odors was paired with an unpredictable aversive unconditioned stimulus (US, i.e., white noise). This odor (CTX+) thereby gained threatening value, while another odor (CTX-) remained unpaired and therefore signaled safety. During a test session, facial stimuli were presented within both conditioned olfactory contexts. Results indicate that autonomic arousal was increased to faces when presented in the threatening odor context. Additionally, participants rated facial stimuli as more aversive when presented in the threatening odor as compared to the safety odor, indicating that faces acquire hedonic value from the odor they were presented in. Strikingly, angry facial expressions received additional processing resources when presented within a threatening olfactory context, as reflected on verbal reports and electrodermal activity (EDA). This latter finding suggests that threat-related stimuli, here angry faces, are preferentially processed within an olfactory context where a threat might happen.
Considering that the hedonic value of an odor may be quite subjective, I conducted a pilot study in order to identify odors with pleasant vs. unpleasant properties for most participants. Seven odors (four pleasant and three unpleasant) were rated with respect to their valence (pleasant vs. unpleasant), arousal (arousing vs. calm), and intensity. Additionally, EDA was measured. Two pleasant (Citral and Eucalyptol) and two unpleasant (“Animalis” and Isobutyraldehyde) odors were chosen from the original seven. The unpleasant odors were rated as more negative, arousing, and intense than the positive ones, but no differences were found regarding EDA.
These four odors were subsequently used in a virtual reality (VR) paradigm with two odor attribution groups. Participants of the social attribution group (n = 59) were always passively guided into the same room (an office) towards one out of two virtual agents who were either paired with the pleasant or the unpleasant odor. Participants of the contextual attribution group (n = 58) were guided into one out of two rooms which were either paired with the pleasant or the unpleasant odor and where they always met the same agent. For both groups, the agents smiled, frowned or remained with a neutral facial expression. This design allowed evaluating the influence of odor valence as a within-subjects factor and the influence of odor attribution as a between-subjects factor. Unpleasant odors facilitated the processing of social cues as reflected by increased verbal and physiological arousal as well as reduced active approach behavior. Specific influence of odor valence on emotional facial expressions was found for ratings, EDA, and facial mimicry, with the unpleasant odor causing a levelling effect on the differences between facial expressions. The social attribution group exhibited larger differences between odors than the contextual group with respect to some variables (i.e., ratings and EDA), but not to others (i.e., electrocortical potentials – ERPs – and approach behavior). In sum, unpleasant in comparison to pleasant odors diminished emotional responses during social interaction, while an additional enhancing effect of the social attribution was observed on some variables. Interestingly, the awareness that an interaction partner would smell (pleasantly or unpleasantly) boosted the emotional reactivity towards them.
In Study 3, I adapted the VR paradigm to a within-subjects design, meaning that the different attribution conditions were now manipulated block-wise. Instead of an approach task, participants had to move away from the virtual agent (withdrawal task). Results on the ratings were replicated from Study 2. Specifically, the difference between pleasant and unpleasant odors on valence, arousal, and sympathy ratings was larger in the social as compared to the contextual attribution condition. No effects of odor or attribution were found on EDA, whereas heart rate (HR) showed a stronger acceleration to pleasant odors while participants were passively guided towards the agent. Instead of an approach task, I focused on withdrawal behavior in this study. Interestingly, independently of the attribution condition, participants spent more time withdrawing from virtual agents, when an unpleasant odor was presented. In sum, I demonstrated that the attribution of the odors to the social agent itself had an enhancing effect on their influence on social interaction.
In the fourth and last study, I applied a similar within-subjects protocol as in Study 3 with an additional Ultimatum Game task as a measure of social interaction. Overall findings replicated the results of Study 3 with respect to HR and EDA. Strikingly, participants offered less money to virtual agents in the bad smelling room than in the good smelling room. In contrast to Study 3, no effects of odor attribution were found in Study 4. In sum, again I demonstrated that unpleasant odor may lessen social interaction not only when the interaction partner smells badly, but also in more complex interaction situations.
In conclusion, I demonstrated that hedonic odors in general influence social interaction. Thus, pleasant odors seem to facilitate, while unpleasant odors seem to reduce interpersonal exchanges. Therefore, the present thesis extends the body of literature on the influence of odors on the processing of social stimuli. Although I found a direct influence of odors on social preferences as well as on the physiological and behavioral responses to social stimuli, I did not disentangle impact of odor per se from the impact of the affective state. Interestingly, odor attribution might play an additional role as mediator of social interactions such as odor effects in social interactions might be boosted when the smell is attributed to an individual. However, the results in this regard were less straightforward, and therefore further investigations are needed. Future research should also take into account gender or other inter-individual differences like social anxiety.
Platelets are continuously produced from megakaryocytes (MK) in the bone marrow by a cytoskeleton-driven process of which the molecular regulation is not fully understood.
As revealed in this thesis, MK/ platelet-specific Profilin1 (Pfn1) deficiency results in micro- thrombocytopenia, a hallmark of the Wiskott-Aldrich syndrome (WAS) in humans, due to accelerated platelet turnover and premature platelet release into the bone marrow. Both Pfn1-deficient mouse platelets and platelets isolated from WAS patients contained abnormally organized and hyper-stable microtubules. These results reveal an unexpected function of Pfn1 as a regulator of microtubule organization and point to a previously unrecognized mechanism underlying the platelet formation defect in WAS patients.
In contrast, Twinfilin2a (Twf2a) was established as a central regulator of platelet reactivity and turnover. Twf2a-deficient mice revealed an age-dependent macrothrombocytopenia that could be explained by a markedly decreased platelet half-life, likely due to the pronounced hyper-reactivity of \(Twf2a^{-/-}\) platelets. The latter was characterized by sustained integrin acti- vation and thrombin generation in vitro that translated into accelerated thrombus formation in vivo. To further elucidate mechanisms of integrin activation, Rap1-GTP-interacting adaptor molecule (RIAM)-null mice were generated. Despite the proposed critical role of RIAM for platelet integrin activation, no alterations in this process could be found and it was concluded that RIAM is dispensable for the activation of β1 and β3 integrins, at least in platelets. These findings change the current mechanistic understanding of platelet integrin activation.
Outside-in signaling by integrins and other surface receptors was supposed to regulate MK migration, but also the temporal and spatial formation of proplatelet protrusions. In this the- sis, phospholipase D (PLD) was revealed as critical regulator of actin dynamics and podo- some formation in MKs. Hence, the unaltered platelet counts and production in \(Pld1/2^{-/-}\) mice and the absence of a premature platelet release in the bone marrow of \(Itga2^{-/-}\) mice question the role of podosomes in platelet production and raise the need to reconsider the proposed inhibitory signaling by α2β1 integrins on proplatelet formation.
Non-muscle myosin IIA (NMMIIA) has been implicated as a downstream effector of the in- hibitory signals transmitted via α2β1 integrins. Besides Rho-GTPase signaling, also \(Mg^{2+}\) and transient receptor potential melastatin-like 7 (TRPM7) channel α-kinase are known regulators of NMMIIA activity. In this thesis, TRPM7 was identified as major regulator of \(Mg^{2+}\) homeostasis in MKs and platelets. Furthermore, decreased \([Mg^{2+}]_i\) led to deregulated NMMIIA activity and altered cytoskeletal dynamics that impaired thrombopoiesis and resulted in macrothrombocytopenia in humans and mice.
Platelets are small anucleate cell fragments derived from bone marrow megakaryocytes (MKs) and are important players in hemostasis and thrombosis. Platelet granules store factors which are released upon activation. There are three major types of platelet granules: alpha-granules, dense granules and lysosomes. While dense granules contain non-proteinacious factors which support platelet aggregation and adhesion, platelet alpha-granules contain more than 300 different proteins involved in various functions such as inflammation, wound healing and the maintenanceof vascular integrity, however, their functional significance in vivo remains unknown. This thesis summarizes analyses using three mouse models generated to investigate the role of platelet granules in thrombosis, hemostasis, stroke and inflammation.
Unc13d-/- mice displayed defective platelet dense granule secretion, which resulted in abrogated thrombosis and hemostasis. Remarkably, Munc13-4-deficient mice were profoundly protected from infarct progression following transient middle cerebral artery occlusion (tMCAO) and this was not associated with increased intracranial bleeding indicating an essential involvementof dense granule secretion in infarct progression but not intracranial hemostasis during acute stroke with obvious therapeutic implications.
In the second part of this thesis, the role of platelet alpha-granules was investigated using the Nbeal2-/- mouse. Mutations in NBEAL2 have been linked to the gray platelet syndrome (GPS), a rare inherited bleeding disorder. Nbeal2-/- mice displayed the characteristics of human GPS, with defective alpha-granule biogenesis in MKs and their absence from platelets. Nbeal2-deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-/- platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction in vivo. In a model of skin wound repair, Nbeal2-/- mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts.
In the third part, the effects of combined deficiency of alpha- and dense granule secretion were analyzed using Unc13d-/-/Nbeal2-/- mice. Platelets of these mice showed impaired aggregation and adhesion to collagen under flow ex vivo, which translated into infinite tail bleeding times and severely defective arterial thrombus formation in vivo. When subjected to in vivo models of skin or lung inflammation, the double mutant mice showed no signs of hemorrhage. In contrast, lack of platelet granule release resulted in impaired vascular integrity in the ischemic brain following tMCAO leading to increased mortality. This indicates that while defective dense granule secretion or the paucity of alpha-granules alone have no effect on vascular integrity after stroke, the combination of both impairs vascular integrity and causes an increase in mortality.
The role of miR-21 in the pathophysiology of neuropathic pain using the model of B7-H1 knockout mice
(2017)
The impact of microRNA (miRNA) as key players in the regulation of immune and neuronal gene expression and their role as master switches in the pathophysiology of neuropathic pain is increasingly recognized. miR-21 is a promising candidate that could be linked to the immune and the nociceptive system. To further investigate the pathophysiological role of miR-21 in neuropathic pain, we assesed mice deficient of B7 homolog 1 (B7-H1 ko), a protein with suppressive effect on inflammatory responses.
B7-H1 ko mice and wildtype littermates (WT) of three different age-groups, young (8 weeks), middle-aged (6 months), and old (12 months) received a spared nerve injury (SNI). Thermal withdrawal latencies and mechanical withdrawal thresholds were determined. Further, we investigated anxiety-, depression-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, dorsal root ganglia and white blood cells (WBC) at distinct time points after SNI.
Naïve B7-H1 ko mice showed mechanical hyposensitivity with increasing age. Young and middle-aged B7-H1 ko mice displayed lower mechanical withdrawal thresholds compared to WT mice. From day three after SNI both genotypes developed mechanical and heat hypersensitivity, without intergroup differences. As supported by the results of three behavioral tests, no relevant differences were found for anxiety-like behavior after SNI in B7-H1 ko and WT mice. Also, there was no indication of depression-like behavior after SNI or any effect of SNI on cognition in both genotypes. The injured nerves of B7-H1 ko and WT mice showed higher miR-21 expression and invasion of macrophages and T cells 7 days after SNI without intergroup differences. Perineurial miR-21 inhibitor injection reversed SNI-induced mechanical and heat hypersensitivity in old B7-H1 ko and WT mice.
This study reveals that reduced mechanical thresholds and heat withdrawal latencies are associated with miR-21 induction in the tibial and common peroneal nerve after SNI, which can be reversed by perineurial injection of a miR-21 inhibitor. Contrary to expectations, miR-21 expression levels were not higher in B7-H1 ko compared to WT mice. Thus, the B7-H1 ko mouse may be of minor importance for the study of miR-21 related pain. However, these results spot the contribution of miR-21 in the pathophysiology of neuropathic pain and emphasize the crucial role of miRNA in the regulation of neuronal and immune circuits that contribute to neuropathic pain.
The Role of DREAM/MMB-mediated mitotic gene expression downstream of mutated K-Ras in lung cancer
(2017)
The evolutionary conserved Myb-MuvB (MMB) multiprotein complex has an essential role in transcriptional activation of mitotic genes. MMB target genes as well as the MMB associated transcription factor B-Myb and FoxM1 are highly expressed in a range of different cancer types. The elevated expression of these genes correlates with an advanced tumor state and a poor prognosis. This suggests that MMB could contribute to tumorigenesis by mediating overexpression of mitotic genes. Although MMB has been extensively characterized biochemically, the requirement for MMB to tumorigenesis in vivo remains largely unknown and has not been tested directly so far.
In this study, conditional knockout of the MMB core member Lin9 inhibits tumor formation in vivo in a mouse model of lung cancer driven by oncogenic K-Ras and loss of p53. The incomplete recombination observed within tumors points towards an enormous selection pressure against the complete loss of Lin9. RNA interference (RNAi)-mediated depletion of Lin9 or the MMB associated subunit B-Myb provides evidence that MMB is required for the expression of mitotic genes in lung cancer cells. Moreover, it was demonstrated that proliferation of lung cancer cells strongly depends on MMB. Furthermore, in this study, the relationship of MMB to the p53 tumor suppressor was investigated in a primary lung cancer cell line with restorable p53 function. Expression analysis revealed that mitotic genes are downregulated after p53 re-expression. Moreover, activation of p53 induces formation of the repressive DREAM complex and results in enrichment of DREAM at mitotic gene promoters. Conversely, MMB is displaced at these promoters.
Based on these findings the following model is proposed: In p53-negative cells, mitogenic stimuli foster the switch from DREAM to MMB. Thus, mitotic genes are overexpressed and may promote chromosomal instability and tumorigenesis.
This study provides evidence that MMB contributes to the upregulation of G2/M phase-specific genes in p53-negative cells and suggests that inhibition of MMB (or its target genes) might be a strategy for treatment of lung cancer.
Central place foragers are faced with the challenge to learn the position of their nest entrance in its surroundings, in order to find their way back home every time they go out to search for food. To acquire navigational information at the beginning of their foraging career, Cataglyphis noda performs learning walks during the transition from interior worker to forager. These small loops around the nest entrance are repeatedly interrupted by strikingly accurate back turns during which the ants stop and precisely gaze back to the nest entrance—presumably to learn the landmark panorama of the nest surroundings. However, as at this point the complete navigational toolkit is not yet available, the ants are in need of a reference system for the compass component of the path integrator to align their nest entrance-directed gazes. In order to find this directional reference system, we systematically manipulated the skylight information received by ants during learning walks in their natural habitat, as it has been previously suggested that the celestial compass, as part of the path integrator, might provide such a reference system. High-speed video analyses of distinct learning walk elements revealed that even exclusion from the skylight polarization pattern, UV-light spectrum and the position of the sun did not alter the accuracy of the look back to the nest behavior. We therefore conclude that C. noda uses a different reference system to initially align their gaze directions. However, a comparison of neuroanatomical changes in the central complex and the mushroom bodies before and after learning walks revealed that exposure to UV light together with a naturally changing polarization pattern was essential to induce neuroplasticity in these high-order sensory integration centers of the ant brain. This suggests a crucial role of celestial information, in particular a changing polarization pattern, in initially calibrating the celestial compass system.
Background:
Platelets are important for effective hemostasis and considered to be involved in pathophysiological processes, e.g. in cardiovascular diseases. Platelets provided for research or for therapeutic use are frequently separated from citrated whole blood (WB) stored for different periods of time. Although functionally intact platelets are required, the stability of platelet integrity, e.g. adenosine diphosphate (ADP) mediated responsiveness, has never been thoroughly investigated in citrated WB under ex vivo conditions.
Objectives:
Platelet integrity was evaluated at different time points in citrated WB units, collected from healthy donors and stored for 5 days at ambient temperature. The analysis included the measurement of activation markers, of induced light transmission aggregometry and of purinergic receptor expression or function. Inhibitory pathways were explored by determination of basal vasodilator-stimulated phosphoprotein (VASP)-phosphorylation, intracellular cyclic nucleotide levels and the content of phosphodiesterase 5A. Fresh peripheral blood (PB) samples served as controls.
Results:
On day 5 of storage, thrombin receptor activating peptide-6 (TRAP-6) stimulated CD62P expression and fibrinogen binding were comparable to PB samples. ADP induced aggregation continuously decreased during storage. Purinergic receptor expression remained unchanged, whereas the P2Y1 activity progressively declined in contrast to preserved P2Y12 and P2X1 function. Inhibitory pathways were unaffected except for a slight elevation of VASP phosphorylation at Ser\(^{239}\) on day 5.
Conclusion:
After 5 days of storage in citrated WB, platelet responsiveness to TRAP-6 is sufficiently maintained. However, ADP-mediated platelet integrity is more sensitive to deterioration, especially after storage for more than 2 days. Decreasing ADP-induced aggregation is particularly caused by the impairment of the purinergic receptor P2Y1 activity. These characteristics should be considered in the use of platelets from stored citrated WB for experimental or therapeutic issues.
The primary transcriptome of Neisseria meningitidis and its interaction with the RNA chaperone Hfq
(2017)
Neisseria meningitidis is a human commensal that can also cause life-threatening meningitis and septicemia. Despite growing evidence for RNA-based regulation in meningococci, their transcriptome structure and output of regulatory small RNAs (sRNAs) are incompletely understood. Using dRNA-seq, we have mapped at single-nucleotide resolution the primary transcriptome of N. meningitidis strain 8013. Annotation of 1625 transcriptional start sites defines transcription units for most protein-coding genes but also reveals a paucity of classical σ70-type promoters, suggesting the existence of activators that compensate for the lack of −35 consensus sequences in N. meningitidis. The transcriptome maps also reveal 65 candidate sRNAs, a third of which were validated by northern blot analysis. Immunoprecipitation with the RNA chaperone Hfq drafts an unexpectedly large post-transcriptional regulatory network in this organism, comprising 23 sRNAs and hundreds of potential mRNA targets. Based on this data, using a newly developed gfp reporter system we validate an Hfq-dependent mRNA repression of the putative colonization factor PrpB by the two trans-acting sRNAs RcoF1/2. Our genome-wide RNA compendium will allow for a better understanding of meningococcal transcriptome organization and riboregulation with implications for colonization of the human nasopharynx.
Automatic orienting to unexpected changes in the environment is a pre-requisite for adaptive behavior. One prominent mechanism of automatic attentional control is the Orienting Response (OR). Despite the fundamental significance of the OR in everyday life, only little is known about how the OR is affected by healthy aging. We tested this question in two age groups (19–38 and 55–72 years) and measured skin-conductance responses (SCRs) and event-related brain potentials (ERPs) to novels (i.e., short environmental sounds presented only once in the experiment; 10% of the trials) compared to standard sounds (600 Hz sinusoidal tones with 200 ms duration; 90% of the trials). Novel and standard stimuli were presented in four conditions differing in the inter-stimulus interval (ISI) with a mean ISI of either 10, 3, 1, or 0.5 s (blocked presentation). In both age groups, pronounced SCRs were elicited by novels in the 10 s ISI condition, suggesting the elicitation of stable ORs. These effects were accompanied by pronounced N1 and frontal P3 amplitudes in the ERP, suggesting that automatic novelty processing and orientation of attention are effective in both age groups. Furthermore, the SCR and ERP effects declined with decreasing ISI length. In addition, differences between the two groups were observable with the fastest presentation rates (i.e., 1 and 0.5 s ISI length). The most prominent difference was a shift of the peak of the frontal positivity from around 300 to 200 ms in the 19–38 years group while in the 55–72 years group the amplitude of the frontal P3 decreased linearly with decreasing ISI length. Taken together, this pattern of results does not suggest a general decline in processing efficacy with healthy aging. At least with very rare changes (here, the novels in the 10 s ISI condition) the OR is as effective in healthy older adults as in younger adults. With faster presentation rates, however, the efficacy of the OR decreases. This seems to result in a switch from novelty to deviant processing in younger adults, but less so in the group of older adults.
Trypanosoma brucei is a protozoan flagellate that is transmitted by tsetse flies into the mammalian bloodstream. The parasite has a huge impact on human health both directly by causing African sleeping sickness and indirectly, by infecting domestic cattle. The biology of trypanosomes involves some highly unusual, nuclear-localised processes. These include polycistronic transcription without classical promoters initiated from regions defined by histone variants, trans-splicing of all transcripts to the exon of a spliced leader RNA, transcription of some very abundant proteins by RNA polymerase I and antigenic variation, a switch in expression of the cell surface protein variants that allows the parasite to resist the immune system of its mammalian host. Here, we provide the nuclear proteome of procyclic Trypanosoma brucei, the stage that resides within the tsetse fly midgut. We have performed quantitative label-free mass spectrometry to score 764 significantly nuclear enriched proteins in comparison to whole cell lysates. A comparison with proteomes of several experimentally characterised nuclear and non-nuclear structures and pathways confirmed the high quality of the dataset: the proteome contains about 80% of all nuclear proteins and less than 2% false positives. Using motif enrichment, we found the amino acid sequence KRxR present in a large number of nuclear proteins. KRxR is a sub-motif of a classical eukaryotic monopartite nuclear localisation signal and could be responsible for nuclear localization of proteins in Kinetoplastida species. As a proof of principle, we have confirmed the nuclear localisation of six proteins with previously unknown localisation by expressing eYFP fusion proteins. While proteome data of several T. brucei organelles have been published, our nuclear proteome closes an important gap in knowledge to study trypanosome biology, in particular nuclear-related processes.
Purpose:
The aim of the study was to evaluate the mucosal immune function and circadian variation of salivary cortisol, Immunoglobin-A (sIgA) secretion rate and mood during a period of high-intensity interval training (HIIT) compared to long-slow distance training (LSD).
Methods:
Recreational male runners (n = 28) completed nine sessions of either HIIT or LSD within 3 weeks. The HIIT involved 4 × 4 min of running at 90–95% of maximum heart rate interspersed with 3 min of active recovery while the LSD comprised of continuous running at 70–75% of maximum heart rate for 60–80 min. The psycho-immunological stress-response was investigated with a full daily profile of salivary cortisol and immunoglobin-A (sIgA) secretion rate along with the mood state on a baseline day, the first and last day of training and at follow-up 4 days after the last day of training. Before and after the training period, each athlete's running performance and peak oxygen uptake (V·O\(_{2peak}\)) was determined with an incremental exercise test.
Results:
The HIIT resulted in a longer time-to-exhaustion (P = 0.02) and increased V·O\(_{2peak}\) compared to LSD (P = 0.01). The circadian variation of sIgA secretion rate showed highest values in the morning immediately after waking up followed by a decrease throughout the day in both groups (P < 0.05). With HIIT, the wake-up response of sIgA secretion rate was higher on the last day of training (P < 0.01) as well as the area under the curve (AUC\(_{G}\)) higher on the first and last day of training and follow-up compared to the LSD (P = 0.01). Also the AUC\(_{G}\) for the sIgA secretion rate correlated with the increase in V·O\(_{2peak}\) and running performance. The AUC\(_{G}\) for cortisol remained unaffected on the first and last day of training but increased on the follow-up day with both, HIIT and LSD (P < 0.01).
Conclusion:
The increased sIgA secretion rate with the HIIT indicates no compromised mucosal immune function compared to LSD and shows the functional adaptation of the mucosal immune system in response to the increased stress and training load of nine sessions of HIIT.
The Minimal Self
(2017)
The aim of The Minimal Self is to undertake a conceptual analysis of the term ‘self’ and thereby establish the minimal conditions that must be met to ascribe selfhood to an entity. This conceptual analysis focuses on what is termed ‘intrinsic reflexivity’, which is taken as the defining feature of selfhood. Three underlying categories of intrinsic reflexivity are distinguished: self-maintenance, self-reproduction and self-containment. These three fundamental categories provide a framework within which it is possible to distinguish entities that can be designated ‘selves’ from entities that are merely ‘self-like’, thus establishing the logical preconditions for the ‘emergence’ of selfhood. By examining the fuzzy borderlines between selves and the merely self-like as manifest in phenomena such as dissipative systems, genetic material, viruses and bacteria, it becomes possible to ascertain a form of ‘minimal selfhood’, a mode of being shared by all selves qua selves. Free-living single-celled organisms such as protozoa are paradigmatic instances of minimal selfhood to the extent that they can be characterized in terms of the three intrinsically reflexive processes of self-maintenance, self-reproduction and self-containment. Minimal selfhood is also presupposed by more complex multicellular selves such as animals. Such an analysis is found to shed light on the origin of life and on the nature of organisms and biological individuals.
The mechanism of excimer formation: an experimental and theoretical study on the pyrene dimer
(2017)
The understanding of excimer formation in organic materials is of fundamental importance, since excimers profoundly influence their functional performance in applications such as light-harvesting, photovoltaics or organic electronics. We present a joint experimental and theoretical study of the ultrafast dynamics of excimer formation in the pyrene dimer in a supersonic jet, which is the archetype of an excimer forming system. We perform simulations of the nonadiabatic photodynamics in the frame of TDDFT that reveal two distinct excimer formation pathways in the gas-phase dimer. The first pathway involves local excited state relaxation close to the initial Franck–Condon geometry that is characterized by a strong excitation of the stacking coordinate exhibiting damped oscillations with a period of 350 fs that persist for several picoseconds. The second excimer forming pathway involves large amplitude oscillations along the parallel shift coordinate with a period of ≈900 fs that after intramolecular vibrational energy redistribution leads to the formation of a perfectly stacked dimer. The electronic relaxation within the excitonic manifold is mediated by the presence of intermolecular conical intersections formed between fully delocalized excitonic states. Such conical intersections may generally arise in stacked π-conjugated aggregates due to the interplay between the long-range and short-range electronic coupling. The simulations are supported by picosecond photoionization experiments in a supersonic jet that provide a time-constant for the excimer formation of around 6–7 ps, in good agreement with theory. Finally, in order to explore how the crystal environment influences the excimer formation dynamics we perform large scale QM/MM nonadiabatic dynamics simulations on a pyrene crystal in the framework of the long-range corrected tight-binding TDDFT. In contrast to the isolated dimer, the excimer formation in the crystal follows a single reaction pathway in which the initially excited parallel slip motion is strongly damped by the interaction with the surrounding molecules leading to the slow excimer stabilization on a picosecond time scale.
The mechanism of excimer formation: an experimental and theoretical study on the pyrene dimer
(2017)
The understanding of excimer formation in organic materials is of fundamental importance, since excimers profoundly influence their functional performance in applications such as light-harvesting, photovoltaics or organic electronics. We present a joint experimental and theoretical study of the ultrafast dynamics of excimer formation in the pyrene dimer in a supersonic jet, which is the archetype of an excimer forming system. We perform simulations of the nonadiabatic photodynamics in the frame of TDDFT that reveal two distinct excimer formation pathways in the gas-phase dimer. The first pathway involves local excited state relaxation close to the initial Franck–Condon geometry that is characterized by a strong excitation of the stacking coordinate exhibiting damped oscillations with a period of 350 fs that persist for several picoseconds. The second excimer forming pathway involves large amplitude oscillations along the parallel shift coordinate with a period of ≈900 fs that after intramolecular vibrational energy redistribution leads to the formation of a perfectly stacked dimer. The electronic relaxation within the excitonic manifold is mediated by the presence of intermolecular conical intersections formed between fully delocalized excitonic states. Such conical intersections may generally arise in stacked π-conjugated aggregates due to the interplay between the long-range and short-range electronic coupling. The simulations are supported by picosecond photoionization experiments in a supersonic jet that provide a time-constant for the excimer formation of around 6–7 ps, in good agreement with theory. Finally, in order to explore how the crystal environment influences the excimer formation dynamics we perform large scale QM/MM nonadiabatic dynamics simulations on a pyrene crystal in the framework of the long-range corrected tight-binding TDDFT. In contrast to the isolated dimer, the excimer formation in the crystal follows a single reaction pathway in which the initially excited parallel slip motion is strongly damped by the interaction with the surrounding molecules leading to the slow excimer stabilization on a picosecond time scale.
Background:
To prevent bone loss in hip arthroplasty, several short stem systems have been developed, including the Mayo conservative hip system. While there is a plethora of data confirming inherent advantages of these systems, only little is known about potential complications, especially when surgeons start to use these systems.
Methods:
In this study, we present a retrospective analysis of the patients’ outcome, complications and the complication management of the first 41 Mayo conservative hips performed in 37 patients. For this reason, functional scores, radiographic analyses, peri- and postoperative complications were assessed at an average follow-up of 35 months.
Results:
The overall HHS improved from 61.2 pre-operatively to 85.6 post-operatively. The German Extra Short Musculoskeletal Function Assessment Questionnaire (XSFMA-D) improved from 30.3 pre-operatively to 12.2 post-operatively. The most common complication was an intraoperative non-displaced fracture of the proximal femur observed in 5 cases (12.1%). Diabetes, higher BMI and older ages were shown to be risk factors for these intra-operative periprosthetic fractures (p < 0.01). Radiographic analysis revealed a good offset reconstruction in all cases.
Conclusion:
In our series, a high complication rate with 12.1% of non-displaced proximal femoral fractures was observed using the Mayo conservative hip. This may be attributed to the flat learning curve of the system or the inherent patient characteristics of the presented cohort."
The issue of quantum mechanical coupling between a semiconductor quantum dot and a quantum well is studied in two families of GaAs- and InP- based structures at cryogenic temperatures. It is shown that by tuning the quantum well parameters one can strongly disturb the 0D-character of the coupled system ground state, initially located in a dot. The out-coupling of either an electron or a hole state from the quantum dot confining potential is viewed by a significant elongation of the photoluminescence decay time constant. Band structure calculations show that in the GaAs-based coupled system at its ground state a hole remains isolated in the dot, whereas an electron gets delocalized towards the quantum well. The opposite picture is built for the ground state of a coupled system based on InP.
The general transcription factor IIH (TFIIH) is a multi-protein complex and its 10 subunits are engaged in an intricate protein–protein interaction network critical for the regulation of its transcription and DNA repair activities that are so far little understood on a molecular level. In this study, we focused on the p44 and the p34 subunits, which are central for the structural integrity of core-TFIIH. We solved crystal structures of a complex formed by the p34 N-terminal vWA and p44 C-terminal zinc binding domains from Chaetomium thermophilum and from Homo sapiens. Intriguingly, our functional analyses clearly revealed the presence of a second interface located in the C-terminal zinc binding region of p34, which can rescue a disrupted interaction between the p34 vWA and the p44 RING domain. In addition, we demonstrate that the C-terminal zinc binding domain of p34 assumes a central role with respect to the stability and function of TFIIH. Our data reveal a redundant interaction network within core-TFIIH, which may serve to minimize the susceptibility to mutational impairment. This provides first insights why so far no mutations in the p34 or p44 TFIIH-core subunits have been identified that would lead to the hallmark nucleotide excision repair syndromes xeroderma pigmentosum or trichothiodystrophy.
Background:
According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of the roots was prepared and analysed in vitro on its effectiveness against head and neck cancer cell lines.
Methods:
Proliferation inhibition was measured with the MTT assay. Invasion inhibition was tested in a spheroid-based 3-D migration assay on different extracellular matrix surfaces. Corresponding changes in gene expression were analysed by qRT-PCR array. Induction of apoptosis was measured by fluorescence activated cell sorting (FACS) with the Annexin V binding method. The plant extract was analysed by preliminary phytochemical tests, liquid chromatography/mass spectroscopy (LC-MS) and thin layer chromatography (TLC). Anti-angiogenetic activity was determined by the tube formation assay.
Results:
O. regalis extract revealed a growth inhibiting effect on the head and neck carcinoma cell lines HLaC78 and FaDu. The toxic effect seems to be partially modulated by p-glycoprotein, as the MDR-1 expressing HLaC79-Tax cells were less sensitive. O. regalis extract inhibited the invasion of cell lines on diverse extracellular matrix substrates significantly. Especially the dispersion of the highly motile cell line HlaC78 on laminin was almost completely abrogated. Motility inhibition on laminin was accompanied by differential gene regulation of a variety of genes involved in cell adhesion and metastasis. Furthermore, O. regalis extract triggered apoptosis in HNSCC cell lines and inhibited tube formation of endothelial cells. Preliminary phytochemical analysis proved the presence of tannins, glycosides, steroids and saponins. Liquid chromatography/mass spectroscopy (LC-MS) revealed a major peak of an unknown substance with a molecular mass of 864.15 Da, comprising about 50% of the total extract. Thin layer chromatography identified ferulic acid to be present in the extract.
Conclusion:
The presented results justify the use of royal fern extracts as an anti-cancer remedy in history and imply a further analysis of ingredients.
Background
40–50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) during the course of the disease. One third of these patients will additionally develop pulmonary metastases.
Methods
137 consecutive patients with CRLM, were analyzed regarding survival data, clinical, histological data and treatment. Results were stratified according to the occurrence of pulmonary metastases and metastases resection.
Results
39% of all patients with liver resection due to CRLM developed additional lung metastases. 44% of these patients underwent subsequent pulmonary resection. Patients undergoing pulmonary metastasectomy showed a significantly better five-year survival compared to patients not qualified for curative resection (5-year survival 71.2% vs. 28.0%; p = 0.001). Interestingly, the 5-year survival of these patients was even superior to all patients with CRLM, who did not develop pulmonary metastases (77.5% vs. 63.5%; p = 0.015). Patients, whose pulmonary metastases were not resected, were more likely to redevelop liver metastases (50.0% vs 78.6%; p = 0.034). However, the rate of distant metastases did not differ between both groups (54.5 vs.53.6; p = 0.945).
Conclusion
The occurrence of colorectal lung metastases after curative liver resection does not impact patient survival if pulmonary metastasectomy is feasible. Those patients clearly benefit from repeated resections of the liver and the lung metastases.
The CCHC-type zinc finger nucleic acid-binding protein (CNBP/ZNF9) is conserved in eukaryotes and is essential for embryonic development in mammals. It has been implicated in transcriptional, as well as post-transcriptional, gene regulation; however, its nucleic acid ligands and molecular function remain elusive. Here, we use multiple systems-wide approaches to identify CNBP targets and function. We used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to identify 8,420 CNBP binding sites on 4,178 mRNAs. CNBP preferentially bound G-rich elements in the target mRNA coding sequences, most of which were previously found to form G-quadruplex and other stable structures in vitro. Functional analyses, including RNA sequencing, ribosome profiling, and quantitative mass spectrometry, revealed that CNBP binding did not influence target mRNA abundance but rather increased their translational efficiency. Considering that CNBP binding prevented G-quadruplex structure formation in vitro, we hypothesize that CNBP is supporting translation by resolving stable structures on mRNAs.
The genetic information encoded with in the genes are transcribed and translated to give rise to
the functional proteins, which are building block of a cell. At first, it was thought that the
regulation of gene expression particularly occurs at the level of transcription by various
transcription factors. Recent discoveries have shown the vital role of gene regulation at the level
of RNA also known as post-transcriptional gene regulation (PTGR). Apart from non-coding RNAs
e.g. micro RNAs, various RNA binding proteins (RBPs) play essential role in PTGR. RBPs have
been implicated in different stages of mRNA life cycle ranging from splicing, processing,
transport, localization and decay. In last 20 years studies have shown the presence of hundreds
of RBPs across eukaryotic systems many of which are widely conserved. Given the rising number
of RBPs and their link to human diseases it is quite evident that RBPs have major role in cellular
processes and their regulation. The current study is aimed to describe the so far unknown
molecular mechanism of CCHC-type Zinc Finger Nucleic Acid Binding Protein (CNBP/ZNF9)
function in vivo.
CNBP is ubiquitously expressed across various human tissues and is a highly conserved RBP in
eukaryotes. It is required for embryonic development in mammals and has been implicated in
transcriptional as well as post-transcriptional gene regulation; however, its molecular function
and direct target genes remain elusive. Here, we use multiple systems-wide approaches to
identify CNBP targets and document the consequences of CNBP binding. We established CNBP as
a cytoplasmic RNA-binding-protein and used Photoactivatable Ribonucleoside Enhanced
Crosslinking and Immunoprecipitation (PAR-CLIP) to identify direct interactions of CNBP with
4178 mRNAs. CNBP preferentially bound a G-rich motif in the target mRNA coding sequences.
Functional analyses, including ribosome profiling, RNA sequencing, and luciferase assays
revealed the CNBP mode of action on target transcripts. CNBP binding was found to increase the
translational efficiency of its target genes. We hypothesize that this is consistent with an RNA
chaperone function of CNBP helping to resolve secondary structures, thus promoting
translation. Altogether this study provides a novel mechanism of CNBP function in vivo and acts
as a step-stone to study the individual CNBP targets that will bring us closer to understand the
disease onset.
A successful therapy for colorectal cancer (CRC), one of the most common malignancies worldwide, requires the greatest possible research effort. Of critical importance is an understanding of the relevant intracellular networks of signaling cascades, their activation, and the resulting cellular changes that are a prerequisite for a more successful CRC therapy. Vascular endothelial growth factor (VEGF) and the appropriate VEGF receptors represent molecular targets that have already been successfully implemented in the clinic (i.e. using monoclonal antibodies, tyrosine kinase inhibitors). However, for platelet derived growth factor (PDGF) and the relevant PDGF receptors, there are currently no clinically approved molecular therapeutics available. However, there are preliminary data to show that PDGF and its associated signaling pathways play an important role in CRC progression. In particular, the PI3K/Akt/mTOR pathway is emerging as an important intracellular partner of PDGF with which to control proliferation, migration, and angiogenesis in tumor cells.
Therefore it was the objective of this work to investigate the multifactorial influence of PDGF on proliferation and metabolism, depending on CRC mutation status. The intention was to identify new therapeutic targets for future cancer therapy through analyses of PDGF-induced intracellular changes.
For this purpose two human colorectal cancer cell lines were analyzed at gene and/or protein level for components of the PI3K/Akt/mTOR and MAPK signaling pathway, c-Myc, p53, and HIF1α (hypoxia-inducible-factor 1α). Changes in proliferation and metabolism, either during stimulation with PDGF and/or PI3K/Akt/mTOR inhibition, were also investigated. Experiments conducted at protein level during PDGF stimulation and/or PI3K/Akt/mTOR inhibition revealed changes in signaling pathways and crosstalk. The influence of the tumor suppressors (retinoblastoma, Rb), oncogenes (c-Myc, p53mut), and HIF1α during stimulation with PDGF, and their interactions in the tumor cell with respect to proliferation and glycolysis warrant further examination in terms of clinical treatment options. Investigations at the gene level of ex vivo samples (UICC I-IV) complete the study with regards to the clinical relevance of PDGF.
PDGF stimulation increases tumor cell proliferation in HT29 cells via the PI3K/Akt/mTOR pathway rather than the MAPK pathway. However, if the PI3K/Akt/mTOR pathway is pharmacologically blocked, PDGF stimulation is mediated by inhibitory crosstalk through the MAPK pathway. Further analyses revealed that specific Akt inhibition impedes tumor cell growth, while PI3K inhibition had little effect on proliferation. Inhibitory crosstalk was found to be responsible for these different effects. Careful intervention strategies are therefore required if future therapies intend to make use of these specific signaling pathways. One aim of future research should be to gain a better understanding of the crosstalk between these signaling pathways. In this fashion, “over-inhibition” of the signal pathways, which would result in additional clinical side effects for patients, could be prevented.
In late stage UICC, more mutation events occur, with tumorigenicity promoted by an increased mutation rate. Given that PDGF is increasingly expressed in the late UICC stages, our data would indicate that PDGF's effects are amplified with increasing malignancy. The activating effect of PDGF on the PI3K/Akt/mTOR pathway and subsequent changes in the activity of p53mut, Rb, c-Myc, and HIF1α, lead to an unfavorable prognosis for colon cancer patients. PDGF acts on colon cancer cells in an Akt-activating, glycolysis-dependent manner. PDGF increases glycolysis and the ability of CRC cells to adjust their energy metabolism. These activities should be taken as possible starting points with which to design therapeutic interventions for CRC therapy.
PDGF, as another representative of the growth factor family, seems to play a similar role to VEGF in CRC. The data from this study underline the importance of the PDGF - PI3K/Akt/mTOR pathway-axis and its potential as a possible target in colorectal cancer. Thus PDGF represents an attractive therapeutic target, besides the VEGF/EGFR-based therapies already used in CRC.
Describing the light-to-energy conversion in OSCs requires a multiscale understanding of the involved optoelectronic processes, i.e., an understanding from the molecular, intermolecular, and aggregate perspective. This thesis presents such a multiscale description to provide insight into the processes in the vicinity of the organic::organic interface, which are crucial for the overall performance of OSCs. Light absorption, exciton diffusion, photoinduced charge transfer at the donor-acceptor interface, and charge separation are included. In order to establish structure-property relationships, a variety of different molecular p-type semiconductors are combined at the organic donor-acceptor heterojunction with fullerene C60, one of the most common acceptors in OSCs. Starting with a comprehensive analysis of the accuracy of diverse ab initio, DFT, and semiempiric methods for the properties of the individual molecules, the intermolecular, and aggregate/device stage are subsequently addressed. At all stages, both methodological concepts and physical aspects in OSCs are discussed to extend the microscopic understanding of the charge generation processes.
Background
Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4–6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen.
Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual.
Methods/design
The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient’s antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depressionmeasured using the Quick Inventory of Depressive Symptoms – Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed.
Discussion
This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients.
Trial registration
ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.
Division of labor is a hallmark of social insects. In the honeybee (Apis mellifera) each sterile female worker performs a series of social tasks. The most drastic changes in behavior occur when a nurse bee, who takes care of the brood and the queen in the hive, transitions to foraging behavior. Foragers provision the colony with pollen, nectar or water. Nurse bees and foragers differ in numerous behaviors, including responsiveness to gustatory stimuli. Differences in gustatory responsiveness, in turn, might be involved in regulating division of labor through differential sensory response thresholds. Biogenic amines are important modulators of behavior. Tyramine and octopamine have been shown to increase gustatory responsiveness in honeybees when injected into the thorax, thereby possibly triggering social organization. So far, most of the experiments investigating the role of amines on gustatory responsiveness have focused on the brain. The potential role of the fat body in regulating sensory responsiveness and division of labor has large been neglected. We here investigated the role of the fat body in modulating gustatory responsiveness through tyramine signaling in different social roles of honeybees. We quantified levels of tyramine, tyramine receptor gene expression and the effect of elevating fat body tyramine titers on gustatory responsiveness in both nurse bees and foragers. Our data suggest that elevating the tyramine titer in the fat body pharmacologically increases gustatory responsiveness in foragers, but not in nurse bees. This differential effect of tyramine on gustatory responsiveness correlates with a higher natural gustatory responsiveness of foragers, with a higher tyramine receptor (Amtar1) mRNA expression in fat bodies of foragers and with lower baseline tyramine titers in fat bodies of foragers compared to those of nurse bees. We suggest that differential tyramine signaling in the fat body has an important role in the plasticity of division of labor through changing gustatory responsiveness.
Background:
Sleep-related eating may occur in the context of mental illness, sleep disorders, or psychopharmacological treatment. Frequently, sleep-related eating leads to severe weight gain and, so far, there are no treatment options for the condition.
Case presentation:
We report the case of a 54-year-old white woman with depression, panic disorder, and sleep apnea under treatment with various antidepressants who developed severe sleep-related eating. Her sleep-related eating completely vanished after addition of agomelatine, it reoccurred after cessation of agomelatine, and vanished again after her re-exposure to another melatonergic drug, extended melatonin.
Conclusions:
This case suggests that melatonergic drugs lead to relief from sleep-related eating, even when the condition occurs in the context of physical and mental disorders as well as psychopharmacological treatment.
The blunt snout bream Megalobrama amblycephala is the economically most important cyprinid fish species. As an herbivore, it can be grown by eco-friendly and resource-conserving aquaculture. However, the large number of intermuscular bones in the trunk musculature is adverse to fish meat processing and consumption. As a first towards optimizing this aquatic livestock, we present a 1.116-Gb draft genome of M. amblycephala, with 779.54 Mb anchored on 24 linkage groups. Integrating spatiotemporal transcriptome analyses, we show that intermuscular bone is formed in the more basal teleosts by intramembranous ossification and may be involved in muscle contractibility and coordinating cellular events. Comparative analysis revealed that olfactory receptor genes, especially of the beta type, underwent an extensive expansion in herbivorous cyprinids, whereas the gene for the umami receptor T1R1 was specifically lost in M. amblycephala. The composition of gut microflora, which contributes to the herbivorous adaptation of M. amblycephala, was found to be similar to that of other herbivores. As a valuable resource for the improvement of M. amblycephala livestock, the draft genome sequence offers new insights into the development of intermuscular bone and herbivorous adaptation.
This thesis investigates the impact of the country-of-origin effect on Chinese luxury brands which intend to enter the German luxury goods market. By means of a questionnaire and a quantitative analysis, possible threats to Chinese newcomers that derive from an unfavorable country image are illustrated. In fact, the Chinese origin of luxury goods has an impact on German consumers' perception.
Nest ventilation in the leaf-cutting ant Atta vollenweideri is driven via a wind-induced mechanism. On their nests, workers construct small turrets that are expected to facilitate nest ventilation. We hypothesized that the construction and structural features of the turrets would depend on the colony’s current demands for ventilation and thus might be influenced by the prevailing environmental conditions inside the nest. Therefore, we tested whether climate-related parameters, namely airflow, air humidity and CO\(_{2}\) levels in the outflowing nest air influenced turret construction in Atta vollenweideri. In the laboratory, we simulated a semi-natural nest arrangement with fungus chambers, a central ventilation tunnel providing outflow of air and an aboveground building arena for turret construction. In independent series, different climatic conditions inside the ventilation tunnel were experimentally generated, and after 24 hours, several features of the built turret were quantified, i.e., mass, height, number and surface area (aperture) of turret openings. Turret mass and height were similar in all experiments even when no airflow was provided in the ventilation tunnel. However, elevated CO\(_{2}\) levels led to the construction of a turret with several minor openings and a larger total aperture. This effect was statistically significant at higher CO\(_{2}\) levels of 5% and 10% but not at 1% CO\(_{2}\). The construction of a turret with several minor openings did not depend on the strong differences in CO\(_{2}\) levels between the outflowing and the outside air, since workers also built permeated turrets even when the CO\(_{2}\) levels inside and outside were both similarly high. We propose that the construction of turrets with several openings and larger opening surface area might facilitate the removal of CO\(_{2}\) from the underground nest structure and could therefore be involved in the control of nest climate in leaf-cutting ants.
The aim of the present study was to examine whether fostering positive activating affect during multimedia learning enhances learning outcome. University students were randomly assigned to either a multimedia learning environment designed to induce positive activating affect through the use of “warm” colours and rounded shapes () or an affectively neutral environment that used achromatic colours and sharp edges (). Participants learned about the topic of functional neuroanatomy for 20 minutes and had to answer several questions for comprehension and transfer afterwards. Affective states as well as achievement goal orientations were investigated before and after the learning phase using questionnaires. The results show that participants in the affectively positive environment were superior in comprehension as well as transfer when initial affect was strong. Preexperimental positive affect was therefore a predictor of comprehension and a moderator for transfer. Goal orientations did not influence these effects. The findings support the idea that positive affect, induced through the design of the particular multimedia learning environment, can facilitate performance if initial affective states are taken into account.
Plants have to tightly control their energy homeostasis to ensure survival and fitness under constantly changing environmental conditions. Thus, it is stringently required that energy-consuming stress-adaptation and growth-related processes are dynamically tuned according to the prevailing energy availability. The evolutionary conserved SUCROSE NON-FERMENTING1 RELATED KINASES1 (SnRK1) and the downstream group C/S\(_{1}\) basic leucine zipper (bZIP) transcription factors (TFs) are well-characterised central players in plants’ low-energy management. Nevertheless, mechanistic insights into plant growth control under energy deprived conditions remains largely elusive. In this work, we disclose the novel function of the low-energy activated group S\(_{1}\) bZIP11-related TFs as regulators of auxin-mediated primary root growth. Whereas transgenic gain-of-function approaches of these bZIPs interfere with the activity of the root apical meristem and result in root growth repression, root growth of loss-of-function plants show a pronounced insensitivity to low-energy conditions. Based on ensuing molecular and biochemical analyses, we propose a mechanistic model, in which bZIP11-related TFs gain control over the root meristem by directly activating IAA3/SHY2 transcription. IAA3/SHY2 is a pivotal negative regulator of root growth, which has been demonstrated to efficiently repress transcription of major auxin transport facilitators of the PIN-FORMED (PIN) gene family, thereby restricting polar auxin transport to the root tip and in consequence auxin-driven primary root growth. Taken together, our results disclose the central low-energy activated SnRK1-C/S\(_{1}\)-bZIP signalling module as gateway to integrate information on the plant’s energy status into root meristem control, thereby balancing plant growth and cellular energy resources.
5’-3’ decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5’-3’ exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5’-3’ degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5’-3’ exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5’-3’ decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5’ polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA’s 5’ end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap.
Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48–72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.
Background:
Colorectal cancer (CRC) is the second leading cause of cancer-related death in men and women. Systemic disease with metastatic spread to distant sites such as the liver reduces the survival rate considerably. The aim of this study was to investigate the changes in gene expression that occur on invasion and expansion of CRC cells when forming metastases in the liver.
Methods:
The livers of syngeneic C57BL/6NCrl mice were inoculated with 1 million CRC cells (CMT-93) via the portal vein, leading to the stable formation of metastases within 4 weeks. RNA sequencing performed on the Illumina platform was employed to evaluate the expression profiles of more than 14,000 genes, utilizing the RNA of the cell line cells and liver metastases as well as from corresponding tumour-free liver.
Results:
A total of 3329 differentially expressed genes (DEGs) were identified when cultured CMT-93 cells propagated as metastases in the liver. Hierarchical clustering on heat maps demonstrated the clear changes in gene expression of CMT-93 cells on propagation in the liver. Gene ontology analysis determined inflammation, angiogenesis, and signal transduction as the top three relevant biological processes involved. Using a selection list, matrix metallopeptidases 2, 7, and 9, wnt inhibitory factor, and chemokine receptor 4 were the top five significantly dysregulated genes.
Conclusion:
Bioinformatics assists in elucidating the factors and processes involved in CRC liver metastasis. Our results support the notion of an invasion-metastasis cascade involving CRC cells forming metastases on successful invasion and expansion within the liver. Furthermore, we identified a gene expression signature correlating strongly with invasiveness and migration. Our findings may guide future research on novel therapeutic targets in the treatment of CRC liver metastasis.
Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton.
C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma.
Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up.
Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed.
In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.
Nowadays, more than half of the biotherapeutics are produced in mammalian cell lines as a result of correct protein folding and assembly as well as their faculty to bring about a variety of post-translational modifications. The widespread progression of biosimilars has moved the focus in mammalian cell-culture process development. Thereby, the modulation of quality attributes of recombinant therapeutic proteins has increasingly gained importance from early process development stages. Protein quality directly shapes the clinical efficacy and safety in vivo, and therefore, the control of the complex post-translational modifications, such as glycosylation (e.g. high mannose, fucosylation, galactosylation and sialylation), charge variants, aggregates and low-molecular-weight species formation, is pivotal for efficient receptor binding and for triggering the desired immune responses in patients. In the frame of biosimilar development, product quality modulation methods using the potential of the host cell line are particularly sought after to match the quality profile of the targeted reference medicinal product (RMP) as closely as possible. The environment the cell is dwelling in directly influences its metabolism and the resulting quality profile of the expressed protein. Thereby the cell culture medium plays a central role in upstream manufacturing. In this work, concentration adjustment of selected media components and supplementation with a variety of compounds was performed to alter various metabolic pathways, enzyme activities and in some cases the gene expression levels of Chinese Hamster Ovary (CHO) cells in culture. The supplementation of cell culture medium with the trisaccharide raffinose in fed-batch cultures entailed an increase of the abundance of high mannose glycans in two different CHO cell lines. Raffinose especially favored mannose 5 glycans. At the same time, it impaired cell culture performance, induced changes on the intracellular nucleotide levels and even varied the expression levels of glycosylation-related genes. Supplementation with a number of galactosyltransferase inhibiting compounds, in particular fluorinated galactose analogs (alpha- and beta-2F-peracetyl-galactose), consistently decreased the production of galactosylated monoclonal antibodies (mAb). By means of targeted addition during the culture rather than at the beginning, the inhibition was further increased, while limiting detrimental effects on both growth and productivity. High-throughput screening in 96-deepwell plates showed that spermine and L-ornithine also reduced the level of galactosylation. On the other hand, exploratory screening of a variety of potentially disulfide-bridge-reducing agents highlighted that the inherent low-molecular-species level of the proprietary platform cell culture process was likely due to favored reduction. This hypothesis was reinforced by the observation that supplementation of cysteine and N-acetylcysteine promoted fragmentation. Additionally, fragmentation decreased with higher protein expression.
At that point, aiming to improve the efficiency in process development, a rational experimental design method was developed to identify and to define the optimal concentration range of quality modulating compounds by calling on a combination of high throughput fed-batch testing and multivariate data analysis. Seventeen medium supplements were tested in five parallel 96-deepwell plate experiments. The selection process of promising modulators for the follow-up experiment in shake tubes consisted in a three-step procedure, including principal component analysis, quantitative evaluation of their performance with respect to the specifications for biosimilarity and selection following a hierarchical order of decisions using a decision tree. The method resulted in a substantial improvement of the targeted glycosylation profile in only two experimental rounds. Subsequent development stages, namely validation and transfer to industrial-scale facilities require tight control of product quality. Accordingly, further mechanistic understanding of the underlying processes was acquired by non-targeted metabolomic profiling of a CHO cell line expressing a mAb cultured in four distinct process formats. Univariate analysis of intra- and extracellular metabolite and temporal glycosylation profiles provided insights in various pathways. The numerous of parameters were the main driver to carry out principal component analysis, and then, using the methodology of partial-least-square (PLS) projection on latent structures, a multivariate model was built to correlate the extracellular data with the distinct glycosylation profiles. The PLS observation model proved to be reliable and showed its great benefit for glycan pattern control in routine manufacturing, especially at large scale. Rather than relying on post-production interpretation of glycosylation results, glycosylation can be predicted in real-time based on the extracellular metabolite levels in the bioreactor.
Finally, for the bioactivity assessment of the glycan differences between the biosimilar and the reference medicinal product (RMP), the health agencies may ask for in the drug registration process, extended ranges of glycan variants need to be generated so that the in vitro assays pick up the changes. The developed glycosylation modulator library enabled the generation of extreme glycosylation variants, including high mannose, afucosylated, galactosylated as well as sialic acid species of both a mAb and an antibody fusion molecule with three N-glycosylation sites. Moreover, to create increased variety, enzymatic glycoengineering was explored for galactosylation and sialylation. The glyco variants induced significant responses in the respective in vitro biological activity assays. The data of this work highlight the immense potential of cell culture medium optimization to adjust product quality. Medium and feed supplementation of a variety of compounds resulted in reproducible and important changes of the product quality profile of both mAbs and a fusion antibody. In addition to the intermediate modulation ranges that largely met the requirements for new-biological-entity and biosimilar development, medium supplementation even enabled quick and straightforward generation of extreme glycan variants suitable for biological activity testing.
In the present report, well-defined WO3 nanorods (NRs) and a rGO–WO\(_3\) composite were successfully synthesized using a one-pot hydrothermal method. The crystal phase, structural morphology, shape, and size of the as-synthesized samples were studied using X-ray diffraction (XRD) and transmission electron microscopy (TEM) measurements. The optical properties of the synthesized samples were investigated by Raman, ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. Raman spectroscopy and TEM results validate the formation of WO\(_3\) (NRs) on the rGO sheet. The value of the dielectric constant (ε′) of WO3 NRs and rGO–WO\(_3\) composite is decreased with an increase in frequency. At low frequency (2.5 to 3.5 Hz), the value of ε′ for the rGO–WO3 composite is greater than that of pure WO\(_3\) NRs. This could be due to the fact that the induced charges follow the ac signal. However, at higher frequency (3.4 to 6.0), the value of ε′ for the rGO–WO\(_3\) composite is less compared to that of the pure WO3 NRs. The overall decrease in the value of ε′ could be due to the occurrence of a polarization process at the interface of the rGO sheet and WO3 NRs. Enhanced interfacial polarization in the rGO–WO\(_3\) composite is observed, which may be attributed to the presence of polar functional groups on the rGO sheet. These functional groups trap charge carriers at the interface, resulting in an enhancement of the interfacial polarization. The value of the dielectric modulus is also calculated to further confirm this enhancement. The values of the ac conductivity of the WO\(_3\) NRs and rGO–WO\(_3\) composite were calculated as a function of the frequency. The greater value of the ac conductivity in the rGO–WO\(_3\) composite compared to that of the WO\(_3\) NRs confirms the restoration of the sp:\(^{++}\) network during the in situ synthesis of the rGO–WO\(_3\) composite, which is well supported by the results obtained by Raman spectroscopy.
Synthesis of Dualsteric Ligands for Muscarinic Acetylcholine Receptors and Cholinesterase Inhibitors
(2017)
The study is dealing with the synthesis and pharmacological investigation of newly designed dualsteric ligands of muscarinic acetylcholine receptors belonging to the superfamily of G protein-coupled receptors. Such bipharmacophoric ligands combine the advantages of the orthosteric binding site (high-affinity) and of the topographically distinct allosteric binding site (subtype-selectivity) resulting in compounds with reduced side effects. This opens the way to a new therapeutic approach in the treatment of e.g. chronic pain, drug withdrawal, Parkinson`s and Alzheimer`s disease. Furthermore, the newly synthesized dualsteric compounds were pharmacologically investigated in order to get a better understanding of the activation and signaling processes in muscarinic acetylcholine receptors, especially with regard to partial agonism.
The development of the “dynamic ligand binding” concept offers new perspectives for ligand binding and signaling at G protein-coupled receptors. GPCRs are no longer considered as simple on/off switches. Dualsteric ligands can bind in a dualsteric pose, reflecting an active receptor state as well as in a purely allosteric binding pose, characterized by an inactive receptor state resulting in partial agonism. The degree of partial agonism depends on the ratio of active versus inactive receptor populations. On this basis, orthosteric/orthosteric hybrid ligands consisting of the antagonist atropine and scopolamine, respectively, as well as of the agonist iperoxo and isoxazole, respectively, linked via different alkyl chain length were synthesized in order to investigate partial agonism (Figure 1).
Figure 1: Structures of the synthesized iperoxo/isoxazole-atropine/scopolamine-hybrids.
Furthermore, different sets of quaternary and tertiary homodimers consisting either of two iperoxo or two acetylcholine units were synthesized in order to study their extent on partial agonism (Figure 2). The two agonists were connected by varying alkyl chain length. Binding studies on CHO-hM2 cells of the quaternary compounds revealed that dimerization of the agonist results in a loss of potency. The iperoxo-dimers reached higher maximum effects on the Gi- as well as on the Gs pathway in comparison to the acetylcholine-dimers. Besides the choice of the orthosteric building block (potency of the agonist), the alkyl chain length is also crucial for the degree of partial agonism.
Figure 2: Structures of the synthesized quat./tert. iperoxo/acetylcholine-homodimers.
Quinolone-based hybrids connected to the superagonist iperoxo and to the endogenous ligand acetylcholine, respectively, linked through an alkyl chain of different length were synthesized in order to develop further partial agonists (Figure 3). FRET studies confirmed M1 subtype-selectivity as well as linker dependent receptor response. The greatest positive FRET signal was observed with quinolone-C6-iper resulting from a positive cooperativity between the two separated moieties, alloster and orthoster. However, the corresponding hybrids with a longer linker led to an inverse FRET signal indicating a different binding mode, e.g. purely allosteric, in contrast to the shorter linked hybrids. Furthermore, the flexible alkyl spacer was replaced by a rigidified linker resulting in the hybrid quinolone-rigid-iperoxo (Figure 3). FRET studies on the M1 receptor showed reduced FRET kinetics, resulting from interactions between the bulky linker and the aromatic lid, located between the orthosteric and allosteric binding site. A bitopic binding mode of the rigidified hybrid is presumed. For further clarity, mutational studies are necessary.
Figure 3: M1-selective hybrid compounds.
Another aim of this work was the design and synthesis of new hybrid compounds, acting as agonists at the M1 and M2 receptor and as inhibitors for AChE and BChE in the context of M. Alzheimer. Several sets of hybrid compounds consisting of different pharmacophoric units (catalytic active site: phthalimide, naphthalimide, tacrine; peripheric anionic site: iperoxo, isoxazole) linked through a polymethylene chain of varying length were synthesized. Tac-C10-iper (Figure 4), consisting of tacrine and the superagonist iperoxo linked by a C10 polymethylene spacer, was found to have excellent anticholinesterase activity for both AChE (pIC50 = 9.81) and BChE (pIC50 = 8.75). Docking experiments provided a structural model to rationalize the inhibitory power towards AChE. Additionally, the tacrine related hybrids showed affinity to the M1 and M2 receptor. Such compounds, addressing more than one molecular target are favorable for multifactorial diseases such as Alzheimer.
Figure 4: Structure of the most active compound regarding anticholinesterase activity.
In summary, the choice of the pharmacophoric units, their connecting point as well as the nature, length, and flexibility of the linker play an important role for the activity of designed bivalent ligands. A shorter linker length cannot bridge both binding sites simultaneously in contrast to longer linker chains. On the other hand, too long linker chains can result in unwanted steric interactions. Further investigations with respect to structural variations of hybrid compounds, with or without quaternary ammonium groups, are necessary in the light of drug development.
Background
The role of hospital water systems in the development of Pseudomonas aeruginosa (P. aeruginosa) surgical site infections (SSIs) in low-income countries is barely studied. This study characterized P. aeruginosa isolates from patients and water in order to establish possible epidemiological links.
Methods:
Between December 2014 and September 2015, rectal and wound swabs, and water samples were collected in the frame of active surveillance for SSIs in the two Tanzanian hospitals. Typing of P. aeruginosa was done by multi-locus sequence typing.
Results:
Of 930 enrolled patients, 536 were followed up, of whom 78 (14.6%, 95% CI; 11.6–17.5) developed SSIs. P. aeruginosa was found in eight (14%) of 57 investigated wounds. Of the 43 water sampling points, 29 were positive for P. aeruginosa. However, epidemiological links to wound infections were not confirmed. The P. aeruginosa carriage rate on admission was 0.9% (8/930). Of the 363 patients re-screened upon discharge, four (1.1%) possibly acquired P. aeruginosa during hospitalization. Wound infections of the three of the eight P. aeruginosa SSIs were caused by a strain of the same sequence type (ST) as the one from intestinal carriage. Isolates from patients were more resistant to antibiotics than water isolates.
Conclusions:
The P. aeruginosa SSI rate was low. There was no evidence for transmission from tap water. Not all P. aeruginosa SSI were proven to be endogenous, pointing to other routes of transmission.
Background:
Fatty Degeneration (FD) of the rotator cuff muscles influences functional and anatomical outcome after rotator cuff repair. The MRI based estimation of fatty degeneration is the gold standard. There is some evidence that Ultrasound elastography (EUS) can detect local differences of tissue stiffness in muscles and tendons. Shear-wave elastography (SWE) was evaluated to determine the extent to which shear wave velocity was associated with measures of fatty degeneration. MRI-spectroscopic fat measurement was used as a reference to quantify the amount of fat in the muscle belly.
Methods:
Forty-two patients underwent SWE of the supraspinatus muscles at its thickest diameter. After ultrasound evaluation an MRI-spectroscopic fat measurement of the supraspinatus muscle was performed using the SPLASH-technique. A gel filled capsule was used to locate the measured area in the MRI. The values of shear wave velocity (SWV) measured with SWE and spectroscopic fat measurement were correlated statistically using Pearson’s correlation test.
Results:
Correlation of the fat amount measured with MRI-spectroscopy and the SWV measured with SWE was ρ =0.82. Spectroscopic measured fat ratio of the supraspinatus muscle ranged from 0% to 77.41% and SWV from 1.59 m/s to 5.32 m/s. In 4 patients no sufficient SWE could be performed, these individuals showed a larger diameter of the overlying soft tissue. SWV measured with SWE showed a good correlation with MRI spectroscopic fat amount of the supraspinatus muscle.
Conclusion:
These preliminary data suggest that SWE may be a sufficient tool in detecting and estimating the amount of fatty degeneration in the supraspinatus muscle in real time. Large overlying soft tissue may be a limitation in performing sufficient EUS.
[60]Fullerene hexakisadducts possessing 12 carboxylic acid side chains form crystalline hydrogen-bonding frameworks in the solid state. Depending on the length of the linker between the reactive sites and the malonate units, the distance of the [60]fullerene nodes and thereby the spacing of the frameworks can be controlled and for the most elongated derivative, continuous channels are obtained within the structure. Stability, structural integrity and porosity of the material were investigated by powder X-ray diffraction, thermogravimetry and sorption measurements.
Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [\(^{11}\)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [\(^{11}\)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.
In early spring, red wood ants Formica polyctena are often observed clustering on the nest surface in large numbers basking in the sun. It has been hypothesized that sun-basking behaviour may contribute to nest heating because of both heat carriage into the nest by sunbasking workers, and catabolic heat production from the mobilization of the workers’ lipid reserves. We investigated sun-basking behaviour in laboratory colonies of F. polyctena exposed to an artificial heat source. Observations on identified individuals revealed that not all ants bask in the sun. Sun-basking and non-sun-basking workers did not differ in body size nor in respiration rates. The number of sun-basking ants and the number of their visits to the hot spot depended on the temperature of both the air and the hot spot. To investigate whether sun basking leads to a physiological activation linked with increased lipolysis, we measured respiration rates of individual workers as a function of temperature, and compared respiration rates of sun-basking workers before and two days after they were allowed to expose themselves to a heat source over 10 days, at self-determined intervals. As expected for ectothermic animals, respiration rates increased with increasing temperatures in the range 5 to 35˚C. However, the respiration rates of sun-basking workers measured two days after a long-term exposure to the heat source were similar to those before sun basking, providing no evidence for a sustained increase of the basal metabolic rates after prolonged sun basking. Based on our measurements, we argue that self-heating of the nest mound in early spring has therefore to rely on alternative heat sources, and speculate that physical transport of heat in the ant bodies may have a significant effect.
Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large‐scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture‐independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single‐nucleotide variation clearly indicates the existence of sub‐populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies‐specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro‐inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.
Summary
Platelet activation and aggregation at sites of vascular injury is critical to prevent excessive blood loss, but may also lead to life-threatening ischemic disease states, such as myocardial infarction and stroke. Glycoprotein (GP) VI and C type lectin-like receptor 2 (CLEC-2) are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter protein (SLAP) and SLAP2 are involved in the regulation of immune cell receptor surface expression and signaling, but their function in platelets is unknown. As revealed in this thesis, single deficiency of SLAP or SLAP2 in mice had only moderate effects on platelet function, while SLAP/SLAP2 double deficiency resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity and thrombin generation following (hem)ITAM-coupled, but not G protein-coupled receptor activation. Slap-/-/Slap2-/- mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. These results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.
GPVI has emerged as a promising novel pharmacological target for treatment of thrombotic and inflammatory disease states, but the exact mechanisms of its immunodepletion in vivo are incompletely understood. It was hypothesized that SLAP and SLAP2 may be involved in the control of GPVI down-regulation because of their role in the internalization of immune cell receptors. As demonstrated in the second part of the thesis, SLAP and SLAP2 were dispensable for antibody-induced GPVI down-regulation, but anti-GPVI treatment resulted in prolonged strong thrombocytopenia in Slap-/-/Slap2-/- mice. The profound thrombocytopenia likely resulted from the powerful platelet activation which the anti-GPVI antibody induced in Slap-/-/Slap2-/- platelets, but importantly, not in wild-type platelets. These data indicate that the expression and activation state of key modulators of the GPVI signaling cascade may have important implications for the safety profile and efficacy of anti-GPVI agents.
Small GTPases of the Rho family, such as RhoA and Cdc42, are critically involved in the regulation of cytoskeletal rearrangements during platelet activation, but little is known about the specific roles and functional redundancy of both proteins in platelet biogenesis. As shown in the final part of the thesis, combined deficiency of RhoA and Cdc42 led to marked alterations in megakaryocyte morphology and the generation of platelets of heterogeneous size and granule content. Despite severe hemostatic defects and profound thrombo¬cytopenia, circulating RhoA-/-/Cdc42-/- platelets were still capable of granule secretion and the formation of occlusive thrombi. These results implicate the existence of both distinct and overlapping roles of RhoA and Cdc42 in platelet production and function.
The production of a \(Z\) boson and a photon in association with a high-mass dijet system is studied using 20.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of \(\sqrt{s}\) = 8 TeV recorded with the ATLAS detector in 2012 at the Large Hadron Collider. Final states with a photon and a Z boson decaying into a pair of either electrons, muons, or neutrinos are analysed. Electroweak and total \(pp\) → \(Zγjj\) cross-sections are extracted in two fiducial regions with different sensitivities to electroweak production processes. Quartic couplings of vector bosons are studied in regions of phase space with an enhanced contribution from pure electroweak production, sensitive to vector-boson scattering processes \(V V → Zγ\). No deviations from Standard Model predictions are observed and constraints are placed on anomalous couplings parameterized by higher-dimensional operators using effective field theory.
The present thesis demonstrates the importance of the solid state packing of dipolar merocyanine dyes with regard to charge transport and exciton coupling.
Due to the charge transport theory for disordered materials, it is expected that high ground state dipole moments in amorphous thin films lead to low mobility values due to a broadening of the density of states. However, due to their inherent dipolarity, merocyanine dyes usually align in antiparallel dimers in an ordered fashion. The examination of twenty different molecules with ground state dipole moments up to 15.0 D shows that by a high dipolarity and well-defined sterics, the molecules pack in a highly regular two-dimensional brickwork-type structure, which is beneficial for hole transport. Utilization of these molecules for organic thin-film transistors (OTFTs) leads to hole mobility values up to 0.21 cm²/Vs. By fabrication of single crystal field-effect transistors (SCFETs) for the derivative showing the highest mobility values in OTFTs, even hole mobilities up to 2.34 cm²/Vs are achieved. Hence, merocyanine based transistors show hole mobility values comparable to those of conventional p-type organic semiconductors and therefore high ground state dipole moments are not necessarily disadvantageous regarding high mobility applications.
By examination of a different series of ten merocyanine dyes with the same chromophore backbone but different donor substituents, it is demonstrated that the size of the donor has a significant influence on the optical properties of thin films. For small and rigid donor substituents, a hypsochromic shift of the absorption compared to the monomer absorption in solution is observed due to the card stack like packing of the molecules in the solid state. By utilization of sterical demanding or flexible donor substituents, a zig-zag type packing is observed, leading to a bathochromical shift of the absorption. These packing motifs and spectral shifts with an offset of 0.93 eV of the H- and J-bands comply with the archetype examples of H- and J-aggregates from Kasha’s exciton theory.
The inhibitory glycine receptors are one of the major mediators of rapid synaptic inhibition in the mammalian brainstem, spinal cord and higher brain centres. They are ligand-gated ion channels that are mainly involved in the regulation of motor functions. Dysfunction of the receptor is associated with motor disorders such as hypereklepxia or some forms of spasticity. GlyR is composed of two glycosylated integral membrane proteins α and β and a peripheral membrane protein of gephyrin. Moreover, there are four known isoforms of the α-subunit (α1-4) of GlyR while there is a single β-subunit. Glycine receptors can be homomeric including α subunits only or heteromeric containing both α and β subunits. To date, strychnine is the ligand that has the highest affinity as glycine receptor ligand. It acts as a competitive antagonist of glycine that results in the inhibition of Cl- ions permeation and consequently reducing GlyR-mediated inhibition.
For a long time, the details of the molecular mechanism of GlyRs inactivation by strychnine were insufficient due to the lack of high-resolution structures of the receptor. Only homology models based on structures of other cys-loop receptors have been available. Recently, 3.0 Å X-ray structure of the human glycine receptor- α3 homopentamer in complex with strychnine, as well as electro cryo-microscopy structures of the zebra fish α1 GlyR in complex with strychnine and glycine were published. Such information provided detailed insight into the molecular recognition of agonists and antagonists and mechanisms of GlyR activation and inactivation.
Very recently, a series of dimeric strychnine analogs obtained by diamide formation of two molecules of 2-aminostrychnine with diacids of different chain length was pharmacologically evaluated at human α1 and α1β glycine receptors. None of the dimeric analogs was superior to strychnine.
The present work focused on the extension of the structure-activity relationships of strychnine derivatives at glycine receptors
All the synthesized compounds were pharmacologically evaluated at human α1 and α1β glycine receptors in a functional FLIPRTM assay and the most potent analogs were pharmacologically evaluated in a whole cell patch-clamp assay and in [3H]strychnine binding studies.
It was reported that 11-(E)-isonitrosostrychnine displayed a 2-times increased binding to both α1 and α1β glycine receptors which prompted us to choose the hydroxyl group as a suitable attachment point to connect two 11-(E)-isonitrosostrychnine molecules using a spacer. In order to explore the GlyR pocket tolerance for oxime extension, a series of oxime ethers with different spacer lengths and sterical/lipophilic properties were synthesized biologically evaluated. Among all the oxime ethers, methyl, allyl and propagyl oxime ethers were the most potent antagonists displaying IC50 values similar to that of strychnine. These findings indicated that strychnine binding site at GlyRs comprises an additional small lipophilic pocket located in close proximity to C11 of strychnine and the groups best accommodated in this pocket are (E)-allyl and (E)-propagyl oxime ethers.
Moreover, 11-aminostrychnine, and the corresponding propionamide were prepared and pharmacologically evaluated to examine the amide function at C11 as potential linker.
A series of dimeric strychnine analogs designed by linking two strychnine molecules through amino groups in position 11 with diacids were synthesized and tested in binding studies and functional assays at human α1 and α1β glycine receptors. The synthesized bivalent ligands were designed to bind simultaneously to two α-subunits of the pentameric glycine receptors causing a possibly stronger inhibition than the monomeric strychnine. However, all the bivalent derivatives showed no significant difference in potency compared to strychnine. When comparing the reference monomeric propionamide containing ethylene spacer to the dimeric ligand containing butylene spacer, a 3-fold increase in potency was observed. Since the dimer containing (CH2)10 spacer length was found to be equipotent to strychnine, it is assumed that one molecule of strychnine binds to the receptor and the ‘additional’ strychnine molecule in the dimer probably protrudes from the orthosteric binding sites of the receptor.
Multifunctional enzyme, type-1 (MFE1) is a monomeric enzyme with a 2E-enoyl-CoA hydratase and a 3S-hydroxyacyl-CoA dehydrogenase (HAD) active site. Enzyme kinetic data of rat peroxisomal MFE1 show that the catalytic efficiencies for converting the short-chain substrate 2E-butenoyl-CoA into acetoacetyl-CoA are much lower when compared with those of the homologous monofunctional enzymes. The mode of binding of acetoacetyl-CoA (to the hydratase active site) and the very similar mode of binding of NAD\(^+\) and NADH (to the HAD part) are described and compared with those of their monofunctional counterparts. Structural comparisons suggest that the conformational flexibility of the HAD and hydratase parts of MFE1 are correlated. The possible importance of the conformational flexibility of MFE1 for its biocatalytic properties is discussed.
Several important cellular processes, including transcription, nucleotide excision repair and cell cycle control are mediated by the multifaceted interplay of subunits within the general transcription factor II H (TFIIH).
A better understanding of the molecular structure of TFIIH is the key to unravel the mechanism of action of this versatile protein complex within these pathways. This becomes especially important in the context of severe diseases like xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, that arise from single point mutations in some of the TFIIH subunits.
In an attempt to structurally characterize the TFIIH complex, we harnessed the qualities of the eukaryotic thermophile Chaetomium thermophilum, a remarkable fungus, which has only recently been recognized as a novel model organism. Homologues of TFIIH from C. thermophilum were expressed in E. coli, purified to homogeneity and subsequently utilized for crystallization trials and biochemical studies.
The results of the present work include the first crystal structure of the p34 subunit of TFIIH, comprising the N-terminal domain of the protein. The structure revealed a von Willebrand Factor A (vWA) like fold, which is generally known to be involved in a multitude of protein-protein interactions. Structural comparison allowed to delineate similarities as well as differences to already known vWA domains, providing insight into the role of p34 within TFIIH. These results indicate that p34 assumes the role of a structural scaffold for other TFIIH subunits via its vWA domain, while likely serving additional functions, which are mediated through its
C-terminal zinc binding domain and are so far unknown.
Within TFIIH p34 interacts strongly with the p44 subunit, a positive regulator of the XPD helicase, which is required for regulation of RNA Polymerase II mediated transcription and essential for eukaryotic nucleotide excision repair. Based on the p34 vWA structure putative protein-protein interfaces were analyzed and binding sites for the p34 p44 interaction suggested. Continuous crystallization efforts then led to the first structure of a p34 p44 minimal complex, comprising the N-terminal vWA domain of p34 and the C-terminal C4C4 RING domain of p44. The structure of the p34 p44 minimal complex verified the previous hypothesis regarding the involved binding sites. In addition, careful analysis of the complex interface allowed to identify critical residues, which were subsequently mutated and analyzed with respect to their significance in mediating the p34 p44 interaction, by analytical size exclusion chromatography, electrophoretic mobility shift assays and isothermal titration calorimetry. The structure of the p34 p44 complex also revealed a binding mode of the p44 C4C4 RING domain, which differed from that of other known RING domains in several aspects, supporting the hypothesis that p44 contains a novel variation of this domain.
Background:
Factors influencing access to stroke unit (SU) care and data on quality of SU care in Germany are scarce. We investigated characteristics of patients directly admitted to a SU as well as patient-related and structural factors influencing adherence to predefined indicators of quality of acute stroke care across hospitals providing SU care.
Methods:
Data were derived from the German Stroke Registers Study Group (ADSR), a voluntary network of 9 regional registers for monitoring quality of acute stroke care in Germany. Multivariable logistic regression analyses were performed to investigate characteristics influencing direct admission to SU. Generalized Linear Mixed Models (GLMM) were used to estimate the influence of structural hospital characteristics (percentage of patients admitted to SU, year of SU-certification, and number of stroke and TIA patients treated per year) on adherence to predefined quality indicators.
Results:
In 2012 180,887 patients were treated in 255 hospitals providing certified SU care participating within the ADSR were included in the analysis; of those 82.4% were directly admitted to a SU. Ischemic stroke patients without disturbances of consciousness (p < .0001), an interval onset to admission time ≤3 h (p < .0001), and weekend admission (p < .0001) were more likely to be directly admitted to a SU. A higher proportion of quality indicators within predefined target ranges were achieved in hospitals with a higher proportion of SU admission (p = 0.0002). Quality of stroke care could be maintained even if certification was several years ago.
Conclusions:
Differences in demographical and clinical characteristics regarding the probability of SU admission were observed. The influence of structural characteristics on adherence to evidence-based quality indicators was low.
Recent advances in the field of cancer immunotherapy have enabled this therapeutic approach to enter the mainstream of modern cancer treatment. In particular, adoptive T cell therapy (ACT) is a potentially powerful immunotherapy approach that relies on the administration of tumor-specific T cells into the patient. There are several strategies to obtain tumor-reactive cytotoxic T lymphocytes (CTLs), which have already been shown to induce remarkable responses in the clinical setting. However, there are concerns and limitations regarding the conventional approaches to obtain tumor-reactive T cells, such as accuracy of the procedure and reproducibility. Therefore, we aimed to develop two approaches to improve the precision and efficacy of tumor-reactive T cells therapy. These two techniques could constitute effective, safe and broadly applicable alternatives to the conventional methods for obtaining tumor-specific CTLs.
The first approach of this study is the so called “Doublet Technology”. Here, we demonstrate that peptide-human leukocyte antigen-T cell receptor (pHLA-TCR) interactions that involve immune reactive peptides are stable and strong. Therefore, the CTLs that are bound by their TCR to tumor cells can be selected and isolated through FACS-based cell sorting taking advantage of this stable interaction between the CTLs and the target cells. The CTLs from acute myeloid leukemia (AML) patients obtained with this technique show cytolytic activity against blast cells suggesting a potential clinical use of these CTLs. “Doublet Technology” offers a personalized therapy in which there is no need for a priori knowledge of the exact tumor antigen.
The second approach of this study is the Chimeric Antigen Receptor (CAR) Technology. We design several CARs targeting the B-Cell Maturation Antigen (BCMA). BCMA CAR T cells show antigen-specific cytolytic activity, production of cytokines including IFN-γ and IL-2, as well as productive proliferation. Although we confirm the presence of soluble BCMA in serum of multiple myeloma (MM) patients, we demonstrate that the presence of soluble protein does not abrogate the efficacy of BCMA CAR T cells suggesting that BCMA CAR T cells can be used in the clinical setting to treat MM patients. The high antigen specificity of CAR T cells allows efficient tumor cell eradication and makes CAR Technology attractive for broadly applicable therapies.
The subject of this thesis is the control of strain in HgTe thin-film crystals. Such systems are members of the new class of topological insulator materials and therefore of special research interest. A major task was the experimental control of the strain in the HgTe films. This was achieved by a new epitaxial approach and confirmed by cristallographic analysis and magneto-transport measurements.
In this work, strain was induced in thin films by means of coherent epitaxy on substrate crystals. This means that the film adopts the lattice constant of the substrate in the plane of the substrate-epilayer interface. The level of strain is determined by the difference between the strain-free lattice constants of the substrate and epilayer material (the so-called lattice mismatch). The film responds to an in-plane strain with a change of its lattice constant perpendicular to the interface. This relationship is crucial for both the correct interpretation of high resolution X-ray diffraction (HRXRD) measurements, and the precise determination of the band dispersion. The lattice constant of HgTe is smaller than the lattice constant of CdTe. Therefore, strain in HgTe is tensile if it is grown on a CdTe substrate. In principle, compressive strain can be achieved by using an appropriate \(\text{Cd}_{1-x}\text{Zn}_{x}\text{Te}\) substrate. This concept was modified and applied in this work.
Epilayers have been fabricated by molecular-beam epitaxy (MBE). The growth of thick buffer layers of CdTe on GaAs:Si was established as an alternative to commercial CdTe and \(text{Cd}_{0.96}\text{Zn}_{0.04}\text{Te}\) substrates. The growth conditions have been optimized by an analysis of atomic force microscopy and HRXRD studies. HRXRD measurements reveal a power-law increase of the crystal quality with increasing thickness. Residual strain was found in the buffer layers, and was attributed to a combination of finite layer thickness and mismatch of the thermal expansion coefficients of CdTe and GaAs. In order to control the strain in HgTe epilayers, we have developed a new type of substrate with freely adjustable lattice constant.
CdTe-\(\text{Cd}_{0.5}\text{Zn}_{0.5}\text{Te}\) strained-layer-superlattices have been grown by a combination of MBE and atomic-layer epitaxy (ALE), and have been analyzed by HRXRD. ALE of the \(\text{Cd}_{0.5}\text{Zn}_{0.5}\text{Te}\) layer is self-limiting to one monolayer, and the effective lattice constant can be controlled reproducibly and straightforward by adjusting the CdTe layer thickness. The crystal quality has been found to degrade with increasing Zn-fraction. However, the effect is less drastic compared to single layer \(\text{Cd}_{1-x}\text{Zn}_{x}\text{Te}\) solid solutions. HgTe quantum wells (QWs) sandwiched in between CdHgTe barriers have been fabricated in a similar fashion on superlattices and conventional CdTe and \(\text{Cd}_{0.96}\text{Zn}_{0.04}\text{Te}\) substrates. The lower critical thickness of the CdHgTe barrier material grown on superlattice substrates had to be considered regarding the sample design. The electronic properties of the QWs depend on the strain and thickness of the QW. We have determined the QW thickness with an accuracy of \(\pm\)0.5 nm by an analysis of the beating patterns in the thickness fringes of HRXRD measurements and X-ray reflectometry measurements. We have, for the first time, induced compressive strain in HgTe QWs by an epitaxial technique (i.e. the effective lattice constant of the superlattice is lower compared to the lattice constant of HgTe). The problem of the lattice mismatch between superlattice and barriers has been circumvented by using CdHgTe-ZnHgTe superlattices instead of CdHgTe as a barrier material. Furthermore, the growth of compressively strained HgTe bulk layers (with a thickness of at least 50 nm) was demonstrated as well.
The control of the state of strain adds a new degree of freedom to the design of HgTe epilayers, which has a major influence on the band structure of QWs and bulk layers. Strain in bulk layers lifts the degeneracy of the \(\Gamma_8\) bands at \(\mathbf{k}=0\). Tensile strain opens an energy gap, compressive strain shifts the touching points of the valence- and conduction band to positions in the Brillouin zone with finite \(\mathbf{k}\). Such a situation has been realized for the first time in the course of this work. For QWs in the inverted regime, it is demonstrated that compressive strain can be used to significantly enhance the thermal energy gap of the two-dimensional electron gas (2DEG). In addition, semi-metallic and semiconducting behavior is expected in wide QWs, depending on the state of strain. An examination of the temperature dependence of the subband ordering in QWs revealed that the band gap is only temperature-stable for appropriate sample parameters and temperature regimes. The band inversion is always lifted for sufficiently high temperatures.
A large number of models investigate the influence of the band gap on the stability of the quantum-spin-Hall (QSH) effect. An enhancement of the stability of QSH edge state conductance is expected for enlarged band gaps. Furthermore, experimental studies on the temperature dependence of the QSH conductance are in contradiction to theoretical predictions. Systematic studies of these aspects have become feasible based on the new flexibility of the sample design.
Detailed low-temperature magnetotransport studies have been carried out on QWs and bulk layers. For this purpose, devices have been fabricated lithographically, which consist of two Hall-bar geometries with different dimensions. This allows to discriminate between conductance at the plane of the 2DEG and the edge of the sample. The Fermi energy in the 2DEG has been adjusted by means of a top gate electrode. The strain-induced transition from semi-metallic to semiconducting characteristics in wide QWs was shown. The magnitude of the semi-metallic overlap of valence- and conduction band was determined by an analysis of the two-carrier conductance and is in agreement with band structure calculations. The band gap of the semiconducting sample was determined by measurements of the temperature dependence of the conductance at the charge-neutrality point. Agreement with the value expected from theory has been achieved for the first time in this work. The influence of the band gap on the stability of QSH edge state conductance has been investigated on a set of six samples. The band gap of the set spans a range of 10 to 55 meV. The latter value has been achieved in a highly compressively strained QW, has been confirmed by temperature-dependent conductance measurements, and is the highest ever reported in the inverted regime. Studies of the carrier mobility reveal a degradation of the sample quality with increasing Zn-fraction in the superlattice, in agreement with HRXRD observations. The enhanced band gap does not suppress scattering mechanisms in QSH edge channels, but lowers the conductance in the plane of the 2DEG. Hence, edge state conductance is the dominant conducting process even at elevated temperatures. An increase in conductance with increasing temperature has been found, in agreement with reports from other groups. The increase follows a power-law dependency, the underlying physical mechanism remains open. A cause for the lack of an increase of the QSH edge state conductance with increasing energy gap has been discussed. Possibly, the sample remains insulating even at finite carrier densities, due to localization effects. The measurement does not probe the QSH edge state conductance at the situation where the Fermi energy is located in the center of the energy gap, but in the regime of maximized puddle-driven scattering. In a first set of measurements, it has been shown that the QSH edge state conductance can be influenced by hysteretic charging effects of trapped states in the insulating dielectric. A maximized conductance of \(1.6\ \text{e}^2/\text{h}\) was obtained in a \(58\ \mu\text{m}\) edge channel. Finally, measurements on three dimensional samples have been discussed. Recent theoretical works assign compressively strained HgTe bulk layers to the Weyl semi-metal class of materials. Such layers have been synthesized and studied in magnetotransport experiments for the first time. Pronounced quantum-Hall- and Shubnikov-de-Haas features in the Hall- and longitudinal resistance indicate two-dimensional conductance on the sample surface. However, this conductance cannot be assigned definitely to Weyl surface states, due to the inversion of \(\Gamma_6\) and \(\Gamma_8\) bands. If a magnetic field is aligned parallel to the current in the device, a decrease in the longitudinal resistance is observed with increasing magnetic field. This is a signature of the chiral anomaly, which is expected in Weyl semi-metals.
Within this thesis, synthetic strategies for self-assembled organic cage compounds have been developed that allow for both stimuli-responsive control over assembly/disassembly processes and spatial control over functionalization. To purposefully operate the reversible assembly of organic cages, boron-nitrogen dative bonds have been exploited for the formation of a well-defined, discrete bipyramidal organic assembly in solution. Thermodynamic association equilibria for cage formation have been investigated by Isothermal Titration Calorimetry (ITC). Temperature-dependent NMR studies revealed a reversible cage opening upon heating and quantitative reassembly upon cooling. For the spatial functionalization of organic cages, two divergent molecular building units have been designed and synthesized, namely tribenzotriquinacene derivatives possessing a terminal alkyne moiety at the apical position and a meta-diboronic acid having a pyridyl group at the 2-position. Facile access to a variety of apically functionalized tribenzotriquinacenes has been illustrated by post-synthetic modifications at the terminal alkyne group by Sonogashira cross-coupling and azide-alkyne click reactions. Finally, these apically functionalized tribenzotriquinacene building blocks have been implemented into boronate ester-based organic cage compounds showing modular exohedral functionalities.
Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.
A search for high-energy neutrino emission correlated with gamma-ray bursts outside the electromagnetic prompt-emission time window is presented. Using a stacking approach of the time delays between reported gamma-ray burst alerts and spatially coincident muon-neutrino signatures, data from the Antares neutrino telescope recorded between 2007 and 2012 are analysed. One year of public data from the IceCube detector between 2008 and 2009 have been also investigated. The respective timing profiles are scanned for statistically significant accumulations within 40 days of the Gamma Ray Burst, as expected from Lorentz Invariance Violation effects and some astrophysical models. No significant excess over the expected accidental coincidence rate could be found in either of the two data sets. The average strength of the neutrino signal is found to be fainter than one detectable neutrino signal per hundred gamma-ray bursts in the Antares data at 90% confidence level.
Successful formulation development of novel, particularly organic APIs of low molecular weight as candidates for ground-breaking pharmaceutical products is a major challenge for the pharmaceutical industry because of the poor aqueous solubility of most of these compounds.
The hit identification strategies of drug development in use today apply high throughput screening techniques for the investigation of thousands of substances. This approach led to a systematical increase in molecular weight and lipophilicity and a decrease of water solubility of lead compounds reaching market access.
The high lipophilicity causes an excellent permeability of the compounds which favours the absorption process from the small intestine, but it causes a decrease of water-solubility. It becomes evident that an adequate aqueous solubility is necessary for absorption of the API from the gastrointestinal fluids into the systemic circulation and hence for efficacy of the pharmaceutical product. Only an dissolved API is getting absorbed and becomes efficacious. The precipitated proportion is resigned directly. Therefore, the development of an individual formulation aligning the physicochemical characteristics is necessary for every API to produce supersaturated solutions in the small intestine and to reach an adequate bioavailability after absorption into the systemic circulation.
In this thesis a specific formulation development was investigated for two exemplary poorly water-soluble APIs to replace the empirical approach often used today. The basic tyrosine-kinase inhibitor imatinib and six different acetylated amino acids were transferred into ILs. As compared to the free base and the mesylate salt, which is marketed by Novartis AG as Gleevec®, the dissolution rate as well as the supersaturation time was increased significantly. By changing the mesylate anion with its potential genotoxic risks, the total toxicity of the drug product could be decreased. The amorphous ILs proved adequate stability under forcing conditions and there was no recrystallization of the free base observed. The amorphous character of the ILs caused an increased amount of water vapour sorption which can be compensated by special packaging materials. Taken together, the presentation of imatinib as an IL is intended for oral administration as a tablet and can cause a reduction of dose because of the increased solubility. Therefore, the occurrence of side effects can be reduced as compared to Gleevec®. If there is actually an increased bioavailability to observe, has to be proved by the execution of animal trials.
The novel NOX inhibitor VAS3947 is intended for the treatment of endothelial dysfunctions causing diseases like heart failure and stroke. The compounds poor aqueous solubility hindered further clinical development so far and make the drug candidate to remain in a very early stage of the drug development process. Therefore, different formulation concepts were evaluated in this study:
An amorphous solid dispersion prepared from VAS3947 and Eudragit® L100 by means of spray drying was able to increase the dissolution rate and solubility of the compound significantly, but with the accomplished kinetic solubility being in the low µM range it is not possible to reach therapeutic plasma concentrations.
In contrast, the incorporation into cyclodextrins resulted in an 760-fold increased solubility. Different cyclodextrins were evaluated. Especially the lipophilic derivatives of the β-cyclodextrin showed to be the most adequate excipients. The incorporation of the API into the cyclodextrin cavity was proved by means of NMR spectroscopy. Additionally, a formulation of VAS3947 and hydroxypropyl-β-cyclodextrin was prepared. This formulation is intended for the intravenous application during animal trials, which have to be conducted to get to know the pharmacokinetics of VAS3947. This formulation reached a concentration of 1 mg/mL spending striking protection of VAS3947 against degradation.
Presentation of VAS3947 as a microemulsion system led also to increase the aqueous solubility of the compound, but not in the same extent as the cyclodextrin formulation. Beside the formulation development a physicochemical characterization was performed to get to know important parameters such as log P and pKa values of VAS3947. An HPLC method was developed and validated to analyse the extent of solubility improvement.
A major issue of the compound VAS3947 and all related triazolopyrimidine derivatives, developed by Vasopharm GmbH, is the insufficient chemical stability because of presence of a hemiaminal moiety in the chemical structure. Stability investigations and an extensive biopharmaceutical characterization confirm the hindering of further clinical development by insufficient drug stability and high cytotoxicity. Poor aqueous solubility is an additional disadvantage which can be handled by a concerted formulation development.
Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS.
Spin- and angle-resolved photoelectron spectroscopy is the prime method to investigate
spin polarized electronic states at solid state surfaces. In how far the spin polarization
of an emitted photoelectron reflects the intrinsic spin character of an electronic state is
the main question in the work at hand. It turns out that the measured spin polarization
is strongly influenced by experimental conditions, namely by the polarization of the
incoming radiation and the excitation energy. The photoemission process thus plays a
non-negligible role in a spin-sensitive measurement. This work is dedicated to unravel
the relation between the result of a spin-resolved measurement and the spin character
in the ground state and, therefore, to gain a deep understanding of the spin-dependent
photoemission process.
Materials that exhibit significant spin-splittings in their electronic structure,
owing to a strong spin-orbit coupling, serve as model systems for the investigations in
this work. Therefore, systems with large Rashba-type spin-splittings as BiTeI(0001)
and the surface alloys BiAg2/Ag(111) and PbAg2/Ag(111) are investigated. Likewise,
the surface electronic structure of the topological insulators Bi2Te2Se(0001) and
Bi2Te3(0001) are analyzed.
Light polarization dependent photoemission experiments serve as a probe of the
orbital composition of electronic states. The knowledge of the orbital structure helps
to disentangle the spin-orbital texture inherent to the different surface states, when
in addition the spin-polarization is probed. It turns out that the topological surface
state of Bi2Te2Se(0001) as well as the Rashba-type surface state of BiTeI(0001) exhibit
chiral spin-textures associated with the p-like in-plane orbitals. In particular, opposite
chiralities are coupled to either tangentially or radially aligned p-like orbitals,
respectively. The results presented here are thus evidence that a coupling between
spin- and orbital part of the wave function occurs under the influence of spin-orbit
coupling, independent of the materials topology.
Systematic photon energy dependent measurements of the out-of-plane spin polarization
of the topological surface state of Bi2Te3(0001) reveal a strong dependence and
even a reversal of the sign of the photoelectron spin polarization with photon energy.
Similarly, the measured spin component perpendicular to the wave vector of the surface
state of BiAg2/Ag(111) shows strong modulations and sign reversals when the photon energy is changed. In BiAg2/Ag(111) the variations in the photoelectron spin
polarization are accompanied by significant changes and even a complete suppression
of the photoemission intensity from the surface state, indicating that the variations of
the spin polarization are strongly related to the photoemission cross section.
This relation is finally analyzed in detail by employing a simple model, which is
based on an evaluation of the transition matrix elements that describe the presented
experiments. The model shows that the underlying cause for the observed photoelectron
spin reversals can be found in the coupling of the spin structure to the spatial part
of the initial state wave function, revealing the crucial role of spin-orbit interaction
in the initial state wave function. The model is supported by ab initio photoemission
calculations, which show strong agreement with the experimental results.
Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, has the potential to spread in the human host and cause a severe complication called disseminated gonococcal infection (DGI). The expression of the major outer membrane porin PorBIA is a characteristic of most gonococci associated with DGI. PorBIA binds to the scavenger receptor expressed on endothelial cells (SREC-I), which mediates the so-called low phosphate-dependent invasion (LPDI). This uptake mechanism enables N. gonorrhoeae to rapidly invade epithelial and endothelial cells in a phosphate-sensitive manner.
We recently demonstrated that the neutral sphingomyelinase, which catalyses the hydrolysis of sphingomyelin to ceramide and phosphorylcholine, is required for the LPDI of gonococci in non-phagocytic cells. Neutral sphingomyelinase 2 (NSM2) plays a key role in the early PorBIA signaling by recruiting the PI3 kinase to caveolin. The following activation of the PI3 kinase-dependent downstream signaling leads to the engulfment of the bacteria. As a part of this work, I could confirm the involvement of the NSM2. The role of the enzyme was further elucidated by the generation of antibodies directed against NSM2 and the construction of an epithelium-based NSM2 knockout cell line using CRISPR/Cas9. The knockout of the NSM2 strongly inhibits the LPDI. The invasion could be, however, restored by the complementation of the knockout using an NSM2-GFP construct. However, the results could not be reproduced.
In this work, I could show the involvement of further members of the sphingolipid pathway in the PorBIA-mediated invasion. Lipidome analysis revealed an increase of the bioactive molecules ceramide and sphingosine due to gonococcal infection. Both molecules do not only affect the host cell, but seem to influence the bacteria as well: while ceramide seems to be incorporated by the gonococci, sphingosine is toxic for the bacteria. Furthermore, the sphingosine kinase 2 (SPHK2) plays an important role in invasion, since the inhibition and knockdown of the enzyme revealed a negative effect on gonococcal invasion. To elucidate the role of the sphingosine kinases in invasion in more detail, an activity assay was established in this study. Additionally, the impact of the sphingosine-1-phosphate lyase (S1PL) on invasion was investigated. Inhibitor studies and infection experiments conducted with a CRISPR/Cas9 HeLa S1PL knockout cell line revealed a role of the enzyme not only in the PorBIA-mediated invasion, but also in the Opa50/HSPG-mediated gonococcal invasion. The signaling experiments allowed the categorization of the SPHK and S1PL activation in the context of infection. Like the NSM2, both enzymes play a role in the early PorBIA signaling events leading to the uptake of the bacteria. All those findings indicate an important role of sphingolipids in the invasion and survival of N. gonorrhoeae.
In the last part of this work, the role of the NSM2 in the inhibition of apoptosis in neutrophils due to gonococcal infection was investigated. It could be demonstrated that the delayed onset of apoptosis is independent of neisserial porin and Opa proteins. Furthermore, the influence of neisserial peptidoglycan on PMN apoptosis was analysed using mutant strains, but no connection could be determined. Since the NSM2 is the most prominent sphingomyelinase in PMNs, fulfils manifold cell physiological functions and has already been connected to apoptosis, the impact of the enzyme on apoptosis inhibition due to gonococcal infection was investigated using inhibitors, with no positive results.
Soft x-ray spectroscopic study of methanol and glycine peptides in different physical environments
(2017)
Ion-specific effects occur in a huge variety of aqueous solutions of electrolytes and larger molecules like peptides, altering properties such as viscosity, enzyme activity, protein stability, and salting-in and salting-out behavior of proteins. Typically, these type of effects are rationalized in terms of the Hofmeister series, which originally orders cations and anions according to their ability to enhance or suppress the solubility of proteins in water. This empirical order, however, is still not understood yet. Quite some effort was made to gain a molecular level understanding of this phenomenon, yet no consensus has been found about the underlying mechanisms and the determination and localization of the interaction sites.
Resonant inelastic soft x-ray scattering (RIXS) combines x-ray emission (XES) and absorption spectroscopies (XAS), probing the partial local density of states of both occupied and unoccupied electronic states and is thus a promising candidate to shed more light onto the issue. The studies presented in this work are directed towards an improved understanding of the interaction between salts and peptides. In order to address this topic, the impact of different physical environments on the electronic structure of small molecules (i.e., methanol and glycine derived peptides) is investigated systematically using soft x-ray spectroscopic methods, corroborated with density functional theory (DFT) calculations.
In a first step, molecules without any interactions to the surrounding are investigated, using gas-phase methanol as a model system. Thereby, the local and element specific character of RIXS is demonstrated and used to separately probe the local electronic structure of methanol’s hydroxyl and methyl group, respectively. The attribution of the observed emission features to distinct molecular orbitals is confirmed by DFT calculations, which also quantitatively explain the different relative intensities of the emission features. For resonant excitation of the O K pre-edge absorption resonance, strong isotope effects are found that are explained by dynamical processes at the hydroxyl group. This serves as an excellent example for possible consequences of a local change in the geometric structure or symmetry of a molecule on its electronic structure.
In the following, the sample system is expanded to the amino acid glycine and its smallest derived peptides diglycine and triglycine. As a first step, they are studied in their crystalline form in solid state. Again, a comprehensive picture of the electronic structure is developed by measuring RIXS maps at the oxygen and nitrogen K absorption edge, corroborated by DFT calculations. Similar to the case of methanol, dynamic processes at the protonated amino group of the molecules after exciting the nitrogen atom have a strong influence on the emission spectra. Furthermore, it is shown that RIXS can be used to selectively excite the peptide nitrogen to probe the electronic structure around it. A simple building block approach for XES spectra is applied to separate the contribution of the emission attributed to transitions into core holes at the peptide and the amino nitrogen, respectively.
In the aqueous solution, the surrounding water molecules slightly change the electronic structure, probably via interactions with the charged functional groups. The effects on the x-ray emission spectra, however, are rather small. Much bigger changes are observed when manipulating the protonation state of the functional groups by adjusting the pH value of the solution. A protonation of the carboxyl group at low pH values, as well as a deprotonation of the amino group at high pH values lead to striking changes in the shape of the RIXS maps. In a comprehensive study of glycine’s XES spectra at varying pH values, changes in the local electronic structure are not only observed in the immediate surrounding of the manipulated functional groups but also in more distant moieties of the molecule.
Finally, the study is extended to mixed aqueous solutions of diglycine and a variety of different salts as examples for systems where Hofmeister effects are observed. To investigate the influence of different cations and anions on the electronic structure of diglycine, two series of chlorine and potassium salts are used. Ion-specific effects are identified for both cases. Some of the changes in the x-ray emission spectra of diglycine in the mixed solutions qualitatively follow the Hofmeister series as a function of the used salt. The observed trends thereby indicate an increased interaction between the electron density around the peptide oxygen with the cations, whereas anions seem to interact with the amino group of the peptide.