Refine
Has Fulltext
- yes (679)
Is part of the Bibliography
- yes (679) (remove)
Year of publication
- 2018 (679) (remove)
Document Type
- Journal article (490)
- Doctoral Thesis (156)
- Preprint (22)
- Conference Proceeding (3)
- Other (2)
- Working Paper (2)
- Book (1)
- Book article / Book chapter (1)
- Habilitation (1)
- Master Thesis (1)
Language
- English (679) (remove)
Keywords
- Parton Distributions (23)
- Hadron-Hadron scattering (experiments) (18)
- Positronen-Emissions-Tomografie (16)
- Extension (14)
- PET (14)
- Decay (13)
- boron (12)
- Squark (11)
- ++ (10)
- positron emission tomography (9)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (106)
- Physikalisches Institut (94)
- Graduate School of Life Sciences (65)
- Klinik und Poliklinik für Nuklearmedizin (36)
- Medizinische Klinik und Poliklinik II (31)
- Institut für Psychologie (25)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (24)
- Institut für Anorganische Chemie (22)
- Institut für Virologie und Immunbiologie (20)
- Medizinische Klinik und Poliklinik I (20)
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (15)
- Johns Hopkins University School of Medicine (5)
- Department of Biomedical Imaging, National Cerebral and Cardiovascular Research Center, Suita, Japan (2)
- Division of Medical Technology and Science, Department of Medical Physics and Engineering, Course of Health Science, Osaka University Graduate School of Medicine, Suita Japan (2)
- Institut for Molecular Biology and CMBI, Department of Genomics, Stem Cell Biology and Regenerative Medicine, Leopold-Franzens-University Innsbruck, Innsbruck, Austria (2)
- International Max Planck Research School Molecular Biology, University of Göttingen, Germany (2)
- Johns Hopkins School of Medicine, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA (2)
- ACC GmbH Analytical Clinical Concepts (1)
- BMBF (1)
- Boehringer Ingelheim Pharma GmbH & Co. KG (1)
ResearcherID
- J-8841-2015 (1)
Overwintering temperature and body condition shift emergence dates of spring-emerging solitary bees
(2018)
Solitary bees in seasonal environments must align their life-cycles with favorable environmental conditions and resources; the timing of their emergence is highly fitness relevant. In several bee species, overwintering temperature influences both emergence date and body weight at emergence. High variability in emergence dates among specimens overwintering at the same temperatures suggests that the timing of emergence also depends on individual body conditions. However, possible causes for this variability, such as individual differences in body size or weight, have been rarely studied. In a climate chamber experiment using two spring-emerging mason bees (Osmia cornuta and O. bicornis), we investigated the relationship between temperature, emergence date, body weight, and body size, the last of which is not affected by overwintering temperature. Our study showed that body weight declined during hibernation more strongly in warm than in cold overwintering temperatures. Although bees emerged earlier in warm than in cold overwintering temperatures, at the time of emergence, bees in warm overwintering temperatures had lower body weights than bees in cold overwintering temperatures (exception of male O. cornuta). Among specimens that experienced the same overwintering temperatures, small and light bees emerged later than their larger and heavier conspecifics. Using a simple mechanistic model we demonstrated that spring-emerging solitary bees use a strategic approach and emerge at a date that is most promising for their individual fitness expectations. Our results suggest that warmer overwintering temperatures reduce bee fitness by causing a decrease in body weight at emergence. We showed furthermore that in order to adjust their emergence dates, bees use not only temperature but also their individual body condition as triggers. This may explain differing responses to climate warming within and among bee populations and may have consequences for bee-plant interactions as well as for the persistence of bee populations under climate change.
Recently, our research group identified in a study novel proalgesic targets in acute and chronic inflammatory pain: oxidized phospholipids (OxPL). OxPL, endogenous chemical irritants, are generated in inflamed tissue and mediate their pain-inducing function by activating the transient receptor potential channels TRPA1 and TRPV1. Both channels are sensors for chemical stimuli on primary afferent nociceptors and are involved in nociception. Here, with the help of calcium imaging and whole cell patch clamp recording techniques, it was found that OxPL metabolites acutely activate TRPA1 and TRPV1 ion channels to excite DRG neurons. OxPL species act predominantly via TRPA1 ion channels and mediate long- lasting non-selective inward currents. Notably, one pure OxPL compound, PGPC, activated a TRPA1 mutant lacking the binding site for electrophilic agonists, suggesting that OxPL activate TRP ion channels by an indirect mechanical mechanism. Next, it was investigated how OxPL influence the excitability of primary sensory neurons. Acute stimulation and fast calcium imaging revealed that OxPL elicit repetitive, spike-like calcium transients in small- diameter DRG neurons, which were fully blocked by antagonists against TRPA1/V1 and N- type voltage-gated calcium channels.
In search of a mechanism that drives repetitive spiking of DRG neurons, it was asked whether NaV1.9, a voltage-gated sodium channel involved in subthreshold excitability and nociception, is needed to trigger OxPL-induced calcium spikes and action potential firing. In electrophysiological recordings, both the combination of local application of OxPL and current injection were required to efficiently increase the action potential (AP) frequency of small-diameter sensory neurons. However, no difference was monitored in the resting membrane potential or OxPL-induced AP firing rate between wt and NaV1.9-deficient small diameter DRG neurons. To see whether NaV1.9 needs inflammatory conditions to be integrated in the OxPL-induced excitation cascade, sensory neurons were pretreated with a mixture of inflammatory mediators before OxPL application. Under inflammatory conditions both the AP and the calcium-spike frequency were drastically enhanced in response to an acute OxPL stimulus. Notably, this potentiation of OxPL stimuli was entirely lost in NaV1.9 deficient sensory neurons. Under inflammatory conditions, the resting membrane potential of NaV1.9-deficient neurons was more negative compared to wt neurons, suggesting that NaV1.9 shows resting activity only under inflammatory conditions.
In conclusion, OxPL are endogenous irritants that induce excitability in small-diameter DRG
neurons, a cellular model of nociceptors, via TRP activation. This effect is potentiated under inflammatory conditions. Under these conditions, NaV1.9 functions as essential mediator as it eases the initiation of excitability after OxPL stimulation.
As mutants in the human NaV1.9 mediate an enhanced or painless perception, this study provides new insight into the mechanism on how NaV1.9 amplifies stimuli of endogenous irritants under inflammatory conditions.
Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Aβ pathology in vivo, transgenic APPSwe/PS1ΔE9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Aβ plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB+1 reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals.
Purpose:
The prescribing of oral chemotherapy agents has introduced the new challenge of ensuring patients’ adherence to therapy. Aspects of a close patient–doctor relationship are reported to be correlated with adherence to oral anticancer drugs, but data on capecitabine are scarce.
Patients and methods:
Sixty-four outpatients with a diagnosis of cancer and prescribed capecitabine were recruited from a German Comprehensive Cancer Center. We used the Patient–Doctor Relationship Questionnaire (PDRQ-9), the Medical Adherence Rating Scale (MARS), the Beliefs about Medicines Questionnaire (BMQ), and the Satisfaction with Information about Medicines Scale (SIMS) to assess patients’ perceptions and behavior. Medical data were extracted from the charts.
Results:
Non-adherence was reported by 20% of the 64 participants. The perceived quality of the patient–doctor relationship was high in general, but it did not emerge as a predictor of adherence in our survey (odds ratio [OR]=0.915, P=0.162, 95% CI=0.808–1.036). However, beliefs about medicine (OR=1.268, P<0.002; 95% CI=1.090–1.475) as well as satisfaction with information about medicine (OR=1.252, P<0.040, 95% CI=1.010–1.551) were predictors of adherence and the quality of the patient–doctor relationship was correlated with both variables (r=0.373, P=0.002 for SIMS sum score; r=0.263, P=0.036 for BMQ necessity/concern difference). Overall, adherence to capecitabine was high with a conviction that the therapy is necessary. However, concerns were expressed regarding the long-term effect of capecitabine use. Patients have unmet information needs regarding interactions of capecitabine with other medicines and the impairment of their intimate life.
Conclusions:
In order to ensure adherence to capecitabine, our results seem to encourage the default use of modern and perhaps more impersonal means of information brokerage (eg, email, internet). However, the contents of some of patients’ informational needs as well as the associations of patients’ beliefs and satisfaction about the information received suggest a benefit from a trustful patient–doctor relationship.
Increasing evidence indicates that forest disturbances are changing in response to global change, yet local variability in disturbance remains high. We quantified this considerable variability and analyzed whether recent disturbance episodes around the globe were consistently driven by climate, and if human influence modulates patterns of forest disturbance. We combined remote sensing data on recent (2001–2014) disturbances with in-depth local information for 50 protected landscapes and their surroundings across the temperate biome. Disturbance patterns are highly variable, and shaped by variation in disturbance agents and traits of prevailing tree species. However, high disturbance activity is consistently linked to warmer and drier than average conditions across the globe. Disturbances in protected areas are smaller and more complex in shape compared to their surroundings affected by human land use. This signal disappears in areas with high recent natural disturbance activity, underlining the potential of climate-mediated disturbance to transform forest landscapes.
Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse. We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA. Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure. Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA.
Obligate intracellular pathogenic Chlamydia trachomatis express several serine proteases whose roles in chlamydial development and pathogenicity are not completely understood. The chlamydial protease CPAF is expressed during the replicative phase of the chlamydial developmental cycle and is secreted into the lumen of the Chlamydia-containing vacuole called inclusion. How the secreted protease is activated in the inclusion lumen is currently not fully understood. We have identified human serine peptidase inhibitor PI15 as a potential host factor involved in the regulation of CPAF activation. Silencing expression as well as over expression of PI15 affected normal development of Chlamydia. PI15 was transported into the chlamydial inclusion lumen where it co-localized with CPAF aggregates. We show that PI15 binds to the CPAF zymogen and potentially induces CPAF protease activity at low concentrations. However, at high concentrations PI15 inhibits CPAF activity possibly by blocking its protease domain. Our findings shed light on a new aspect of chlamydial host co-evolution which involves the recruitment of host cell proteins into the inclusion to control the activation of bacterial proteases like CPAF that are important for the normal development of Chlamydia.
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors.
Methods:
We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT.
Results:
PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively.
Conclusion:
Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted.
CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
Background:
We hypothesized, that periprosthetic joint infection (PJI) accounts for the major proportion of first (primary) and repeated (secondary) Total Knee Arthroplasty revisions at our university referral arthroplasty center.
Methods:
One thousand one hundred forty-three revisions, performed between 2008 and 2016 were grouped into primary (55%) and secondary (45%) revisions. The rate of revision indications was calculated and indications were categorized by time after index operation. The odds ratios of the indications for primary versus secondary revision were calculated.
Results:
In the primary revision group PJI accounted for 22.3%, instability for 20.0%, aseptic loosening for 14.9% and retropatellar arthrosis for 14.2%. PJI (25.6%) was the most common indication up to 1 year after implantation, retropatellar arthrosis (26.8%) 1–3 years and aseptic loosening (25.6%) more than 3 years after implantation. In the secondary revision group PJI accounted for 39.7%, aseptic loosening for 16.2% and instability for 13.2%. PJI was the most common indication at any time of revision with 43.8% up to one, 35.4% 1–3 years and 39.4% more the 3 years after index operation. The odds ratios in repeated revision were 2.32 times higher (p = 0.000) for PJI. For instability and retropatellar arthrosis the odds ratios were 0.60 times (p = 0.006) and 0.22 times (p = 0.000) lower.
Conclusions:
PJI is the most common indication for secondary TKA revision and within one year after primary TKA. Aseptical failures such as instability, retropatellar arthrosis and aseptical loosening are the predominant reasons for revision more than one year after primary TKA.
Quantitative mass spectrometry has established proteome-wide regulation of protein abundance and post-translational modifications in various biological processes. Here, we used quantitative mass spectrometry to systematically analyze the thermal stability and solubility of proteins on a proteome-wide scale during the eukaryotic cell cycle. We demonstrate pervasive variation of these biophysical parameters with most changes occurring in mitosis and G1. Various cellular pathways and components vary in thermal stability, such as cell-cycle factors, polymerases, and chromatin remodelers. We demonstrate that protein thermal stability serves as a proxy for enzyme activity, DNA binding, and complex formation in situ. Strikingly, a large cohort of intrinsically disordered and mitotically phosphorylated proteins is stabilized and solubilized in mitosis, suggesting a fundamental remodeling of the biophysical environment of the mitotic cell. Our data represent a rich resource for cell, structural, and systems biologists interested in proteome regulation during biological transitions.
Background
The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease.
Methods
To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events.
Results
In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25–34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55–64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65–74 years), and rarely in females (3%).
Conclusion
p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.
The regulation of immune cell migration throughout the body is essential to warrant immunosurveillance and to maintain immune homeostasis. Marking and tracking of these cells has proven important to study mechanisms of immune cell trafficking and cell interaction in vivo. Photoconversion is a well-suited technique for intravital application because it enables contactless time- and location-specific marking of cells in the tissue without surgically manipulating the microenvironment of the cells in question. However, in dividing cells the converted fluorescent protein may decline quickly. Here, we provide a detailed description of the photoconversion technique and its applicability to tracking highly proliferating T cells from the priming site of T cell activation to peripheral target organs of effector function in a preclinical model. Dendra2+ T cells were photoconverted in the Peyer’s patches during the initiation phase of acute graft-versus-host disease (GvHD) and tracked through the mesenteric lymph nodes and the peripheral blood to the small intestine with flow cytometry and intravital two-photon microscopy. Photoconverted alloreactive T cells preserved the full proliferative capacity, homing, and migration of alloreactive T cells in the intestinal lamina propria. We conclusively proved that photoconversion of highly proliferative alloreactive T cells in the Peyer’s patches is an effective tool to study trafficking of alloreactive T cells under physiologic conditions and to GvHD target tissues. This technique can also be applied to the study of immune cell tracking under inflammatory and non-inflammatory conditions.
This thesis will outline studies performed on the fluorescence dynamics of phenyl-benzo-
[c]-tetrazolo-cinnolium chloride (PTC) in alcoholic solutions with varying viscosity using
time-resolved fluoro-spectroscopic methods. Furthermore, the properties of femtosecond
Laguerre-Gaussian (LG) laser pulses will be investigated with respect to their temporal
and spatial features and an approach will be developed to measure and control the spatial
intensity distribution on the time scale of the pulse.
Tetrazolium salts are widely used in biological assays for their low oxidation and reduction
thresholds and spectroscopic properties. However, a neglected feature in these applications
is the advantage that detection of emitted light has over the determination of the
absorbance. To corroborate this, PTC as one of the few known fluorescent tetrazolium
salts was investigated with regard to its luminescent features. Steady-state spectroscopy
revealed how PTC can be formed by a photoreaction from 2,3,5-triphenyl-tetrazolium
chloride (TTC) and how the fluorescence quantum yield behaved in alcoholic solvents
with different viscosity. In the same array of solvents time correlated single photon counting
(TCSPC) measurements were performed and the fluorescence decay was investigated.
Global analysis of the results revealed different dynamics in the different solvents, but
although the main emission constant did change with the solvent, taking the fluorescence
quantum yield into consideration resulted in an independence of the radiative rate from
the solvent. The non-radiative rate, however, was highly solvent dependent and responsible
for the observed solvent-related changes in the fluorescence dynamics. Further studies
with the increased time resolution of femtosecond fluorescence upconversion revealed an
independence of the main emission constant from the excitation energy, however the dynamics
of the cooling processes prior to emission were prolonged for higher excitation
energy. This led to a conceivable photoreaction scheme with one emissive state with a
competing non-radiative relaxation channel, that may involve an intermediate state.
LG laser beams and their properties have seen a lot of scientific attention over the past two
decades. Also in the context of new techniques pushing the limit of technology further to
explore new phenomena, it is essential to understand the features of this beam class and
check the consistency of the findings with theoretical knowledge. The mode conversion
of a Hermite-Gaussian (HG) mode into a LG mode with the help of a spiral phase plate
(SPP) was investigated with respect to its space-time characteristics. It was found that
femtosecond LG and HG pulses of a given temporal duration share the same spectrum
and can be characterized using the same well-established methods. The mode conversion
proved to only produce the desired LG mode with its characteristic orbital angular momentum
(OAM), that is conserved after frequency doubling the pulse. Furthermore, it
was demonstrated that temporal shaping of the HG pulse does not alter the result of its
mode-conversion, as three completely different temporal pulse shapes produced the same
LG mode. Further attention was given to the sum frequency generation of fs LG beams
and dynamics of the interference of a HG and a LG pulse. It was found that if both are
chirped with inverse signs the spatial intensity distribution does rotate around the beam
axis on the time scale of the pulse. A strategy was found that would enable a measurement
of these dynamics by upconversion of the interference with a third gate pulse. The results
of which are discussed theoretically and an approach of an experimental realization had
been made. The simulated findings had only been reproduced to a limited extend due to
experimental limitations, especially the interferometric stability of the setup.
The noninvasive magnetic resonance imaging technique allows for the investigation of functional processes in the living plant. For this purpose during this work, different NMR imaging methods were further developed and applied.
For the localisation of the intrusion of water into the germinating rape seed with the simultaneous depiction of the lipid-rich tissue via a 3D rendering, in Chap. 5 the technique of interleaved chemical selective acquisition of water and lipid was used in the germinating seed. The utilization of high-resolution MR images of germinated seeds enabled the localization of a predetermined water gap in the lipid-rich aleurone layer, which resides directly under the seed coat. The for a long time in biology prevalent discussion, whether such a gap exists or the seed soaks up the water from all sides, rather like a sponge, could hereby, at least for the rapeseed seed, be answered clearly. Furthermore, the segmentation and 3D visualization of the vascular tissue in the rapeseed seeds was enabled by the high-resolution datasets, a multiply branched structure preconstructed in the seed could be shown. The water is directed by the vascular tissue and thus awakens the seed gradually to life. This re-awakening could as well be tracked by means of invasive imaging via an oxygen sensor. In the re-awakened seeds, the lipid degradation starts, other than expected, not in the lipid-rich cotyledons but in the residual endosperm remaining from seed development and in the aleurone layer which previously protected the embryo. Within this layer, the degradation could be verified in the high-resolution MR datasets.
The method presented in Chap. 6 provides a further characteristic trait for phenotyping of seeds and lipid containing plants in general. The visualization of the compounds of fatty acids in plant seeds and fruits could be achieved by the distinct utilization of chemical shift-selective imaging techniques. Via the application of a CSI sequence the fatty acid compounds in an olive were localized in a 2D slice. In conjunction with an individually adjusted CHESS presaturation module Haa85 the high-resolution 3D visualization of saturated and unsaturated fatty acid compounds in different seeds was achieved. The ratio maps calculated from these datasets allow to draw conclusions from the developmental stage or the type of seed. Furthermore, it could be shown that the storage condition of two soybean seeds with different storage time durations lead to no degradation of the fatty acid content.
Additional structural information from inside of dry seeds are now accessible via MRI. In this work the imaging of cereal seeds could be significantly improved by the application of the UTE sequence. The hitherto existing depictions of the lipid distribution, acquired with the spin echo sequence, were always sufficient for examinations of the lipid content, yet defects in the starchy endosperm or differences in the starch concentration within the seed remained constantly unseen with this technique. In a direct comparison of the datasets acquired with the previous imaging technique (spin echo) and with UTE imaging, the advantage of data acquisition with UTE could be shown. By investigating the potential seed compounds (starch, proteins, sugar) in pure form, the constituent parts contributing to the signal could be identified as bound water (residual moisture) and starch. The application of a bi-exponential fit on the datasets of the barley seed enabled the separate mapping of magnetization and of relaxation time of two components contributing to the NMR signal. The direct comparison with histological stainings verified the previous results, thus this technique can be used for the selective imaging of starch in dry seeds.
Conclusions on the translocation characteristics in plants can be drawn by the technique proposed in Chap. 8. The associated translocation velocities can now, even in the range of several um/h, be determined in the living plant. Based on calculated concentrations of an MR contrast agent, which was taken up by the plant, these translocation velocities were estimated both in longitudinal direction, thus along the vascular bundle, and in horizontal direction, thus out of the bundle. The latter velocity is located below the contrast agent's velocity value of free diffusion. By adjusting a dynamic contrast-enhancing imaging technique (DCE-Imaging, Tof91) the acquisition duration of a T1-map was significantly reduced. By means of these maps, local concentrations of the contrast agent in plant stems and the siliques of the rapeseed plant could be determined.
Numerous questions in plant science can only be answered by non-invasive techniques such as MRI. For this reason, besides the experimental results achieved in this work, further NMR methods were tested and provided for the investigation of plants.
As an example, the study on the imaging of magnetic exchange processes are mentioned, which provided the groundwork for a possible transfer of CEST experiments (Chemical Exchange Saturation Transfer) to the plant. The results are presented in the bachelor thesis of A. Jäger Jae17, which was performed under my supervision, they find great interest under biologists.
The development of new technologies, which extend the possibilities for the investigation of living organisms, is of great importance. For this reason, I have contributed to the development of the currently unpublished method RACETE (Refocused Acquisition of Chemical Exchange Transferred Excitations [Jak17, Reu17, Gut18a]). By rephasing the transferred magnetization the utilization of properties which have not been available in chemical "`exchange"' experiments is enabled. With this method a positive contrast is generated, thus a reference experiment is not mandatory. Furthermore, the image phase, which in classical experiments contains no information about the exchanged protons, can be used for the distinct identification of multiple substances which have been excited simultaneously.
This recently at the Department of Experimental Physics V developed method can be used in particular for the identification of lipids and for the localization of sugars and amino acids, thus it can serve the enhancement and improvement of non-invasive analytical methods.
Impervious surface areas (ISA) are heavily influenced by urban structure and related structural features. We examined the effects of object-based impervious surface spatial pattern analysis on land surface temperature and population density in Guangzhou, China, in comparison to classic per-pixel analyses. An object-based support vector machine (SVM) and a linear spectral mixture analysis (LSMA) were integrated to estimate ISA fraction using images from the Chinese HJ-1B satellite for 2009 to 2011. The results revealed that the integrated object-based SVM-LSMA algorithm outperformed the traditional pixel-wise LSMA algorithm in classifying ISA fraction. More specifically, the object-based ISA spatial patterns extracted were more suitable than pixel-wise patterns for urban heat island (UHI) studies, in which the UHI areas (landscape surface temperature >37 °C) generally feature high ISA fraction values (ISA fraction >50%). In addition, the object-based spatial patterns enable us to quantify the relationship of ISA with population density (correlation coefficient >0.2 in general), with global human settlement density (correlation coefficient >0.2), and with night-time light map (correlation coefficient >0.4), and, whereas pixel-wise ISA did not yield significant correlations. These results indicate that object-based spatial patterns have a high potential for UHI detection and urbanization monitoring. Planning measures that aim to reduce the urbanization impacts and UHI intensities can be better supported.
Glycine receptors (GlyRs) are important mediators of fast inhibitory neurotransmission in the mammalian central nervous system. Their function is controlled by multiple cellular mechanisms, including intracellular regulatory processes. Modulation of GlyR function by protein kinases has been reported for many cell types, involving different techniques, and often yielding contradictory results. Here, we studied the effects of protein kinase C (PKC) and cAMP-dependent protein kinase A (PKA) on glycine induced currents in HEK293 cells expressing human homomeric \(\alpha\)1 and heteromeric \(\alpha\)1-\(\beta\) GlyRs using whole-cell patch clamp techniques as well as internalization assays. In whole-cell patch-clamp measurements, modulators were applied in the intracellular buffer at concentrations between 0.1 \(\mu\)M and 0.5 \(\mu\)M. EC50 of glycine increased upon application of the protein kinase activators Forskolin and phorbol-12-myristate-13-acetate (PMA) but decreased in the presence of the PKC inhibitor Staurosporine aglycon and the PKA inhibitor H-89. Desensitization of recombinant \(\alpha\)1 receptors was significantly increased in the presence of Forskolin. Staurosporine aglycon, on the other hand decreased desensitization of heteromeric \(\alpha\)1-\(\beta\) GlyRs. The time course of receptor activation was determined for homomeric \(\alpha\)1 receptors and revealed two simultaneous effects: cells showed a decrease of EC50 after 3-6 min of establishing whole-cell configuration. This effect was independent of protein kinase modulators. All modulators of PKA and PKC, however, produced an additional shift of EC50, which overlay and eventually exceeded the cells intrinsic variation of EC50. The effect of kinase activators was abolished if the corresponding inhibitors were co-applied, consistent with PKA and PKC directly mediating the modulation of GlyR function. Direct effects of PKA-and PKC-modulators on receptor expression on transfected HEK cells were monitored within 15 min of drug application, showing a significant increase of receptor internalization with PKA and PKC activators, while the corresponding inhibitors had no significant effect on receptor surface expression or internalization. Our results confirm the observation that phosphorylation via PKA and PKC has a direct effect on the GlyR ion channel complex and plays an important role in the fine-tuning of glycinergic signaling.
Species' functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird-fruit, bird-flower and insect-flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant-animal interaction networks.
Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.
Catheter-related bloodstream infections (CRBSI) are major complications for patients with life-threatening conditions requiring chronic vascular catheterization. The wide range of etiologic microbes and the ongoing development of resistance to antimicrobials with specific mechanisms of action make this an appropriate target for applying a nonspecific antimicrobial therapeutic. Taurolidine hydrolyzes into two antimicrobial moieties, formaldehyde and methylene glycol, which react with microbial surfaces. NeutrolinA (R) (taurolidine, heparin, calcium citrate) was recently introduced in Germany as an antimicrobial catheter lock solution. This postmarketing experience collected data on 201 patients at 20 centers from January 2014 through September 2016. Likely CRBSI was observed in 13 episodes in 47,118 days (0.2759 per 1000 days [0.1468, 0.4718]). Thrombosed catheter was observed in seven catheters in 47,118 days (0.1486 per 1000 days [0.0595, 0.3061]). No adverse drug reactions that led to the discontinuation of NeutrolinA (R) use were reported. Two patients experienced occasional transient dysgeusia. NeutrolinA (R), when used in conjunction with guideline-based catheter care, showed reduction in the rate of both CRBSI and catheter thrombosis relative to recent historical controls.
Chronic Obstructive Pulmonary Disease (COPD) exacerbations are a considerable reason for increased morbidity and mortality in patients. Infections with influenza virus (H1N1), respiratory syncytial virus (RSV) or nontypeable Haemophilus influenzae (NTHi) are important triggers of exacerbations. To date, no treatments are available which can stop the progression of COPD. Novel approaches are urgently needed. Pre-clinical models of the disease are crucial for the development of novel therapeutic options.
In order to establish pre-clinical models which mimic aspects of human COPD exacerbations, mice were exposed to cigarette smoke (CS) and additionally infected with H1N1, RSV and/or NTHi. Clinically relevant treatments such as the corticosteroids Fluticasone propionate and Dexamethasone, the phosphodiesterase-4 (PDE-4) inhibitor Roflumilast and the long-acting muscarinic receptor antagonist Tiotropium were tested in the established models. Furthermore, a novel treatment approach using antibodies (Abs) directed against IL-1α, IL-1β or IL-1R1 was examined in the established CS/H1N1 model. Levels of IFN-γ, IL-1β, IL-2, IL-6, KC, TNF-α, RANTES, IL-17, MCP-1, MIP 1α and MIP-1β were measured in lung homogenate. Numbers of total cells, neutrophils and macrophages were assessed in bronchoalveolar lavage (BAL) fluid. Hematoxylin- and eosin- (H&E-) stained lung slices were analyzed to detect pathological changes. Quantitative polymerase-chain-reaction (qPCR) was used to investigate gene expression of ICAM-1 and MUC5 A/C. The viral/bacterial load was investigated in lung homogenate or BAL fluid. In addition to the in vivo studies, the effects of the above mentioned treatments were investigated in vitro in H1N1, RSV or NTHi-infected (primary) human bronchial epithelial cells using submerged or air-liquid-interface (ALI) cell culture systems.
Four pre-clinical models (CS/H1N1, CS/RSV, CS/NTHi, CS/H1N1/NTHi) were established depicting clinically relevant aspects of COPD exacerbations such as increased inflammatory cells and cytokines in the airways and impaired lung function.
In the CS/H1N1 model, Tiotropium improved lung function and was superior in reducing inflammation in comparison to Fluticasone or Roflumilast. Moreover, Fluticasone increased the loss of body-weight, levels of IL-6, KC and TNF-α and worsened lung function. In CS/RSV-exposed mice Tiotropium but not Fluticasone or Roflumilast treatment reduced neutrophil numbers and IL-6 and TNF α levels in the lung. The viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after Fluticasone and Dexamethasone treatment. The results from these studies demonstrate that Tiotropium has anti-inflammatory effects on CS/virus-induced inflammation and might help to explain the observed reduction of exacerbation rates in Tiotropium-treated COPD patients. Furthermore, the findings from this work indicate that treatment with Fluticasone or Dexamethasone might not be beneficial to reduce inflammation in the airways of COPD patients and supports clinical studies that link treatment with corticosteroids to an increased risk for pneumonia.
Testing of anti-IL-1α, anti-IL-1β or anti-IL-1R1 Abs in the CS/H1N1 model suggests that, in line with clinical data, antagonization of IL-1β is not sufficient to reduce pulmonary inflammation and indicates a predominant role of IL-1α in CS/virus-induced airway inflammation. In line with the in vivo findings, anti-IL-1α but not anti-IL-1β Abs reduced levels of TNF-α and IL-6 in H1N1-infected primary human bronchial epithelial ALI cell culture. Blocking the IL-1R1 provided significant inhibitory effects on inflammatory cells in vivo but was inferior compared to inhibiting both its soluble ligands IL-1α and IL-1β. Concomitant usage of Abs against IL-1α/IL-1β revealed strong effects and reduced total cells, neutrophils and macrophages. Additionally, levels of KC, IL-6, TNF-α, MCP-1, MIP-1α and MIP-1β were significantly reduced and ICAM-1 mRNA expression was attenuated. These results suggest that combined inhibition of IL-1α/IL-1β might be beneficial to reduce inflammation and exacerbations in COPD patients. Moreover, combined targeting of both IL-1α/IL-1β might be more efficient compared to inhibition of the IL-1R1.
As in the CS/virus models, corticosteroid treatment failed to reduce inflammatory cells in the CS/NTHi and CS/H1N1/NTHi models, increased the loss of body-weight and the bacterial load. Furthermore, Roflumilast administration had no significant effects on cell counts or cytokines. However, it improved compliance in the CS/NTHi model. Treatment with Azithromycin reduced the bacterial load in the CS/NTHi model and reduced numbers of total cells, neutrophils, macrophages and levels of KC and TNF-α in the CS/H1N1/NTHi model.
In conclusion, the established CS/H1N1, CS/RSV, CS/NTHi, CS/H1N1/NTHi models depict clinically relevant aspects of human COPD exacerbations in mice and provide the opportunity to investigate underlying disease mechanisms and to test novel therapies.
Purpose: Early identification of aggressive disease could improve decision-support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-PET before PRRT was analyzed.
Procedures: 31 patients with G1/G2 pNET were enrolled (G2, n=23/31). Prior to PRRT with [\(^{177}\)Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET/CT was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV\(_{mean/max}\)), imaging-based TF as well as clinical parameters (Ki67, CgA) for prediction of both progression-free (PFS) and overall survival (OS) after PRRT was evaluated.
Results: Within a median follow-up of 3.7y, tumor progression was detected in 21 patients (median, 1.5y) and 13/31 deceased (median, 1.9y). In ROC analysis, the TF Entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff=6.7, AUC=0.71, p=0.02). Of note, increasing Entropy could predict a longer survival (>6.7, OS=2.5y, 17/31), whereas less voxel-based derangement portended inferior outcome (<6.7, OS=1.9y, 14/31). These findings were supported in a G2 subanalysis (>6.9, OS=2.8y, 9/23 vs. <6.9, OS=1.9y, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using Entropy (n=31, p<0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n=31, p=0.04). Ki67 was negatively associated with PFS (p=0.002); however, SUVmean/max failed in prognostication (n.s.).
Conclusions: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification.
Purpose: Early identification of aggressive disease could improve decision-support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-PET before PRRT was analyzed.
Procedures: 31 patients with G1/G2 pNET were enrolled (G2, n=23/31). Prior to PRRT with [\(^{177}\)Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET/CT was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV\(_{mean/max}\)), imaging-based TF as well as clinical parameters (Ki67, CgA) for prediction of both progression-free (PFS) and overall survival (OS) after PRRT was evaluated.
Results: Within a median follow-up of 3.7y, tumor progression was detected in 21 patients (median, 1.5y) and 13/31 deceased (median, 1.9y). In ROC analysis, the TF Entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff=6.7, AUC=0.71, p=0.02). Of note, increasing Entropy could predict a longer survival (>6.7, OS=2.5y, 17/31), whereas less voxel-based derangement portended inferior outcome (<6.7, OS=1.9y, 14/31). These findings were supported in a G2 subanalysis (>6.9, OS=2.8y, 9/23 vs. <6.9, OS=1.9y, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using Entropy (n=31, p<0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n=31, p=0.04). Ki67 was negatively associated with PFS (p=0.002); however, SUVmean/max failed in prognostication (n.s.).
Conclusions: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification.
African trypanosomes are the causative agents of fatal diseases in humans and livestock. Trypanosomes show a complex lifecycle and shuttle between the transmitting vector, the tsetse (Glossina spec.), and the mammalian host. As a result of this the parasite undergoes tremendous changes in morphology and metabolism to adapt to the different living environments.
The two best-studied lifecycle stages are the procyclic forms (PCF) that live in the tsetse fly and the proliferative bloodstream form (BSF) that resides in the mammalian blood. The most conspicuous weapon that trypanosomes use to evade the host immune attack is a dense layer of a single protein type, the variant surface glycoprotein (VSG), which shields the entire cell surface. Immune evasion required high rates of surface membrane turnover and surface coat recycling.
Trypanosomes show highly polarised cell architecture with all major eukaryotic organelles (endoplasmic reticulum, Golgi apparatus, endosomal apparatus, lysosome, mitochondrion and peroxisome-like glycosomes) generally present in single copy. Furthermore, trypanosomes possess a single flagellum, which is important not only for cellular motility but also for cell division.
How the duplication of all these cellular components is coordinated in order to progresss through the cell division cycle is poorly understood.
We used trypanosomes as a model organism due to the relative simplicity and the polarised nature of their cell architecture and determined the duplication of all their compartments. This was only possible due to a new synchronisation approach developed during this project.
In the first part of the thesis a precise temporal map of the cell division cycle of the BSF T. brucei cell division cycle was generated. By the use of well-described morphological markers (K/N status, new flagellum outgrowth and DNA synthesis) the position of individual cells was determined with high temporal resolution; this allowed us for the first time to synchronise a cell population in silico without affecting the naturally asynchronous growth.
In the second part of the thesis we used this tool to follow duplication events of the Major organelles during progression through the cell division cycle. We precisely determined the time points of organelle duplication and found that it is ordered in trypanosomes. Furthermore we found that BSF T. brucei cells do not grow continuously, cell size start to increase rapidly, during a short period of time, late in the cell division cycle. We speculate that the initiation of cell volume increase is temporally separated from the formation of all secretory organelles in order to ensure maintenance of the protective coat, which must remain intact at all times in order for BSF trypanosomes to be able to evade the host immune response.
Introduction: Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKI). We
aimed to assess the role of metabolic imaging using 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography/computed tomography (PET/CT) shortly before and 3 months after initiation of TKI treatment.
Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after TKI treatment initiation. During follow-up, CT scans were performed every 3 months and analyzed according to Response Evaluation Criteria In Solid Tumors (RECIST). The predictive value for estimating progression-free (PFS) and overall survival (OS) was examined by investigating \(^{18}\)F-FDG mean/maximum standardized uptake values (SUVmean/max) of the metabolically most active lesion as well as by analyzing clinical parameters (tumor marker doubling times {calcitonin, carcinoembryonic antigen (CEA)}, prior therapies, RET (rearranged during transfection) mutational status, and disease type).
Results: Within a median follow-up of 5.2 years, 9 patients experienced disease progression after a median time interval of 2.1y whereas the remainder had ongoing disease control (n=5 partial response and n=4 stable disease). Eight of the 9 patients with progressive disease died from MTC after a median of 3.5y after TKI initiation.
Pre-therapeutic SUVmean >4.0 predicted a significantly shorter PFS (PFS: 1.9y vs. 5.2y; p=0.04). Furthermore, sustained high 18F-FDG uptake at 3 months with a SUVmean>2.8 tended to portend an unfavorable prognosis with a PFS of 1.9y (vs. 3.5y; p=0.3). Prolonged CEA doubling times were significantly correlated with longer PFS (r=0.7) and OS (r=0.76, p<0.01, respectively). None of the other clinical parameters had prognostic significance.
Conclusions: Pre-therapeutic \(^{18}\)F-FDG PET/CT holds prognostic information in patients with advanced MTC scheduled for treatment with the TKI vandetanib. Low tumor metabolism of SUVmean < 4.0 prior to treatment predicts longer progression-free survival.
Bloodstream infections by the human-pathogenic fungi Candida albicans and Candida glabrata increasingly occur in hospitalized patients and are associated with high mortality rates. The early immune response against these fungi in human blood comprises a concerted action of humoral and cellular components of the innate immune system. Upon entering the blood, the majority of fungal cells will be eliminated by innate immune cells, i.e., neutrophils and monocytes. However, recent studies identified a population of fungal cells that can evade the immune response and thereby may disseminate and cause organ dissemination, which is frequently observed during candidemia. In this study, we investigate the so far unresolved mechanism of fungal immune evasion in human whole blood by testing hypotheses with the help of mathematical modeling. We use a previously established state-based virtual infection model for whole-blood infection with C. albicans to quantify the immune response and identified the fungal immune-evasion mechanism. While this process was assumed to be spontaneous in the previous model, we now hypothesize that the immune-evasion process is mediated by host factors and incorporate such a mechanism in the model. In particular, we propose, based on previous studies that the fungal immune-evasion mechanism could possibly arise through modification of the fungal surface by as of yet unknown proteins that are assumed to be secreted by activated neutrophils. To validate or reject any of the immune-evasion mechanisms, we compared the simulation of both immune-evasion models for different infection scenarios, i.e., infection of whole blood with either C. albicans or C. glabrata under non-neutropenic and neutropenic conditions. We found that under non-neutropenic conditions, both immune-evasion models fit the experimental data from whole-blood infection with C. albicans and C. glabrata. However, differences between the immune-evasion models could be observed for the infection outcome under neutropenic conditions with respect to the distribution of fungal cells across the immune cells. Based on these predictions, we suggested specific experimental studies that might allow for the validation or rejection of the proposed immune-evasion mechanism.
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6-12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05-0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.
Background
There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods
The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results
A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions
Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Background: In a 2008-10 study, we found a pretreatment HIV drug resistance (PDR) prevalence of 18.2% in patients at Bugando Medical Centre (BMC) in Mwanza, Tanzania.
Objectives: To determine the prevalence of PDR and transmitted HIV drug resistance (TDR) in patients visiting the BMC from 2013 to 2015.
Methods: Adult outpatients were sequentially enrolled into two groups, separated by whether they were initiating ART. Previous exposure to antiretroviral drugs, except for prevention of mother-to-child transmission, was an exclusion criterion. HIV pol sequences were analysed according to WHO guidelines for surveillance of PDR and TDR.
Results: Two hundred and thirty-five sequences were analysed (138 ART initiators, 97 non-initiators). The prevalence of PDR was 4.7% (95% CI 2.6%-8.2%) overall, 3.1% (95% CI 1.1%-8.7%) for non-initiators and 5.8% (95% CI 3.0%-11.0%) for ART initiators. PDR to NNRTIs and nucleoside or nucelotide reverse transcriptase inhibitors was found in 3.0% (95% CI 1.5%-6.0%) and 1.7% (95% CI 0.7%-4.3%) of patients, respectively. Resistance to PIs was not observed. The prevalence of TDR was 6.0% (95% CI 3.6%-9.8%).
Conclusions: Prevalence of PDR significantly decreased compared with 2008-10 and was below the WHO-defined threshold for triggering a public health response. National and systematic surveillance is needed to inform Tanzania's public health strategy.
During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.
The main focus of this thesis was the processing of different calcium and magnesium phosphate cements together with an optimization of mechanical and biological properties. Therefore, different manufacturing techniques like 3D powder printing and centrifugally casting were employed for the fabrication of reinforced or biomedically improved implants.
One of the main problems during 3D powder printing is the low green strength of many materials, especially when they are only physically bonded and do not undergo a setting reaction. Such materials need post-treatments like sintering to exhibit their full mechanical performance. However, the green bodies have to be removed from the printer requiring a certain stability. With the help of fiber reinforcement, the green strength of printed gypsum samples could be increased by the addition of polymeric and glass fibers within the printing process. The results showed that fiber reinforcement during 3D powder printing is possible and opens up diverse opportunities to enhance the damage tolerance of green bodies as well as directly printed samples. The transfer to biomedically relevant materials like calcium and magnesium phosphate cements and biocompatible fibers would be the next step towards reinforced patient-specific implants.
In a second approach, centrifugally casting derived from construction industries was established for the fabrication of hollow bioceramic cylinders. The aim was the replacement of the diaphysis of long bones, which exhibit a tubular structure with a high density of cortical bone on the fringe. By centrifugation, cement slurries with and without additives could be fabricated to tubes. As a first establishment, the processing parameters regarding the material (e.g. cement composition) as well as the set-up (e.g. rotation times) had to be optimized for each system. In respect of mechanics, such tubes can keep up with 3D powder printed tubes, although the mechanical performance of 3D printed tubes is strongly dependent on printing directions. Additionally, some material compositions like dual setting systems cannot be fabricated by 3D powder printing. Therefore, a transfer of such techniques to centrifugally casting enabled the fabrication of tubular structures with an extremely high damage tolerance due to high deformation ability. A similar effect was achieved by fiber (mesh) addition, as already shown for 3D powder printing. Another possibility of centrifugally casting is the combination of different materials resulting in graded structures to adjust implant degradation or bone formation. This became especially apparent for the incorporation of the antibiotic vancomycin, which is used for the treatment of bacterial implant infections. A long-term release could be achieved by the entrapment of the drug between magnesium phosphate cement layers. Therefore, the release of the drug could be regulated by the degradation of the outer shell, which supports the release into an acidic bacterial environment. The centrifugally casting technique exhibited to be a versatile tool for numerous materials and applications including the fabrication of non-centrosymmetric patient-specific implants for the reconstruction of human long bones.
The third project aimed to manufacture strontium-substituted magnesium phosphate implants with improved biological behavior by 3D powder printing. As the promoting effect of strontium on bone formation and the inhibitory impact on bone resorption is already well investigated, the incorporation of strontium into a degradable magnesium phosphate cement promised a fast integration and replacement of the implant. Porous structures were obtained with a high pore interconnectivity that is favorable for cell invasion and bone ingrowth. Despite the porosity, the mechanical performance was comparable to pure magnesium phosphate cement with a high reliability of the printed samples as quantitatively determined by Weibull statistics. However, the biological testing was impeded by the high degradation rate and the relating ion release. The high release of phosphate ions into surrounding media and the detachment of cement particles from the surface inhibited osteoblast growth and activity. To distinguish those two effects, a direct and indirect cell seeding is always required for degradable materials. Furthermore, the high phosphate release compared to the strontium release has to be managed during degradation such that the adverse effect of phosphate ions does not overwhelm the bone promoting effect of the strontium ions.
The manufacturing techniques presented in this thesis together with the material property improvement offer a diverse tool box for the fabrication of patient-specific implants. This includes not just the individual implant shape but also the application like bone growth promotion, damage tolerance and local drug delivery. Therefore, this can act as the basis for further research on specific medical indications.
The aim was to examine certain aspects of circulatory, metabolic, hormonal, thermoregulatory, cognitive, and perceptual responses while sitting following a brief session of high-intensity interval exercise. Twelve students (five men; age, 22 ± 2 years) performed two trials involving either simply sitting for 180 min (SIT) or sitting for this same period with a 6-min session of high-intensity exercise after 60 min (SIT+HIIT). At T\(_0\) (after 30 min of resting), T\(_1\) (after a 20-min breakfast), T\(_2\) (after sitting for 1 h), T\(_3\) (immediately after the HIIT), T\(_4\), T\(_5\), T\(_6\), and T\(_7\) (30, 60, 90, and 120 min after the HIIT), circulatory, metabolic, hormonal, thermoregulatory, cognitive, and perceptual responses were assessed. The blood lactate concentration (at T\(_3\)–T\(_5\)), heart rate (at T\(_3\)–T\(_6\)), oxygen uptake (at T\(_3\)–T\(_7\)), respiratory exchange ratio, and sensations of heat (T\(_3\)–T\(_5\)), sweating (T\(_3\), T\(_4\)) and odor (T\(_3\)), as well as perception of vigor (T\(_3\)–T\(_6\)), were higher and the respiratory exchange ratio (T\(_4\)–T\(_7\)) and mean body and skin temperatures (T\(_3\)) lower in the SIT+HIIT than the SIT trial. Levels of blood glucose and salivary cortisol, cerebral oxygenation, and feelings of anxiety/depression, fatigue or hostility, as well as the variables of cognitive function assessed by the Stroop test did not differ between SIT and SIT+HIIT. In conclusion, interruption of prolonged sitting with a 6-min session of HIIT induced more pronounced circulatory and metabolic responses and improved certain aspects of perception, without affecting selected hormonal, thermoregulatory or cognitive functions.
A measurement of J/psi and psi(2S) production is presented. It is based on a data sample from Pb+Pb collisions at root s(NN) = 5.02 TeV and pp collisions at root s = 5.02 TeV recorded by the ATLAS detector at the LHC in 2015, corresponding to an integrated luminosity of 0.42 nb(-1) and 25 pb(-1) in Pb+Pb and pp, respectively. The measurements of per-event yields, nuclear modification factors, and non-prompt fractions are performed in the dimuon decay channel for 9 < p(T)(mu mu) < 40 GeV in dimuon transverse momentum, and -2 < y(mu mu) < 2 in rapidity. Strong suppression is found in Pb+Pb collisions for both prompt and non-prompt J/psi, increasing with event centrality. The suppression of prompt psi(2S) is observed to be stronger than that of J/psi, while the suppression of non-prompt psi(2S) is equal to that of the non-prompt J/psi within uncertainties, consistent with the expectation that both arise from b-quarks propagating through the medium. Despite prompt and non-prompt J/psi arising from different mechanisms, the dependence of their nuclear modification factors on centrality is found to be quite similar.
The modular Hamiltonian of reduced states, given essentially by the logarithm of the reduced density matrix, plays an important role within the AdS/CFT correspondence in view of its relation to quantum information. In particular, it is an essential ingredient for quantum information measures of distances between states, such as the relative entropy and the Fisher information metric. However, the modular Hamiltonian is known explicitly only for a few examples. For a family of states rho(lambda) that is parametrized by a scalar lambda, the first order contribution in (lambda) over tilde = lambda-lambda(0) of the modular Hamiltonian to the relative entropy between rho(lambda) and a reference state rho(lambda 0) is completely determined by the entanglement entropy, via the first law of entanglement. For several examples, e.g. for ball-shaped regions in the ground state of CFTs, higher order contributions are known to vanish. In these cases the modular Hamiltonian contributes to the Fisher information metric in a trivial way. We investigate under which conditions the modular Hamiltonian provides a non-trivial contribution to the Fisher information metric, i.e. when the contribution of the modular Hamiltonian to the relative entropy is of higher order in (lambda) over tilde. We consider one-parameter families of reduced states on two entangling regions that form an entanglement plateau, i.e. the entanglement entropies of the two regions saturate the Araki-Lieb inequality. We show that in general, at least one of the relative entropies of the two entangling regions is expected to involve (lambda) over tilde contributions of higher order from the modular Hamiltonian. Furthermore, we consider the implications of this observation for prominent AdS/CFT examples that form entanglement plateaux in the large N limit.
Fungi possess diverse photosensory proteins that allow them to perceive different light wavelengths and to adapt to changing light conditions in their environment. The biological and physiological roles of the green light-sensing rhodopsins in fungi are not yet resolved. The rice plant pathogen Fusarium fujikuroi exhibits two different rhodopsins, CarO and OpsA. CarO was previously characterized as a light-driven proton pump. We further analyzed the pumping behavior of CarO by patch-clamp experiments. Our data show that CarO pumping activity is strongly augmented in the presence of the plant hormone indole-3-acetic acid and in sodium acetate, in a dose-dependent manner under slightly acidic conditions. By contrast, under these and other tested conditions, the Neurospora rhodopsin (NR)-like rhodopsin OpsA did not exhibit any pump activity. Basic local alignment search tool (BLAST) searches in the genomes of ascomycetes revealed the occurrence of rhodopsin-encoding genes mainly in phyto-associated or phytopathogenic fungi, suggesting a possible correlation of the presence of rhodopsins with fungal ecology. In accordance, rice plants infected with a CarO-deficient F. fujikuroi strain showed more severe bakanae symptoms than the reference strain, indicating a potential role of the CarO rhodopsin in the regulation of plant infection by this fungus.
Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
(2018)
Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others, activates G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancerbinding protein (C/EBP)-α and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, loss of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.
Brain-Computer Interfaces (BCIs) provide communication channels independent from muscular control. In the current study we used two versions of the P300-BCI: one based on visual the other on auditory stimulation. Up to now, data on the impact of psychological variables on P300-BCI control are scarce. Hence, our goal was to identify new predictors with a comprehensive psychological test-battery. A total of N = 40 healthy BCI novices took part in a visual and an auditory BCI session. Psychological variables were measured with an electronic test-battery including clinical, personality, and performance tests. The personality factor “emotional stability” was negatively correlated (Spearman's rho = −0.416; p < 0.01) and an output variable of the non-verbal learning test (NVLT), which can be interpreted as ability to learn, correlated positively (Spearman's rho = 0.412; p < 0.01) with visual P300-BCI performance. In a linear regression analysis both independent variables explained 24% of the variance. “Emotional stability” was also negatively related to auditory P300-BCI performance (Spearman's rho = −0.377; p < 0.05), but failed significance in the regression analysis. Psychological parameters seem to play a moderate role in visual P300-BCI performance. “Emotional stability” was identified as a new predictor, indicating that BCI users who characterize themselves as calm and rational showed worse BCI performance. The positive relation of the ability to learn and BCI performance corroborates the notion that also for P300 based BCIs learning may constitute an important factor. Further studies are needed to consolidate or reject the presented predictors.
Background
Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double-blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations.
Methods
A total of 15 patients were programmed using a pulse width of 30 µs (test) or 60 µs (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients’ efficacy and side effect thresholds.
Results
The therapeutic window was significantly larger at 30 µs than 60 µs (P = ·0009) and the efficacy (UPDRS III score) was noninferior (P = .00008).
Interpretation
Subthalamic neurostimulation at 30 µs versus 60 µs pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
In this thesis various aspects of Quality of Experience (QoE) research are examined. The work is divided into three major blocks: QoE Assessment, QoE Monitoring, and VNF Performance Evaluation. First, prominent cloud applications such as Google Docs and a cloud-based photo album are explored. The QoE is characterized and the influence of packet loss and delay is studied. Afterwards, objective QoE monitoring for HTTP Adaptive Video Streaming (HAS) in the cloud is investigated. Additionally, by using a Virtual Network Function (VNF) for QoE monitoring in the cloud, the feasibility of an interworking of Network Function Virtualization (NFV) and cloud paradigm is evaluated. To this end, a VNF that exploits deep packet inspection technique was used to parse the video traffic. An algorithm is then designed accordingly to estimate video quality and QoE based on network and application layer parameters. To assess the accuracy of the estimation, the VNF is measured in different scenarios under different network QoS and the virtual environment of the cloud architecture. The insights show that the different geographical deployments of the VNF influence the accuracy of the video quality and QoE estimation. Various Service Function Chain (SFC) placement algorithms have been proposed and compared in the context of edge cloud networks. On the one hand, this research is aimed at cloud service providers by providing methods for evaluating QoE for cloud applications. On the other hand, network operators can learn the pitfalls and disadvantages of using the NFV paradigm for such a QoE monitoring mechanism.
Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.
Background:
Minimally invasive pedicle screw fixation has less approach-related morbidity than open screw placement and is allegedly less traumatizing on paravertebral muscles, as there is no requirement to mobilize and retract the adjacent muscle portion. The approach-related long-term effects to the morphology of the paravertebral muscles are unknown. The purpose of this study was to compare the long-term amount of fatty degeneration of the multifidus muscle in patients treated with a classical open or a minimally invasive approach.
Methods:
Fourteen Patients meeting inclusion criteria were selected. In all patients a singular fracture of the thoracolumbar spine with a two-level posterior instrumentation was treated, either using an open approach or a minimally invasive approach. All patients underwent quantitative MRI spectroscopy for quantification of the fatty degeneration in the multifidus muscle as a long-term proof for muscle loss after minimum 4-year follow-up. Clinical outcome was assessed using Oswestry Low Back Pain Disability Questionnaire, SF-36 and VA-scale for pain.
Results:
The minimally invasive approach group failed to show less muscle degeneration in comparison to the open group. Total amount of fatty degeneration was 14.22% in the MIS group and 12.60% in the open group (p = 0.64). In accordance to MRI quantitative results there was no difference in the clinical outcome after a mean follow up of 5.9 years (±1.8).
Conclusion:
As short-term advantages of minimal invasive screw placement have been widely demonstrated, no advantage of the MIS, displaying a significant difference in the amount of fatty degeneration and resulting in a better clinical outcome could be found. Besides the well-known short-term advantage of minimally invasive pedicle screw placement, a long-term advantage, such as less muscle degeneration and thus superior clinical results, compared to the open approach could not be shown.
The presented thesis summarizes the results from four and a half years of intense lithography development on (Cd,Hg)Te/HgTe/(Cd,Hg)Te quantum well structures. The effort was motivated by the unique properties of this topological insulator. Previous work from Molenkamp at al.\ has proven that the transport through such a 2D TI is carried by electrons with opposite spin, counter-propagating in 1D channels along the sample edge. However, up to this thesis, the length of quantized spin Hall channels has never been reported to exceed 4 µm. Therefore, the main focus was put on a reproducible and easy-to-handle fabrication process that reveals the intrinsic material parameters.
Every single lithography step in macro as well as microscopic sample fabrication has been re-evaluated. In the Development, the process changes have been presented along SEM pictures, microgaphs and, whenever possible, measurement responses.
We have proven the conventional ion milling etch method to damage the remaining mesa and result in drastically lower electron mobilities in samples of microscopic size.
The novel KI:I2:HBr wet etch method for macro and microstructure mesa fabrication has been shown to leave the crystalline structure intact and result in unprecedented mobilities, as high as in macroscopic characterization Hall bars. Difficulties, such as an irregular etch start and slower etching of the conductive QW have been overcome by concentration, design and etch flow adaptations. In consideration of the diffusive regime, a frame around the EBL write field electrically decouples the structure mesa from the outside wafer. As the smallest structure, the frame is etched first and guarantees a non-different etching of the conductive layer during the redox reaction. A tube-pump method assures reproducible etch results with mesa heights below 300 nm. The PMMA etch mask is easy to strip and leaves a clean mesa with no redeposition. From the very first attempts, to the final etch process, the reader has been provided with the characteristics and design requirements necessary to enable the fabrication of nearly any mesa shape within an EBL write field of 200 µm.
Magneto resistance measurement of feed-back samples have been presented along the development chronology of wet etch method and subsequent lithography steps. With increasing feature quality, more and more physics has been revealed enabling detailed evaluation of smallest disturbances. The following lithography improvements have been implemented. They represent a tool-box for high quality macro and microstructure fabrication on (CdHg)Te/HgTe of almost any kind.
The optical positive resist ECI 3027 can be used as wet and as dry etch mask for structure sizes larger than 1 µm. It serves to etch mesa structures larger than the EBL write field.
The double layer PMMA is used for ohmic contact fabrication within the EBL write field. Its thickness allows to first dry etch the (Cd,Hg)Te cap layer and then evaporate the AuGe contact, in situ and self-aligned. Because of an undercut, up to 300 nm can be metalized without any sidewalls after the lift-off. An edge channel mismatch within the contact leads can be avoided, if the ohmic contacts are designed to reach close to the sample and beneath the later gate electrode.
The MIBK cleaning step prior to the gate application removes PMMA residuals and thereby improves gate and potential homogeneity.
The novel low HfO2-ALD process enables insulator growth into optical and EBL lift-off masks of any resolvable shape. Directly metalized after the insulator growth, the self-aligned method results in thin and homogeneous gate electrode reproducibly withholding gate voltages to +-10 V.
The optical negative resist ARN 4340 exhibits an undercut when developed. Usable as dry etch mask and lift-off resist, it enables an in-situ application of ohmic contacts first etching close to the QW, then metalizing AuGe. Up to 500 nm thickness, the undercut guarantees an a clean lift-off with no sidewalls.
The undertaken efforts have led to micro Hall bar measurements with Hall plateaus and SdH-oszillations in up to now unseen levels of detail.
The gap resistance of several micro Hall bars with a clear QSH signal have been presented in Quantum Spin Hall. The first to exhibit longitudinal resistances close to the expected h/2e2 since years, they reveal unprecedented details in features and characteristics. It has been shown that their protection against backscattering through time reversal symmetry is not as rigid as previously claimed. Values below and above 12.9 kΩ been explained, introducing backscattering within the Landauer-Büttiker formalism of edge channel transport. Possible reasons have been discussed. Kondo, interaction and Rashba-backscattering arising from density inhomogeneities close to the edge are most plausible to explain features on and deviations from a quantized value. Interaction, tunneling and dephasing mechanisms as well as puddle size, density of states and Rashba Fields are gate voltage dependent. Therefore, features in the QSH signal are fingerprints of the characteristic potential landscape.
Stable up to 11 K, two distinct but clear power laws have been found in the higher temperature dependence of the QSH in two samples. However, with ΔR = Tα, α = ¼ in one (QC0285) and α = 2 in the other (Q2745), none of the predicted dependencies could be confirmed. Whereas, the gap resistances of QC0285 remains QSH channel dominated up to 3.9 T and thereby confirmed the calculated lifting of the band inversion in magnetic field. The gate-dependent oscillating features in the QSH signal of Q2745 immediately increase in magnetic field. The distinct field dependencies allowed the assumption of two different dominant backscattering mechanisms.
Resulting in undisturbed magneto transport and unprecedented QSH measurements The Novel Micro Hall Bar Process has proven to enable the fabrication of a new generation of microstructures.
In the context of quantum mechanical calculations, the properties of non-adiabatic coupling in a small system, the Shin-Metiu model, is investigated.
The transition from adiabatic to non-adiabatic dynamics is elucidated in modifying the electron-nuclear interaction. This allows the comparison of weakly correlated electron-nuclear motion with the case where the strong correlations determine the dynamics.
The studies of the model are extended to include spectroscopical transitions being present in two-dimensional and degenerate four-wave mixing spectroscopy.
Furthermore, the quantum and classical time-evolution of the coupled motion in the complete electron-nuclear phase space is compared for the two coupling cases.
Additionally, the numerically exact electron flux within the weak coupling case is compared to the Born-Oppenheimer treatment.
In the last part of the thesis, the model is extended to two dimensions.
The system then possesses potential energy surfaces which exhibit a typical 'Mexican hat'-like structure and a conical intersection in the adiabatic representation.
Thus, it is possible to map properties of the system onto a vibronic coupling (Jahn-Teller) hamiltonian. Exact wave-packet propagations as well as nuclear wave-packet dynamics in the adiabatic and diabatic representation are performed.
Two-level emitters are the main building blocks of photonic quantum technologies and are model systems for the exploration of quantum optics in the solid state. Most interesting is the strict resonant excitation of such emitters to control their occupation coherently and to generate close to ideal quantum light, which is of utmost importance for applications in photonic quantum technology. To date, the approaches and experiments in this field have been performed exclusively using bulky lasers, which hinders the application of resonantly driven two-level emitters in compact photonic quantum systems. Here we address this issue and present a concept for a compact resonantly driven single-photon source by performing quantum-optical spectroscopy of a two-level system using a compact high-β microlaser as the excitation source. The two-level system is based on a semiconductor quantum dot (QD), which is excited resonantly by a fiber-coupled electrically driven micropillar laser. We dress the excitonic state of the QD under continuous wave excitation, and trigger the emission of single photons with strong multi-photon suppression (g\(^{(2)}\)(0)=0.02) and high photon indistinguishability (V = 57±9%) via pulsed resonant excitation at 156 MHz. These results clearly demonstrate the high potential of our resonant excitation scheme, which can pave the way for compact electrically driven quantum light sources with excellent quantum properties to enable the implementation of advanced quantum communication protocols.
Although questionable research practices (QRPs) and p-hacking have received attention in recent years, little research has focused on their prevalence and acceptance in students. Students are the researchers of the future and will represent the field in the future. Therefore, they should not be learning to use and accept QRPs, which would reduce their ability to produce and evaluate meaningful research. 207 psychology students and fresh graduates provided self-report data on the prevalence and predictors of QRPs. Attitudes towards QRPs, belief that significant results constitute better science or lead to better grades, motivation, and stress levels were predictors. Furthermore, we assessed perceived supervisor attitudes towards QRPs as an important predictive factor. The results were in line with estimates of QRP prevalence from academia. The best predictor of QRP use was students’ QRP attitudes. Perceived supervisor attitudes exerted both a direct and indirect effect via student attitudes. Motivation to write a good thesis was a protective factor, whereas stress had no effect. Students in this sample did not subscribe to beliefs that significant results were better for science or their grades. Such beliefs further did not impact QRP attitudes or use in this sample. Finally, students engaged in more QRPs pertaining to reporting and analysis than those pertaining to study design. We conclude that supervisors have an important function in shaping students’ attitudes towards QRPs and can improve their research practices by motivating them well. Furthermore, this research provides some impetus towards identifying predictors of QRP use in academia.
Background
Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC.
Methods
This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery.
Results
Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms.
Conclusions
Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.
Ras genes are among the most commonly mutated genes in human cancer; yet our understanding of their oncogenic activity at the molecular mechanistic level is incomplete. To identify downstream events that mediate ras-induced cellular transformation in vivo, we analyzed global microRNA expression in three different models of Ras-induction and tumor formation in zebrafish. Six microRNAs were found increased in Ras-induced melanoma, glioma and in an inducible model of ubiquitous Ras expression. The upregulation of the microRNAs depended on the activation of the ERK and AKT pathways and to a lesser extent, on mTOR signaling. Two Ras-induced microRNAs (miR-146a and 193a) target Jmjd6, inducing downregulation of its mRNA and protein levels at the onset of Ras expression during melanoma development. However, at later stages of melanoma progression, jmjd6 levels were found elevated. The dynamic of Jmjd6 levels during progression of melanoma in the zebrafish model suggests that upregulation of the microRNAs targeting Jmjd6 may be part of an anti-cancer response. Indeed, triple transgenic fish engineered to express a microRNA-resistant Jmjd6 from the onset of melanoma have increased tumor burden, higher infiltration of leukocytes and shorter melanoma-free survival. Increased JMJD6 expression is found in several human cancers, including melanoma, suggesting that the up-regulation of Jmjd6 is a critical event in tumor progression.
The following link has been created to allow review of record GSE37015: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jjcrbiuicyyqgpc&acc=GSE37015.
Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA (R) trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk.
Methods: CARMELINA (R) is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, >= 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA (R) was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided a-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure.
Results: Between July 2013 and August 2016, 6980 patients were randomized and took >= 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean +/- SD age was 65.8 +/- 9.1 years, HbA1c 7.9 +/- 1.0%, BMI 31.3 +/- 5.3 kg/m(2), and eGFR 55 +/- 25 mL/min/1.73 m(2). A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m(2) or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common.
Conclusions: CARMELINA (R) will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk.
The sequencing of several ant genomes within the last six years open new research avenues for understanding not only the genetic basis of social species but also the complex systems such as immune responses in general. Similar to other social insects, ants live in cooperative colonies, often in high densities and with genetically identical or closely related individuals. The contact behaviours and crowd living conditions allow the disease to spread rapidly through colonies. Nevertheless, ants can efficiently combat infections by using diverse and effective immune mechanisms. However, the components of the immune system of carpenter ant Camponotus floridanus and also the factors in bacteria that facilitate infection are not well understood.
To form a better view of the immune repository and study the C. floridanus immune responses against the bacteria, experimental data from Illumina sequencing and mass-spectrometry (MS) data of haemolymph in normal and infectious conditions were analysed and integrated with the several bioinformatics approaches. Briefly, the tasks were accomplished in three levels. First, the C. floridanus genome was re-annotated for the improvement of the existing annotation using the computational methods and transcriptomics data. Using the homology based methods, the extensive survey of literature, and mRNA expression profiles, the immune repository of C. floridanus were established. Second, large-scale protein-protein interactions (PPIs) and signalling network of C. floridanus were reconstructed and analysed and further the infection induced functional modules in the networks were detected by mapping of the expression data over the networks. In addition, the interactions of the immune components with the bacteria were identified by reconstructing inter-species PPIs networks and the interactions were validated by literature. Third, the stage-specific MS data of larvae and worker ants were analysed and the differences in the immune response were reported.
Concisely, all the three omics levels resulted to multiple findings, for instance, re-annotation and transcriptome profiling resulted in the overall improvement of structural and functional annotation and detection of alternative splicing events, network analysis revealed the differentially expressed topologically important proteins and the active functional modules, MS data analysis revealed the stage specific differences in C. floridanus immune responses against bacterial pathogens.
Taken together, starting from re-annotation of C. floridanus genome, this thesis provides a transcriptome and proteome level characterization of ant C. floridanus, particularly focusing on the immune system responses to pathogenic bacteria from a biological and a bioinformatics point of view. This work can serve as a model for the integration of omics data focusing on the immuno-transcriptome of insects.
Although it is becoming increasingly popular to monitor parameters related to training, recovery, and health with wearable sensor technology (wearables), scientific evaluation of the reliability, sensitivity, and validity of such data is limited and, where available, has involved a wide variety of approaches. To improve the trustworthiness of data collected by wearables and facilitate comparisons, we have outlined recommendations for standardized evaluation. We discuss the wearable devices themselves, as well as experimental and statistical considerations. Adherence to these recommendations should be beneficial not only for the individual, but also for regulatory organizations and insurance companies.