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Institute
- Theodor-Boveri-Institut für Biowissenschaften (84)
- Graduate School of Life Sciences (51)
- Physikalisches Institut (37)
- Institut für Psychologie (28)
- Institut für Anorganische Chemie (27)
- Institut für Organische Chemie (27)
- Institut für deutsche Philologie (24)
- Neuphilologisches Institut - Moderne Fremdsprachen (24)
- Neurologische Klinik und Poliklinik (24)
- Medizinische Klinik und Poliklinik II (23)
Schriftenreihe
Sonstige beteiligte Institutionen
- VolkswagenStiftung (24)
- Johns Hopkins School of Medicine (2)
- Bio-Imaging Center Würzburg (1)
- CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - the development agency of the Brazilian Federal Government (1)
- Center for Nanosystems Chemistry (CNC), Universität Würzburg (1)
- DAAD - Deutscher Akademischer Austauschdienst (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society (ESI) (1)
ResearcherID
- B-4606-2017 (1)
2D electrophysiology is often used to determine the electrical properties of neurons, while in the brain, neurons form extensive 3D networks. Thus, performing electrophysiology in a 3D environment provides a closer situation to the physiological condition and serves as a useful tool for various applications in the field of neuroscience. In this study, we established 3D electrophysiology within a fiber-reinforced matrix to enable fast readouts from transfected cells, which are often used as model systems for 2D electrophysiology. Using melt electrowriting (MEW) of scaffolds to reinforce Matrigel, we performed 3D electrophysiology on a glycine receptor-transfected Ltk-11 mouse fibroblast cell line. The glycine receptor is an inhibitory ion channel associated when mutated with impaired neuromotor behaviour. The average thickness of the MEW scaffold was 141.4 ± 5.7µm, using 9.7 ± 0.2µm diameter fibers, and square pore spacings of 100 µm, 200 µm and 400 µm. We demonstrate, for the first time, the electrophysiological characterization of glycine receptor-transfected cells with respect to agonist efficacy and potency in a 3D matrix. With the MEW scaffold reinforcement not interfering with the electrophysiology measurement, this approach can now be further adapted and developed for different kinds of neuronal cultures to study and understand pathological mechanisms under disease conditions.
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor.
Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.
Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.
Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
Honeybees (Apis mellifera) are threatened by numerous pathogens and parasites. To prevent infections they apply cooperative behavioral defenses, such as allo-grooming and hygiene, or they use antimicrobial plant resin. Resin is a chemically complex and highly variable mixture of many bioactive compounds. Bees collect the sticky material from different plant species and use it for nest construction and protection. Despite its importance for colony health, comparatively little is known about the precise origins and variability in resin spectra collected by honeybees. To identify the botanical resin sources of A. mellifera in Western Europe we chemically compared resin loads of individual foragers and tree resins. We further examined the resin intake of 25 colonies from five different apiaries to assess the effect of location on variation in the spectra of collected resin. Across all colonies and apiaries, seven distinct resin types were categorized according to their color and chemical composition. Matches between bee-collected resin and tree resin indicated that bees used poplar (Populus balsamifera, P. x canadensis), birch (Betula alba), horse chestnut (Aesculus hippocastanum) and coniferous trees (either Picea abies or Pinus sylvestris) as resin sources. Our data reveal that honeybees collect a comparatively broad and variable spectrum of resin sources, thus assuring protection against a variety of antagonists sensitive to different resins and/or compounds. We further unravel distinct preferences for specific resins and resin chemotypes, indicating that honeybees selectively search for bioactive resin compounds.
Background
The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking.
Results
Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1.
Conclusion
This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.
Chronic alcohol use leads to specific neurobiological alterations in the dopaminergic brain reward system, which probably are leading to a reward deficiency syndrome in alcohol dependence. The purpose of our study was to examine the effects of such hypothesized neurobiological alterations on the behavioral level, and more precisely on the implicit and explicit reward learning. Alcohol users were classified as dependent drinkers (using the DSM-IV criteria), binge drinkers (using criteria of the USA National Institute on Alcohol Abuse and Alcoholism) or low-risk drinkers (following recommendations of the Scientific board of trustees of the German Health Ministry). The final sample (n = 94) consisted of 36 low-risk alcohol users, 37 binge drinkers and 21 abstinent alcohol dependent patients. Participants were administered a probabilistic implicit reward learning task and an explicit reward- and punishment-based trial-and-error-learning task. Alcohol dependent patients showed a lower performance in implicit and explicit reward learning than low risk drinkers. Binge drinkers learned less than low-risk drinkers in the implicit learning task. The results support the assumption that binge drinking and alcohol dependence are related to a chronic reward deficit. Binge drinking accompanied by implicit reward learning deficits could increase the risk for the development of an alcohol dependence.
Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384–402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.
Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
A new strategy is demonstrated for the synthesis of warped, negatively curved, all‐sp\(^2\)‐carbon π‐scaffolds. Multifold C−C coupling reactions are used to transform a polyaromatic borinic acid into a saddle‐shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X‐ray crystallographic studies and pronounced flexibility of this π‐scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one‐electron oxidations at mild potentials.
Although usually asymptomatically colonizing the human nasopharynx, the Gram-negative bacterium Neisseria meningitidis (meningococcus) can spread to the blood stream and cause invasive disease. For survival in blood, N. meningitidis evades the complement system by expression of a polysaccharide capsule and surface proteins sequestering the complement regulator factor H (fH). Meningococcal strains belonging to the sequence type (ST-) 41/44 clonal complex (cc41/44) cause a major proportion of serogroup B meningococcal disease worldwide, but they are also common in asymptomatic carriers. Proteome analysis comparing cc41/44 isolates from invasive disease versus carriage revealed differential expression levels of the outer membrane protein NspA, which binds fH. Deletion of nspA reduced serum resistance and NspA expression correlated with fH sequestration. Expression levels of NspA depended on the length of a homopolymeric tract in the nspA promoter: A 5-adenosine tract dictated low NspA expression, whereas a 6-adenosine motif guided high NspA expression. Screening German cc41/44 strain collections revealed the 6-adenosine motif in 39% of disease isolates, but only in 3.4% of carriage isolates. Thus, high NspA expression is associated with disease, but not strictly required. The 6-adenosine nspA promoter is most common to the cc41/44, but is also found in other hypervirulent clonal complexes.
In this work models for molecular networks consisting of ordinary differential equations are extended by terms that include the interaction of the corresponding molecular network with the environment that the molecular network is embedded in. These terms model the effects of the external stimuli on the molecular network. The usability of this extension is demonstrated with a model of a circadian clock that is extended with certain terms and reproduces data from several experiments at the same time.
Once the model including external stimuli is set up, a framework is developed in order to calculate external stimuli that have a predefined desired effect on the molecular network. For this purpose the task of finding appropriate external stimuli is formulated as a mathematical optimal control problem for which in order to solve it a lot of mathematical methods are available. Several methods are discussed and worked out in order to calculate a solution for the corresponding optimal control problem. The application of the framework to find pharmacological intervention points or effective drug combinations is pointed out and discussed. Furthermore the framework is related to existing network analysis tools and their combination for network analysis in order to find dedicated external stimuli is discussed.
The total framework is verified with biological examples by comparing the calculated results with data from literature. For this purpose platelet aggregation is investigated based on a corresponding gene regulatory network and associated receptors are detected. Furthermore a transition from one to another type of T-helper cell is analyzed in a tumor setting where missing agents are calculated to induce the corresponding switch in vitro. Next a gene regulatory network of a myocardiocyte is investigated where it is shown how the presented framework can be used to compare different treatment strategies with respect to their beneficial effects and side effects quantitatively. Moreover a constitutively activated signaling pathway, which thus causes maleficent effects, is modeled and intervention points with corresponding treatment strategies are determined that steer the gene regulatory network from a pathological expression pattern to physiological one again.
Background
High-intensity interval training (HIIT) is frequently employed to improve the endurance of various types of athletes. To determine whether youth soccer players may benefit from the intermittent load and time efficiency of HIIT, we performed a meta-analysis of the relevant scientific literature.
Objectives
Our primary objective was to compare changes in various physiological parameters related to the performance of youth soccer players in response to running-based HIIT to the effects of other common training protocols (i.e., small-sided games, technical training and soccer-specific training, or high-volume endurance training). A secondary objective was to compare specifically running-based HIIT to a soccer-specific form of HIIT known as small-sided games (SSG) in this same respect, since this latter type of training is being discussed extensively by coaches.
Method
A systematic search of the PubMed, SPORTDiscus, and Web of Science databases was performed in August of 2017 and updated during the review process in December of 2018. The criteria for inclusion of articles for analysis were as follows: (1) comparison of HIIT to SSG or some other training protocol employing a pre-post design, (2) involvement of healthy young athletes (≤ 18 years old), and (3) assessment of variables related to endurance or soccer performance. Hedges’ g effect size (dppc2) and associated 95% confidence intervals for the comparison of the responses to HIIT and other interventions were calculated.
Results
Nine studies, involving 232 young soccer players (mean age 16.2 ± 1.6 years), were examined. Endurance training in the form of HIIT or SSG produced similar positive effects on most parameters assessed, including peak oxygen uptake and maximal running performance during incremental running (expressed as Vmax or maximal aerobic speed (MAS)), shuttle runs (expressed as the distance covered or time to exhaustion), and time-trials, as well as submaximal variables such as running economy and running velocity at the lactate threshold. HIIT induced a moderate improvement in soccer-related tests involving technical exercises with the soccer ball and other game-specific parameters (i.e., total distance covered, number of sprints, and number of involvements with the ball). Neuromuscular parameters were largely unaffected by HIIT or SSG.
Conclusion
The present meta-analysis indicates that HIIT and SSG have equally beneficial impacts on variables related to the endurance and soccer-specific performance of youth soccer players, but little influence on neuromuscular performance.
Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
Due to the complexityof research objects, theoretical concepts, and stimuli in media research, researchers in psychology and communications presumably need sophisticated measures beyond self-report scales to answer research questions on media use processes. The present study evaluates stimulus-dependent structure in spontaneous eye-blink behavior as an objective, corroborative measure for the media use phenomenon of spatial presence. To this end, a mixed methods approach is used in an experimental setting to collect, combine, analyze, and interpret data from standardized participant self-report, observation of participant behavior, and content analysis of the media stimulus. T-pattern detection is used to analyze stimulus-dependent blinking behavior, and this structural data is then contrasted with self-report data. The combined results show that behavioral indicators yield the predicted results, while self-report data shows unpredicted results that are not predicted by the underlying theory. The use of a mixed methods approach offered insights that support further theory development and theory testing beyond a traditional, mono-method experimental approach.
Background
Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
Methods
We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
Results
We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas.
Conclusions
The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
The culture of human induced pluripotent stem cells (hiPSCs) at large-scale becomes feasible with the aid of scalable suspension setups in continuously stirred tank reactors (CSTRs). Suspension cul- tures of hiPSCs are characterized by the self-aggregation of single cells into macroscopic cell aggre- gates that increase in size over time. The development of these free-floating aggregates is dependent on the culture vessel and thus represents a novel process parameter that is of particular interest for hiPSC suspension culture scaling. Further, aggregates surpassing a critical size are prone to spon- taneous differentiation or cell viability loss. In this regard, and, for the first time, a hiPSC-specific suspension culture unit was developed that utilizes in situ microscope imaging to monitor and to characterize hiPSC aggregation in one specific CSTR setup to a statistically significant degree while omitting the need for error-prone and time-intensive sampling. For this purpose, a small-scale CSTR system was designed and fabricated by fused deposition modeling (FDM) using an in-house 3D- printer. To provide a suitable cell culture environment for the CSTR system and in situ microscope, a custom-built incubator was constructed to accommodate all culture vessels and process control devices. Prior to manufacture, the CSTR design was characterized in silico for standard engineering parameters such as the specific power input, mixing time, and shear stress using computational fluid dynamics (CFD) simulations. The established computational model was successfully validated by comparing CFD-derived mixing time data to manual measurements. Proof for system functionality was provided in the context of long-term expansion (4 passages) of hiPSCs. Thereby, hiPSC aggregate size development was successfully tracked by in situ imaging of CSTR suspensions and subsequent automated image processing. Further, the suitability of the developed hiPSC culture unit was proven by demonstrating the preservation of CSTR-cultured hiPSC pluripotency on RNA level by qRT-PCR and PluriTest, and on protein level by flow cytometry.
The measurement of the mass of the $W$ boson is currently one of the most promising precision analyses of the Standard Model, that could ultimately reveal a hint for new physics.
The mass of the $W$ boson is determined by comparing the $W$ boson, which cannot be reconstructed directly, to the $Z$ boson, where the full decay signature is available. With the help of Monte Carlo simulations one can extrapolate from the $Z$ boson to the $W$ boson.
Technically speaking, the measurement of the $W$ boson mass is performed by comparing data taken by the ATLAS experiment to a set of calibrated Monte Carlo simulations, which reflect different mass hypotheses.\
A dedicated calibration of the reconstructed objects in the simulations is crucial for a high precision of the measured value.
The comparison of simulated $Z$ boson events to reconstructed $Z$ boson candidates in data allows to derive event weights and scale factors for the calibration.
This thesis presents a new approach to reweight the hadronic recoil in the simulations. The focus of the calibration is on the average hadronic activity visible in the mean of the scalar sum of the hadronic recoil $\Sigma E_T$ as a function of pileup. In contrast to the standard method, which directly reweights the scalar sum, the dependency to the transverse boson momentum is less strongly affected here.
The $\Sigma E_T$ distribution is modeled first by means of its pileup dependency. Then, the remaining differences in the resolution of the vector sum of the hadronic recoil are scaled. This is done separately for the parallel and the pterpendicular component of the hadronic recoil with respect to the reconstructed boson.
This calibration was developed for the dataset taken by the ATLAS experiment at a center of mass energy of $8\,\textrm{TeV}$ in 2012. In addition, the same reweighting procedure is applied to the recent dataset with a low pileup contribution, the \textit{lowMu} runs at $5\,\textrm{TeV}$ and at $13\,\textrm{TeV}$, taken by ATLAS in November 2017. The dedicated aspects of the reweighting procedure are presented in this thesis. It can be shown that this reweighting approach improves the agreement between data and the simulations effectively for all datasets.
The uncertainties of this reweighting approach as well as the statistical errors are evaluated for a $W$ mass measurement by a template fit to pseudodata for the \textit{lowMu} dataset. A first estimate of these uncertainties is given here. For the pfoEM algorithm a statistical uncertainty of $17\,\text{MeV}$ for the $5\,\textrm{TeV}$ dataset and of $18\,\text{MeV}$ for the $13\,\textrm{TeV}$ are found for the $W \rightarrow \mu \nu$ analysis. The systematic uncertainty introduced by the resolution scaling has the largest effect, a value of $15\,\text{MeV}$ is estimated for the $13\,\textrm{TeV}$ dataset in the muon channel.
Regardless of political boundaries, river basins are a functional unit of the Earth’s land surface and provide an abundance of resources for the environment and humans. They supply livelihoods supported by the typical characteristics of large river basins, such as the provision of freshwater, irrigation water, and transport opportunities. At the same time, they are impacted i.e., by human-induced environmental changes, boundary conflicts, and upstream–downstream inequalities. In the framework of water resource management, monitoring of river basins is therefore of high importance, in particular for researchers, stake-holders and decision-makers. However, land surface and surface water properties of many major river basins remain largely unmonitored at basin scale. Several inventories exist, yet consistent spatial databases describing the status of major river basins at global scale are lacking. Here, Earth observation (EO) is a potential source of spatial information providing large-scale data on the status of land surface properties. This review provides a comprehensive overview of existing research articles analyzing major river basins primarily using EO. Furthermore, this review proposes to exploit EO data together with relevant open global-scale geodata to establish a database and to enable consistent spatial analyses and evaluate past and current states of major river basins.
This thesis deals with a new so-called sequential quadratic Hamiltonian (SQH) iterative scheme to solve optimal control problems with differential models and cost functionals ranging from smooth to discontinuous and non-convex. This scheme is based on the Pontryagin maximum principle (PMP) that provides necessary optimality conditions for an optimal solution. In this framework, a Hamiltonian function is defined that attains its minimum pointwise at the optimal solution of the corresponding optimal control problem. In the SQH scheme, this Hamiltonian function is augmented by a quadratic penalty term consisting of the current control function and the control function from the previous iteration. The heart of the SQH scheme is to minimize this augmented Hamiltonian function pointwise in order to determine a control update. Since the PMP does not require any differ- entiability with respect to the control argument, the SQH scheme can be used to solve optimal control problems with both smooth and non-convex or even discontinuous cost functionals. The main achievement of the thesis is the formulation of a robust and efficient SQH scheme and a framework in which the convergence analysis of the SQH scheme can be carried out. In this framework, convergence of the scheme means that the calculated solution fulfills the PMP condition. The governing differential models of the considered optimal control problems are ordinary differential equations (ODEs) and partial differential equations (PDEs). In the PDE case, elliptic and parabolic equations as well as the Fokker-Planck (FP) equation are considered. For both the ODE and the PDE cases, assumptions are formulated for which it can be proved that a solution to an optimal control problem has to fulfill the PMP. The obtained results are essential for the discussion of the convergence analysis of the SQH scheme. This analysis has two parts. The first one is the well-posedness of the scheme which means that all steps of the scheme can be carried out and provide a result in finite time. The second part part is the PMP consistency of the solution. This means that the solution of the SQH scheme fulfills the PMP conditions. In the ODE case, the following results are obtained that state well-posedness of the SQH scheme and the PMP consistency of the corresponding solution. Lemma 7 states the existence of a pointwise minimum of the augmented Hamiltonian. Lemma 11 proves the existence of a weight of the quadratic penalty term such that the minimization of the corresponding augmented Hamiltonian results in a control updated that reduces the value of the cost functional. Lemma 12 states that the SQH scheme stops if an iterate is PMP optimal. Theorem 13 proves the cost functional reducing properties of the SQH control updates. The main result is given in Theorem 14, which states the pointwise convergence of the SQH scheme towards a PMP consistent solution. In this ODE framework, the SQH method is applied to two optimal control problems. The first one is an optimal quantum control problem where it is shown that the SQH method converges much faster to an optimal solution than a globalized Newton method. The second optimal control problem is an optimal tumor treatment problem with a system of coupled highly non-linear state equations that describe the tumor growth. It is shown that the framework in which the convergence of the SQH scheme is proved is applicable for this highly non-linear case. Next, the case of PDE control problems is considered. First a general framework is discussed in which a solution to the corresponding optimal control problem fulfills the PMP conditions. In this case, many theoretical estimates are presented in Theorem 59 and Theorem 64 to prove in particular the essential boundedness of the state and adjoint variables. The steps for the convergence analysis of the SQH scheme are analogous to that of the ODE case and result in Theorem 27 that states the PMP consistency of the solution obtained with the SQH scheme. This framework is applied to different elliptic and parabolic optimal control problems, including linear and bilinear control mechanisms, as well as non-linear state equations. Moreover, the SQH method is discussed for solving a state-constrained optimal control problem in an augmented formulation. In this case, it is shown in Theorem 30 that for increasing the weight of the augmentation term, which penalizes the violation of the state constraint, the measure of this state constraint violation by the corresponding solution converges to zero. Furthermore, an optimal control problem with a non-smooth L\(^1\)-tracking term and a non-smooth state equation is investigated. For this purpose, an adjoint equation is defined and the SQH method is used to solve the corresponding optimal control problem. The final part of this thesis is devoted to a class of FP models related to specific stochastic processes. The discussion starts with a focus on random walks where also jumps are included. This framework allows a derivation of a discrete FP model corresponding to a continuous FP model with jumps and boundary conditions ranging from absorbing to totally reflecting. This discussion allows the consideration of the drift-control resulting from an anisotropic probability of the steps of the random walk. Thereafter, in the PMP framework, two drift-diffusion processes and the corresponding FP models with two different control strategies for an optimal control problem with an expectation functional are considered. In the first strategy, the controls depend on time and in the second one, the controls depend on space and time. In both cases a solution to the corresponding optimal control problem is characterized with the PMP conditions, stated in Theorem 48 and Theorem 49. The well-posedness of the SQH scheme is shown in both cases and further conditions are discussed that ensure the convergence of the SQH scheme to a PMP consistent solution. The case of a space and time dependent control strategy results in a special structure of the corresponding PMP conditions that is exploited in another solution method, the so-called direct Hamiltonian (DH) method.
The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in ~1 h and describes the workflow in detail for use by researchers with limited bioinformatics training.
Background
Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ.
Methods
Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method.
Results
Median overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47–3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21–3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504).
Conclusions
Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.
This work deals with the development and application of novel quantum Monte Carlo methods to simulate fermion-boson models. Our developments are based on the path-integral formalism, where the bosonic degrees of freedom are integrated out exactly to obtain a retarded fermionic interaction. We give an overview of three methods that can be used to simulate retarded interactions. In particular, we develop a novel quantum Monte Carlo method with global directed-loop updates that solves the autocorrelation problem of previous approaches and scales linearly with system size. We demonstrate its efficiency for the Peierls transition in the Holstein model and discuss extensions to other fermion-boson models as well as spin-boson models. Furthermore, we show how with the help of generating functionals bosonic observables can be recovered directly from the Monte Carlo configurations. This includes estimators for the boson propagator, the fidelity susceptibility, and the specific heat of the Holstein model. The algorithmic developments of this work allow us to study the specific heat of the spinless Holstein model covering its entire parameter range. Its key features are explained from the single-particle spectral functions of electrons and phonons. In the adiabatic limit, the spectral properties are calculated exactly as a function of temperature using a classical Monte Carlo method and compared to results for the Su-Schrieffer-Heeger model.
The importance of Clinical Data Warehouses (CDW) has increased significantly in recent years as they support or enable many applications such as clinical trials, data mining, and decision making.
CDWs integrate Electronic Health Records which still contain a large amount of text data, such as discharge letters or reports on diagnostic findings in addition to structured and coded data like ICD-codes of diagnoses.
Existing CDWs hardly support features to gain information covered in texts.
Information extraction methods offer a solution for this problem but they have a high and long development effort, which can only be carried out by computer scientists.
Moreover, such systems only exist for a few medical domains.
This paper presents a method empowering clinicians to extract information from texts on their own. Medical concepts can be extracted ad hoc from e.g. discharge letters, thus physicians can work promptly and autonomously. The proposed system achieves these improvements by efficient data storage, preprocessing, and with powerful query features. Negations in texts are recognized and automatically excluded, as well as the context of information is determined and undesired facts are filtered, such as historical events or references to other persons (family history).
Context-sensitive queries ensure the semantic integrity of the concepts to be extracted.
A new feature not available in other CDWs is to query numerical concepts in texts and even filter them (e.g. BMI > 25).
The retrieved values can be extracted and exported for further analysis.
This technique is implemented within the efficient architecture of the PaDaWaN CDW and evaluated with comprehensive and complex tests.
The results outperform similar approaches reported in the literature.
Ad hoc IE determines the results in a few (milli-) seconds and a user friendly GUI enables interactive working, allowing flexible adaptation of the extraction.
In addition, the applicability of this system is demonstrated in three real-world applications at the Würzburg University Hospital (UKW).
Several drug trend studies are replicated: Findings of five studies on high blood pressure, atrial fibrillation and chronic renal failure can be partially or completely confirmed in the UKW. Another case study evaluates the prevalence of heart failure in inpatient hospitals using an algorithm that extracts information with ad hoc IE from discharge letters and echocardiogram report (e.g. LVEF < 45 ) and other sources of the hospital information system.
This study reveals that the use of ICD codes leads to a significant underestimation (31%) of the true prevalence of heart failure.
The third case study evaluates the consistency of diagnoses by comparing structured ICD-10-coded diagnoses with the diagnoses described in the diagnostic section of the discharge letter.
These diagnoses are extracted from texts with ad hoc IE, using synonyms generated with a novel method.
The developed approach can extract diagnoses from the discharge letter with a high accuracy and furthermore it can prove the degree of consistency between the coded and reported diagnoses.
Insulin-like growth factor-I (IGF-I) is a 70-amino acid polypeptide with a molecular weight of approximately 7.6 kDa acting as an anabolic effector. It is essential for tissue growth and remodeling. Clinically, it is used for the treatment of growth disorders and has been proposed for various other applications including musculoskeletal diseases. Unlike insulin, IGF-I is complexed to at least six high-affinity binding proteins (IGFBPs) exerting homeostatic effects by modulating IGF-I availability to its receptor (IGF-IR) on most cells in the body as well as changing the distribution of the growth factor within the organism.1-3 Short half-lived IGF-I have been the driving forces for the design of localized IGF-I depot systems or protein modification with enhanced pharmacokinetic properties. In this thesis, we endeavor to present a versatile biologic into which galenical properties were engineered through chemical synthesis, e.g., by site-specific coupling of biomaterials or complex composites to IGF-I. For that, we redesigned the therapeutic via genetic codon expansion resulting in an alkyne introduced IGF-I, thereby becoming a substrate for biorthogonal click chemistries yielding a site-specific decoration.
In this approach, an orthogonal pyrrolysine tRNA synthetase (PylRS)/tRNAPyl CUA pair was employed to direct the co-translational incorporation of an unnatural amino acid—¬propargyl-L-lysine (plk)—bearing a clickable alkyne functional handle into IGF-I in response to the amber stop codon (UAG) introduced into the defined position in the gene of interest. We summarized the systematic optimization of upstream and downstream process alike with the ultimate goal to increase the yield of plk modified IGF-I therapeutic, from the construction of gene fusions resulting in (i) Trx-plk-IGF-I fusion variants, (ii) naturally occurring pro-IGF-I protein (IGF-I + Ea peptide) (plk-IGF-I Ea), over the subsequent bacterial cultivation and protein extraction to the final chromatographic purification. The opportunities and hurdles of all of the above strategies were discussed. Evidence was provided that the wild-type IGF-I yields were pure by exploiting the advantages of the pHisTrx expression vector system in concert with a thrombin enzyme with its highly specific proteolytic digestion site and multiple-chromatography steps. The alkyne functionality was successfully introduced into IGF-I by amber codon suppression. The proper folding of plk-IGF-I Ea was assessed by WST-1 proliferation assay and the detection of phosphorylated AKT in MG-63 cell lysate. The purity of plk-IGF-I Ea was monitored with RP-HPLC and SDS-PAGE analysis. This work also showed site-specific coupling an alkyne in plk-IGF-I Ea by copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) with potent activities in vitro. The site-specific immobilization of plk-IGF-I Ea to the model carrier (i.e., agarose beads) resulted in enhanced cell proliferation and adhesion surrounding the IGF-I-presenting particles. Cell proliferation and differentiation were enhanced in the accessibility of IGF-I decorated beads, reflecting the multivalence on cellular performance.
Next, we aimed at effectively showing the disease environment by co-delivery of fibroblast growth factor 2 (FGF2) and IGF-I, deploying localized matrix metalloproteinases (MMPs) upregulation as a surrogate marker driving the response of the drug delivery system. For this purpose, we genetically engineered FGF2 variant containing an (S)-2-amino-6-(((2-azidoethoxy)carbonyl)amino)hexanoic acid incorporated at its N-terminus, followed by an MMPs-cleavable linker (PCL) and FGF2 sequence, thereby allowing site-directed, specific decoration of the resultant azide-PCL-FGF2 with the previously mentioned plk-IGF-I Ea to generate defined protein-protein conjugates with a PCL in between. The click reaction between plk-IGF-I Ea and azide-PCL-FGF2 was systematically optimized to increase the yield of IGF-FGF conjugates, including reaction temperature, incubation duration, the addition of anionic detergent, and different ratios of the participating biopharmaceutics. The challenge here was that CuAAC reaction components or conditions might oxidize free cysteines of azide-PCL-FGF2 and future work needs to present the extent of activity retention after conjugation. Furthermore, our study provides potential options for dual-labeling of IGF-I either by the introduction of unnatural amino acids within two distinct positions of the protein of interest for parallel “double-click” labeling of the resultant plk-IGF-I Ea-plk or by using a combination of enzymatic-catalyzed and CuAAC bioorthogonal coupling strategies for sequentially dual-labeling of plk-IGF-I Ea.
In conclusion, genetic code expansion in combination with click-chemistry provides the fundament for novel IGF-I analogs allowing unprecedented site specificity for decoration. Considerable progress towards IGF-I based therapies with enhanced pharmacological properties was made by demonstrating the feasibility of the expression of plk incorporated IGF-I using E. coli and retained activity of unconjugated and conjugated IGF-I variant. Dual-labeling of IGF-I provides further insights into the functional requirements of IGF-I. Still, further investigation warrants to develop precise IGF-I therapy through unmatched temporal and spatial regulation of the pleiotropic IGF-I.
Previous magnetic resonance imaging (MRI) studies revealed structural-functional brain reorganization 12 months after gastric-bypass surgery, encompassing cortical and subcortical regions of all brain lobes as well as the cerebellum. Changes in the mean of cluster-wise gray/white matter density (GMD/WMD) were correlated with the individual loss of body mass index (BMI), rendering the BMI a potential marker of widespread surgery-induced brain plasticity. Here, we investigated voxel-by-voxel associations between surgery-induced changes in adiposity, metabolism and inflammation and markers of functional and structural neural plasticity. We re-visited the data of patients who underwent functional and structural MRI, 6 months (n = 27) and 12 months after surgery (n = 22), and computed voxel-wise regression analyses. Only the surgery-induced weight loss was significantly associated with brain plasticity, and this only for GMD changes. After 6 months, weight loss overlapped with altered GMD in the hypothalamus, the brain's homeostatic control site, the lateral orbitofrontal cortex, assumed to host reward and gustatory processes, as well as abdominal representations in somatosensory cortex. After 12 months, weight loss scaled with GMD changes in right cerebellar lobule VII, involved in language-related/cognitive processes, and, by trend, with the striatum, assumed to underpin (food) reward. These findings suggest time-dependent and weight-loss related gray matter plasticity in brain regions involved in the control of eating, sensory processing and cognitive functioning.
Advanced Analytics in Operations Management and Information Systems: Methods and Applications
(2019)
The digital transformation of business and society presents enormous potentials for companies across all sectors. Fueled by massive advances in data generation, computing power, and connectivity, modern organizations have access to gigantic amounts of data. Companies seek to establish data-driven decision cultures to leverage competitive advantages in terms of efficiency and effectiveness. While most companies focus on descriptive tools such as reporting, dashboards, and advanced visualization, only a small fraction already leverages advanced analytics (i.e., predictive and prescriptive analytics) to foster data-driven decision-making today. Therefore, this thesis set out to investigate potential opportunities to leverage prescriptive analytics in four different independent parts.
As predictive models are an essential prerequisite for prescriptive analytics, the first two parts of this work focus on predictive analytics. Building on state-of-the-art machine learning techniques, we showcase the development of a predictive model in the context of capacity planning and staffing at an IT consulting company. Subsequently, we focus on predictive analytics applications in the manufacturing sector. More specifically, we present a data science toolbox providing guidelines and best practices for modeling, feature engineering, and model interpretation to manufacturing decision-makers. We showcase the application of this toolbox on a large data-set from a German manufacturing company.
Merely using the improved forecasts provided by powerful predictive models enables decision-makers to generate additional business value in some situations. However, many complex tasks require elaborate operational planning procedures. Here, transforming additional information into valuable actions requires new planning algorithms. Therefore, the latter two parts of this thesis focus on prescriptive analytics. To this end, we analyze how prescriptive analytics can be utilized to determine policies for an optimal searcher path problem based on predictive models. While rapid advances in artificial intelligence research boost the predictive power of machine learning models, a model uncertainty remains in most settings. The last part of this work proposes a prescriptive approach that accounts for the fact that predictions are imperfect and that the arising uncertainty needs to be considered. More specifically, it presents a data-driven approach to sales-force scheduling. Based on a large data set, a model to predictive the benefit of additional sales effort is trained. Subsequently, the predictions, as well as the prediction quality, are embedded into the underlying team orienteering problem to determine optimized schedules.
Since its first experimental implementation in 2005, single-molecule localization microscopy (SMLM) emerged as a versatile and powerful imaging tool for biological structures with nanometer resolution. By now, SMLM has compiled an extensive track-record of novel insights in sub- and inter- cellular organization.\\
Moreover, since all SMLM techniques rely on the analysis of emission patterns from isolated fluorophores, they inherently allocate molecular information $per$ $definitionem$.\\
Consequently, SMLM transitioned from its origin as pure high-resolution imaging instrument towards quantitative microscopy, where the key information medium is no longer the highly resolved image itself, but the raw localization data set.\\
The work presented in this thesis is part of the ongoing effort to translate those $per$ $se$ molecular information gained by SMLM imaging to insights into the structural organization of the targeted protein or even beyond. Although largely consistent in their objectives, the general distinction between global or segmentation clustering approaches on one side and particle averaging or meta-analyses techniques on the other is usually made.\\
During the course of my thesis, I designed, implemented and employed numerous quantitative approaches with varying degrees of complexity and fields of application.\\ \\
In my first major project, I analyzed the localization distribution of the integral protein gp210 of the nuclear pore complex (NPC) with an iterative \textit{k}-means algorithm. Relating the distinct localization statistics of separated gp210 domains to isolated fluorescent signals led, among others, to the conclusion that the anchoring ring of the NPC consists of 8 homo-dimers of gp210.\\
This is of particular significance, both because it answered a decades long standing question about the nature of the gp210 ring and it showcased the possibility to gain structural information well beyond the resolution capabilities of SMLM by crafty quantification approaches.\\ \\
The second major project reported comprises an extensive study of the synaptonemal complex (SNC) and linked cohesin complexes. Here, I employed a multi-level meta-analysis of the localization sets of various SNC proteins to facilitate the compilation of a novel model of the molecular organization of the major SNC components with so far unmatched extend and detail with isotropic three-dimensional resolution.\\
In a second venture, the two murine cohesin components SMC3 and STAG3 connected to the SNC were analyzed. Applying an adapted algorithm, considering the disperse nature of cohesins, led to the realization that there is an apparent polarization of those cohesin complexes in the SNC, as well as a possible sub-structure of STAG3 beyond the resolution capabilities of SMLM.\\ \\
Other minor projects connected to localization quantification included the study of plasma membrane glycans regarding their overall localization distribution and particular homogeneity as well as the investigation of two flotillin proteins in the membrane of bacteria, forming clusters of distinct shapes and sizes.\\ \\
Finally, a novel approach to three-dimensional SMLM is presented, employing the precise quantification of single molecule emitter intensities. This method, named TRABI, relies on the principles of aperture photometry which were improved for SMLM.\\
With TRABI it was shown, that widely used Gaussian fitting based localization software underestimates photon counts significantly. This mismatch was utilized as a $z$-dependent parameter, enabling the conversion of 2D SMLM data to a virtual 3D space. Furthermore it was demonstrated, that TRABI can be combined beneficially with a multi-plane detection scheme, resulting in superior performance regarding axial localization precision and resolution.\\
Additionally, TRABI has been subsequently employed to photometrically characterize a novel dye for SMLM, revealing superior photo-physical properties at the single-molecule level.\\
Following the conclusion of this thesis, the TRABI method and its applications remains subject of diverse ongoing research.
Background
Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response.
Results
Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI.
Conclusions
Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.
Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF‐α is CEACAM1‐dependently upregulated in the aging vasculature. Vice versa, TNF‐α induces CEACAM1 expression. This results in a feed‐forward loop in the aging vasculature that maintains a chronic pro‐inflammatory milieu. Furthermore, we demonstrate that age‐associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age‐dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR‐2 signaling. Consequently, aging‐related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.
Allopolyploid plants are long known to be subject to a homoeolog expression bias of varying degree. The same phenomenon was only much later suspected to occur also in animals based on studies of single selected genes in an allopolyploid vertebrate, the Iberian fish Squalius alburnoides. Consequently, this species became a good model for understanding the evolution of gene expression regulation in polyploid vertebrates. Here, we analyzed for the first time genome-wide allele-specific expression data from diploid and triploid hybrids of S. alburnoides and compared homoeolog expression profiles of adult livers and of juveniles. Co-expression of alleles from both parental genomic types was observed for the majority of genes, but with marked homoeolog expression bias, suggesting homoeolog specific reshaping of expression level patterns in hybrids. Complete silencing of one allele was also observed irrespective of ploidy level, but not transcriptome wide as previously speculated. Instead, it was found only in a restricted number of genes, particularly ones with functions related to mitochondria and ribosomes. This leads us to hypothesize that allelic silencing may be a way to overcome intergenomic gene expression interaction conflicts, and that homoeolog expression bias may be an important mechanism in the achievement of sustainable genomic interactions, mandatory to the success of allopolyploid systems, as in S. alburnoides.
Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 x 10(4)-5 x 10(6) CD3(+) cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0 center dot 3-2 x 10(6) CD3(+) cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.
We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n =187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice.
The membrane protein EsaA is a conserved component of the type VIIb secretion system. Limited proteolysis of purified EsaA from Staphylococcus aureus USA300 identified a stable 48 kDa fragment, which was mapped by fingerprint mass spectrometry to an uncharacterized extracellular segment of EsaA. Analysis by circular dichroism spectroscopy showed that this fragment folds into a single stable domain made of mostly α‐helices with a melting point of 34.5°C. Size‐exclusion chromatography combined with multi‐angle light scattering indicated the formation of a dimer of the purified extracellular domain. Octahedral crystals were grown in 0.2 M ammonium citrate tribasic pH 7.0, 16% PEG 3350 using the hanging‐drop vapor‐diffusion method. Diffraction data were analyzed to 4.0 Å resolution, showing that the crystals belonged to the enantiomorphic tetragonal space groups P41212 or P43212, with unit‐cell parameters a = 197.5, b = 197.5, c = 368.3 Å, α = β = γ = 90°.
Background:
Employees insured in pension insurance, who are incapable of working due to ill health, are entitled to a disability pension. To assess whether an individual meets the medical requirements to be considered as disabled, a work capacity evaluation is conducted. However, there are no official guidelines on how to perform an external quality assurance for this evaluation process. Furthermore, the quality of medical reports in the field of insurance medicine can vary substantially, and systematic evaluations are scarce. Reliability studies using peer review have repeatedly shown insufficient ability to distinguish between high, moderate and low quality. Considering literature recommendations, we developed an instrument to examine the quality of medical experts’reports.
Methods:
The peer review manual developed contains six quality domains (formal structure, clarity, transparency, completeness, medical-scientific principles, and efficiency) comprising 22 items. In addition, a superordinate criterion (survey confirmability) rank the overall quality and usefulness of a report. This criterion evaluates problems of innerlogic and reasoning. Development of the manual was assisted by experienced physicians in a pre-test. We examined the observable variance in peer judgements and reliability as the most important outcome criteria. To evaluate inter-rater reliability, 20 anonymous experts’ reports detailing the work capacity evaluation were reviewed by 19 trained raters (peers). Percentage agreement and Kendall’s W, a reliability measure of concordance between two or more peers, were calculated. A total of 325 reviews were conducted.
Results:
Agreement of peer judgements with respect to the superordinate criterion ranged from 29.2 to 87.5%. Kendall’s W for the quality domain items varied greatly, ranging from 0.09 to 0.88. With respect to the superordinate criterion, Kendall’s W was 0.39, which indicates fair agreement. The results of the percentage agreement revealed systemic peer preferences for certain deficit scale categories.
Conclusion:
The superordinate criterion was not sufficiently reliable. However, in comparison to other reliability studies, this criterion showed an equivalent reliability value. This report aims to encourage further efforts to improve evaluation instruments. To reduce disagreement between peer judgments, we propose the revision of the peer review instrumentand the development and implementation of a standardized rater training to improve reliability.
The heterotrimeric protein kinase SNF1 plays a key role in the metabolic adaptation of the pathogenic yeast Candida albicans. It consists of the essential catalytic α-subunit Snf1, the γ-subunit Snf4, and one of the two β-subunits Kis1 and Kis2. Snf4 is required to release the N-terminal catalytic domain of Snf1 from autoinhibition by the C-terminal regulatory domain, and snf4Δ mutants cannot grow on carbon sources other than glucose. In a screen for suppressor mutations that restore growth of a snf4Δ mutant on alternative carbon sources, we isolated a mutant in which six amino acids between the N-terminal kinase domain and the C-terminal regulatory domain of Snf1 were deleted. The deletion was caused by an intragenic recombination event between two 8-bp direct repeats flanking six intervening codons. In contrast to truncated forms of Snf1 that contain only the kinase domain, the Snf4-independent Snf1\(^{Δ311 − 316}\) was fully functional and could replace wild-type Snf1 for normal growth, because it retained the ability to interact with the Kis1 and Kis2 β-subunits via its C-terminal domain. Indeed, the Snf4-independent Snf1\(^{Δ311 − 316}\) still required the β-subunits of the SNF1 complex to perform its functions and did not rescue the growth defects of kis1Δ mutants. Our results demonstrate that a preprogrammed in-frame deletion event within the SNF1 coding region can generate a mutated form of this essential kinase which abolishes autoinhibition and thereby overcomes growth deficiencies caused by a defect in the γ-subunit Snf4.
Maps are the main tool to represent geographical information. Users often zoom in and out to access maps at different scales. Continuous map generalization tries to make the changes between different scales smooth, which is essential to provide users with comfortable zooming experience.
In order to achieve continuous map generalization with high quality, we optimize some important aspects of maps. In this book, we have used optimization in the generalization of land-cover areas, administrative boundaries, buildings, and coastlines. According to our experiments, continuous map generalization indeed benefits from optimization.
A series of seven unusual dimeric naphthylisoquinoline alkaloids was isolated from the leaves of the tropical liana Ancistrocladus ealaensis J. Léonard, named cyclombandakamine A (1), 1-epi-cyclombandakamine A (2), and cyclombandakamines A3–7 (3–7). These alkaloids have a chemically thrilling structural array consisting of a twisted dihydrofuran-cyclohexenone-isochromene system. The 1′″-epimer of 4, cyclombandakamine A1 (8), had previously been discovered in an unidentified Ancistrocladus species related to A. ealaensis. Both lianas produce the potential parent precursor, mbandakamine A (9), but only A. ealaensis synthesizes the corresponding cyclized form, along with a broad series of slightly modified analogs. The challenging isolation required, besides multi-dimensional chromatography, the use of a pentafluorophenyl stationary phase. Featuring up to six stereocenters and two types of chiral axes, their structures were elucidated by means of 1D and 2D NMR, HRESIMS, in combination with oxidative chemical degradation experiments as well as chiroptical (electronic circular dichroism spectroscopy) and quantum chemical calculations. Compared to the ‘open-chain’ parent compound 9, these dimers displayed rather moderate antiplasmodial activities.
Background:
Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125g dosed every 2weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6years was shown.
Main text
In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted.
Conclusions
This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience.
In mammals the melanocortin 4 receptor (Mc4r) signaling system has been mainly associated with the regulation of appetite and energy homeostasis. In fish of the genus Xiphophorus (platyfish and swordtails) puberty onset is genetically determined by a single locus, which encodes the mc4r. Wild populations of Xiphophorus are polymorphic for early and late-maturing individuals. Copy number variation of different mc4r alleles is responsible for the difference in puberty onset. To answer whether this is a special adaptation of the Mc4r signaling system in the lineage of Xiphophorus or a more widely conserved mechanism in teleosts, we studied the role of Mc4r in reproductive biology of medaka (Oryzias latipes), a close relative to Xiphophorus and a well-established model to study gonadal development. To understand the potential role of Mc4r in medaka, we characterized the major features of the Mc4r signaling system (mc4r, mrap2, pomc, agrp1). In medaka, all these genes are expressed before hatching. In adults, they are mainly expressed in the brain. The transcript of the receptor accessory protein mrap2 co-localizes with mc4r in the hypothalamus in adult brains indicating a conserved function of modulating Mc4r signaling. Comparing growth and puberty between wild-type and mc4r knockout medaka revealed that absence of Mc4r does not change puberty timing but significantly delays hatching. Embryonic development of knockout animals is retarded compared to wild-types. In conclusion, the Mc4r system in medaka is involved in regulation of growth rather than puberty.
Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin-conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.
A unique series of six biaryl natural products displaying four different coupling types (5,10 , 7,10 , 7,80 , and 5,80) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A–D (12–14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and entdioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A–D (12–14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical ‘Ancistrocladaceae-type’ compounds. Ancistrobreveine C (14), is the first – and so far only – example of a 7,80-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrugresistant subline, CEM/ADR5000.
In plants, antimicrobial immune responses involve the cellular release of anions and are responsible for the closure of stomatal pores. Detection of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) induces currents mediated via slow-type (S-type) anion channels by a yet not understood mechanism. Here, we show that stomatal closure to fungal chitin is conferred by the major PRRs for chitin recognition, LYK5 and CERK1, the receptor-like cytoplasmic kinase PBL27, and the SLAH3 anion channel. PBL27 has the capacity to phosphorylate SLAH3, of which S127 and S189 are required to activate SLAH3. Full activation of the channel entails CERK1, depending on PBL27. Importantly, both S127 and S189 residues of SLAH3 are required for chitin-induced stomatal closure and anti-fungal immunity at the whole leaf level. Our results demonstrate a short signal transduction module from MAMP recognition to anion channel activation, and independent of ABA-induced SLAH3 activation.
In the treatment of bone non-unions, an alternative to bone autografts is the use of bone morphogenetic proteins (BMPs), e.g., BMP–2, BMP–7, with powerful osteoinductive and osteogenic properties. In clinical settings, these osteogenic factors are applied using absorbable collagen sponges for local controlled delivery. Major side effects of this strategy are derived from the supraphysiological doses of BMPs needed, which may induce ectopic bone formation, chronic inflammation, and excessive bone resorption. In order to increase the efficiency of the delivered BMPs, we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic) or trabecular bone (random distributed porosity, isotropic). We hypothesize that an anisotropic structure would enhance the osteoconductive properties of the scaffolds by increasing the regenerative performance of the provided rhBMP–2. In vitro, both scaffolds presented similar mechanical properties, rhBMP–2 retention and delivery capacity, as well as scaffold degradation time. In vivo, anisotropic scaffolds demonstrated better bone regeneration capabilities in a rat femoral critical-size defect model by increasing the defect bridging. In conclusion, anisotropic cryostructured collagen scaffolds improve bone regeneration by increasing the efficiency of rhBMP–2 mediated bone healing.
o build, run, and maintain reliable manufacturing machines, the condition of their components has to be continuously monitored. When following a fine-grained monitoring of these machines, challenges emerge pertaining to the (1) feeding procedure of large amounts of sensor data to downstream processing components and the (2) meaningful analysis of the produced data. Regarding the latter aspect, manifold purposes are addressed by practitioners and researchers. Two analyses of real-world datasets that were generated in production settings are discussed in this paper. More specifically, the analyses had the goals (1) to detect sensor data anomalies for further analyses of a pharma packaging scenario and (2) to predict unfavorable temperature values of a 3D printing machine environment. Based on the results of the analyses, it will be shown that a proper management of machines and their components in industrial manufacturing environments can be efficiently supported by the detection of anomalies. The latter shall help to support the technical evangelists of the production companies more properly.
The green synthesis of silver nanoparticles (SNPs) using plant extracts is an eco-friendly method. It is a single step and offers several advantages such as time reducing, cost-effective and environmental non-toxic. Silver nanoparticles are a type of Noble metal nanoparticles and it has tremendous applications in the field of diagnostics, therapeutics, antimicrobial activity, anticancer and neurodegenerative diseases. In the present work, the aqueous extracts of aerial parts of Lampranthus coccineus and Malephora lutea F. Aizoaceae were successfully used for the synthesis of silver nanoparticles. The formation of silver nanoparticles was early detected by a color change from pale yellow to reddish-brown color and was further confirmed by transmission electron microscope (TEM), UV–visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), and energy-dispersive X-ray diffraction (EDX). The TEM analysis of showed spherical nanoparticles with a mean size between 12.86 nm and 28.19 nm and the UV- visible spectroscopy showed λ\(_{max}\) of 417 nm, which confirms the presence of nanoparticles. The neuroprotective potential of SNPs was evaluated by assessing the antioxidant and cholinesterase inhibitory activity. Metabolomic profiling was performed on methanolic extracts of L. coccineus and M. lutea and resulted in the identification of 12 compounds, then docking was performed to investigate the possible interaction between the identified compounds and human acetylcholinesterase, butyrylcholinesterase, and glutathione transferase receptor, which are associated with the progress of Alzheimer’s disease. Overall our SNPs highlighted its promising potential in terms of anticholinesterase and antioxidant activity as plant-based anti-Alzheimer drug and against oxidative stress.
Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model
(2019)
Background:
Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown.
Methods:
In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison.
Results:
Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1.
Conclusions:
Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.
From the leaves of a botanically and phytochemically as yet unexplored Ancistrocladus liana discovered in the rainforests of the Central region of the Democratic Republic of the Congo in the vicinity of the town of Ikela, six new naphthylisoquinoline alkaloids were isolated, viz., two constitutionally unsymmetric dimers, the mbandakamines B\(_3\) (3) and B\(_4\) (4), and four related 5,8′-linked monomeric alkaloids, named ikelacongolines A–D (5a, 5b, 6, and 7). The dimers 3 and 4 are structurally unusual quateraryls comprising two 5,8′-coupled monomers linked via a sterically strongly constrained 6′,1′′-connection between their naphthalene units. These compounds contain seven elements of chirality, four stereogenic centers and three consecutive chiral axes. They were identified along with two known related compounds, the mbandakamines A (1) and B\(_2\) (2), which had so far only been detected in two Ancistrocladus species indigenous to the Northwestern Congo Basin. In addition, five known monomeric alkaloids, previously found in related Central African Ancistrocladus species, were isolated from the here investigated Congolese liana, three of them belonging to the subclass of 5,8′-coupled naphthylisoquinoline alkaloids, whereas two compounds exhibited a less frequently occurring 7,8′-biaryl linkage. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR), chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. The mbandakamines B\(_3\) (3) and B\(_4\) (4) displayed pronounced activities in vitro against the malaria parasite Plasmodium falciparum and the pathogen of African sleeping sickness, Trypanosoma brucei rhodesiense.
Objective
To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms.
Methods
Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays.
Results
Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti–NF-155 IgG4 were directed against the NF-155–specific Fn3Fn4 domain. The description of a second phenotype of anti–NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year.
Conclusions
Our results indicate that anti–pan-NF-associated neuropathy differs from anti–NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti–NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.
Predation on pest organisms is an essential ecosystem function supporting yields in modern agriculture. However, assessing predation rates is intricate, and they can rarely be linked directly to predator densities or functions. We tested whether sentinel prey aphid cards are useful tools to assess predation rates in the field. Therefore, we looked at aphid cards of different sizes on the ground level as well as within the vegetation. Additionally, by trapping ground‐dwelling predators, we examined whether obtained predation rates could be linked to predator densities and traits. Predation rates recorded with aphid cards were independent of aphid card size. However, predation rates on the ground level were three times higher than within the vegetation. We found both predatory carabid activity densities as well as community weighted mean body size to be good predictors for predation rates. Predation rates obtained from aphid cards are stable over card type and related to predator assemblages. Aphid cards, therefore, are a useful, efficient method for rapidly assessing the ecosystem function predation. Their use might especially be recommended for assessments on the ground level and when time and resource limitations rule out more elaborate sentinel prey methods using exclosures with living prey animals.
Bulb, leaf, scape and flower samples of British bluebells (Hyacinthoides non-scripta) were collected regularly for one growth period. Methanolic extracts of freeze-dried and ground samples showed antitrypanosomal activity, giving more than 50% inhibition, for 20 out of 41 samples. High-resolution mass spectrometry was used in the dereplication of the methanolic extracts of the different plant parts. The results revealed differences in the chemical profile with bulb samples being distinctly different from all aerial parts. High molecular weight metabolites were more abundant in the flowers, shoots and leaves compared to smaller molecular weight ones in the bulbs. The anti-trypanosomal activity of the extracts was linked to the accumulation of high molecular weight compounds, which were matched with saponin glycosides, while triterpenoids and steroids occurred in the inactive extracts. Dereplication studies were employed to identify the significant metabolites via chemotaxonomic filtration and considering their previously reported bioactivities. Molecular networking was implemented to look for similarities in fragmentation patterns between the isolated saponin glycoside at m/z 1445.64 [M + formic-H](-) equivalent to C64H104O33 and the putatively found active metabolite at m/z 1283.58 [M + formic-H](-) corresponding to scillanoside L-1. A combination of metabolomics and bioactivity-guided approaches resulted in the isolation of a norlanostane-type saponin glycoside with antitrypanosoma I activity of 98.9% inhibition at 20 mu M.
Approaches to mimic the complexity of the skeletal mesenchymal stem/stromal cell niche in vitro
(2019)
Mesenchymal stem/stromal cells (MSCs) are an essential element of most modern tissue engineering and regenerative medicine approaches due to their multipotency and immunoregulatory functions. Despite the prospective value of MSCs for the clinics, the stem cells community is questioning their developmental origin, in vivo localization, identification, and regenerative potential after several years of far-reaching research in the field. Although several major progresses have been made in mimicking the complexity of the MSC niche in vitro, there is need for comprehensive studies of fundamental mechanisms triggered by microenvironmental cues before moving to regenerative medicine cell therapy applications. The present comprehensive review extensively discusses the microenvironmental cues that influence MSC phenotype and function in health and disease – including cellular, chemical and physical interactions. The most recent and relevant illustrative examples of novel bioengineering approaches to mimic biological, chemical, and mechanical microenvironmental signals present in the native MSC niche are summarized, with special emphasis on the forefront techniques to achieve bio-chemical complexity and dynamic cultures. In particular, the skeletal MSC niche and applications focusing on the bone regenerative potential of MSC are addressed. The aim of the review was to recognize the limitations of the current MSC niche in vitro models and to identify potential opportunities to fill the bridge between fundamental science and clinical application of MSCs.
Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL).
Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values.
Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95% CI 1.12–11.18, p = 0.03), female sex (OR 3.11, 95% CI 1.19–8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95% CI 1.16–6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95% CI 0.93–5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs.
Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.
Cristae architecture is important for the function of mitochondria, the organelles that play the central role in many cellular processes. The mitochondrial contact site and cristae organizing system (MICOS) together with the sorting and assembly machinery (SAM) forms the mitochondrial intermembrane space bridging complex (MIB), a large protein complex present in mammalian mitochondria that partakes in the formation and maintenance of cristae. We report here a new subunit of the mammalian MICOS/MIB complex, an armadillo repeat-containing protein 1 (ArmC1). ArmC1 localizes both to cytosol and mitochondria, where it associates with the outer mitochondrial membrane through its carboxy-terminus. ArmC1 interacts with other constituents of the MICOS/MIB complex and its amounts are reduced upon MICOS/MIB complex depletion. Mitochondria lacking ArmC1 do not show defects in cristae structure, respiration or protein content, but appear fragmented and with reduced motility. ArmC1 represents therefore a peripheral MICOS/MIB component that appears to play a role in mitochondrial distribution in the cell.
Both low-level physical saliency and social information, as presented by human heads or bodies, are known to drive gaze behavior in free-viewing tasks. Researchers have previously made use of a great variety of face stimuli, ranging from photographs of real humans to schematic faces, frequently without systematically differentiating between the two. In the current study, we used a Generalized Linear Mixed Model (GLMM) approach to investigate to what extent schematic artificial faces can predict gaze when they are presented alone or in competition with real human faces. Relative differences in predictive power became apparent, while GLMMs suggest substantial effects for real and artificial faces in all conditions. Artificial faces were accordingly less predictive than real human faces but still contributed significantly to gaze allocation. These results help to further our understanding of how social information guides gaze in complex naturalistic scenes.
The quest for finding a unifying theory for both quantum theory and gravity lies at the heart of much of the research in high energy physics. Although recent years have witnessed spectacular experimental confirmation of our expectations from Quantum Field Theory and General Relativity, the question of unification remains as a major open problem. In this context, the perturbative aspects of quantum black holes represent arguably the best of our knowledge of how to proceed in this pursue.
In this thesis we investigate certain aspects of quantum gravity in 2 + 1 dimensional anti-de Sitter space (AdS3), and its connection to Conformal field theories in 1 + 1 dimensions (CFT2), via the AdS/CFT correspondence.
We study the thermodynamics properties of higher spin black holes. By focusing on the spin-4 case, we show that black holes carrying higher spin charges display a rich phase diagram in the grand canonical ensemble, including phase transitions of the Hawking-Page type, first order inter-black hole transitions, and a second order critical point.
We investigate recent proposals on the connection between bulk codimension-1 volumes and computational complexity in the CFT. Using Tensor Networks we provide concrete evidence of why these bulk volumes are related to the number of gates in a quantum circuit, and exhibit their topological properties. We provide a novel formula to compute this complexity directly in terms of entanglement entropies, using techniques from Kinematic space.
We then move in a slightly different direction, and study the quantum properties of black holes via de Functional Renormalisation Group prescription coming from Asymptotic safety. We avoid the arbitrary scale setting by restricting to a narrower window in parameter space, where only Newton’s coupling and the cosmological constant are allowed to vary. By one assumption on the properties of Newton’s coupling, we find black hole solutions explicitly. We explore their thermodynamical properties, and discover that very large black holes exhibit very unusual features.
Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the adaptable saprophytic fungus Aspergillus fumigatus. The healthy human immune system is capable to ward off A. fumigatus infections however immune-deficient patients are highly vulnerable to invasive aspergillosis. A. fumigatus can persist during infection due to its ability to survive the immune response of human DCs. Therefore, the study of the metabolism specific to the context of infection may allow us to gain insight into the adaptation strategies of both the pathogen and the immune cells. We established a metabolic model of A. fumigatus central metabolism during infection of DCs and calculated the metabolic pathway (elementary modes; EMs). Transcriptome data were used to identify pathways activated when A. fumigatus is challenged with DCs. In particular, amino acid metabolic pathways, alternative carbon metabolic pathways and stress regulating enzymes were found to be active. Metabolic flux modeling identified further active enzymes such as alcohol dehydrogenase, inositol oxygenase and GTP cyclohydrolase participating in different stress responses in A. fumigatus. These were further validated by qRT-PCR from RNA extracted under these different conditions. For DCs, we outlined the activation of metabolic pathways in response to the confrontation with A. fumigatus. We found the fatty acid metabolism plays a crucial role, along with other metabolic changes. The gene expression data and their analysis illuminate additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular, Toll-like receptor signaling, NOD-like receptor signaling and RIG-I-like receptor signaling were active pathways. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR, and CUL3 of DCs to be activated in response to A. fumigatus. In conclusion, we analyze the metabolic and regulatory responses of A. fumigatus and DCs when confronted with each other.
Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time‐consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus‐specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high‐risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85%, sensitivity varied markedly in BAL (64%), CSF (100%), tissue samples (67%) as opposed to concurrent blood samples (8%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis.
Polygonum cuspidatum (Japanese knotweed, also known as Huzhang in Chinese), a plant that produces bioactive components such as stilbenes and quinones, has long been recognized as important in traditional Chinese herbal medicine. To better understand the biological features of this plant and to gain genetic insight into the biosynthesis of its natural products, we assembled a draft genome of P. cuspidatum using Illumina sequencing technology. The draft genome is ca. 2.56 Gb long, with 71.54% of the genome annotated as transposable elements. Integrated gene prediction suggested that the P. cuspidatum genome encodes 55,075 functional genes, including 6,776 gene families that are conserved in the five eudicot species examined and 2,386 that are unique to P. cuspidatum. Among the functional genes identified, 4,753 are predicted to encode transcription factors. We traced the gene duplication history of P. cuspidatum and determined that it has undergone two whole-genome duplication events about 65 and 6.6 million years ago. Roots are considered the primary medicinal tissue, and transcriptome analysis identified 2,173 genes that were expressed at higher levels in roots compared to aboveground tissues. Detailed phylogenetic analysis demonstrated expansion of the gene family encoding stilbene synthase and chalcone synthase enzymes in the phenylpropanoid metabolic pathway, which is associated with the biosynthesis of resveratrol, a pharmacologically important stilbene. Analysis of the draft genome identified 7 abscisic acid and water deficit stress-induced protein-coding genes and 14 cysteine-rich transmembrane module genes predicted to be involved in stress responses. The draft de novo genome assembly produced in this study represents a valuable resource for the molecular characterization of medicinal compounds in P. cuspidatum, the improvement of this important medicinal plant, and the exploration of its abiotic stress resistance.
Air temperatures in the Arctic have increased substantially over the last decades, which has extensively altered the properties of the land surface. Capturing the state and dynamics of Land Surface Temperatures (LSTs) at high spatial detail is of high interest as LST is dependent on a variety of surficial properties and characterizes the land–atmosphere exchange of energy. Accordingly, this study analyses the influence of different physical surface properties on the long-term mean of the summer LST in the Arctic Mackenzie Delta Region (MDR) using Landsat 30 m-resolution imagery between 1985 and 2018 by taking advantage of the cloud computing capabilities of the Google Earth Engine. Multispectral indices, including the Normalized Difference Vegetation Index (NDVI), Normalized Difference Water Index (NDWI) and Tasseled Cap greenness (TCG), brightness (TCB), and wetness (TCW) as well as topographic features derived from the TanDEM-X digital elevation model are used in correlation and multiple linear regression analyses to reveal their influence on the LST. Furthermore, surface alteration trends of the LST, NDVI, and NDWI are revealed using the Theil-Sen (T-S) regression method. The results indicate that the mean summer LST appears to be mostly influenced by the topographic exposition as well as the prevalent moisture regime where higher evapotranspiration rates increase the latent heat flux and cause a cooling of the surface, as the variance is best explained by the TCW and northness of the terrain. However, fairly diverse model outcomes for different regions of the MDR (R2 from 0.31 to 0.74 and RMSE from 0.51 °C to 1.73 °C) highlight the heterogeneity of the landscape in terms of influential factors and suggests accounting for a broad spectrum of different factors when modeling mean LSTs. The T-S analysis revealed large-scale wetting and greening trends with a mean decadal increase of the NDVI/NDWI of approximately +0.03 between 1985 and 2018, which was mostly accompanied by a cooling of the land surface given the inverse relationship between mean LSTs and vegetation and moisture conditions. Disturbance through wildfires intensifies the surface alterations locally and lead to significantly cooler LSTs in the long-term compared to the undisturbed surroundings.
This study investigates synthetic aperture radar (SAR) time series of the Sentinel-1 mission acquired over the Atacama Desert, Chile, between March 2015 and December 2018. The contribution analyzes temporal and spatial variations of Sentinel-1 interferometric SAR (InSAR) coherence and exemplarily illustrates factors that are responsible for observed signal differences. The analyses are based on long temporal baselines (365–1090 days) and temporally dense time series constructed with short temporal baselines (12–24 days). Results are compared to multispectral data of Sentinel-2, morphometric features of the digital elevation model (DEM) TanDEM-X WorldDEM™, and to a detailed governmental geographic information system (GIS) dataset of the local hydrography. Sentinel-1 datasets are suited for generating extensive, nearly seamless InSAR coherence mosaics covering the entire Atacama Desert (>450 × 1100 km) at a spatial resolution of 20 × 20 meter per pixel. Temporal baselines over several years lead only to very minor decorrelation, indicating a very high signal stability of C-Band in this region, especially in the hyperarid uplands between the Coastal Cordillera and the Central Depression. Signal decorrelation was associated with certain types of surface cover (e.g., water or aeolian deposits) or with actual surface dynamics (e.g., anthropogenic disturbance (mining) or fluvial activity and overland flow). Strong rainfall events and fluvial activity in the periods 2015 to 2016 and 2017 to 2018 caused spatial patterns with significant signal decorrelation; observed linear coherence anomalies matched the reference channel network and indicated actual episodic and sporadic discharge events. In the period 2015–2016, area-wide loss of coherence appeared as strip-like patterns of more than 80 km length that matched the prevailing wind direction. These anomalies, and others observed in that period and in the period 2017–2018, were interpreted to be caused by overland flow of high magnitude, as their spatial location matched well with documented heavy rainfall events that showed cumulative precipitation amounts of more than 20 mm.
Aims
Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal‐regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen‐activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO‐induced cardiac remodelling as this was unknown.
Methods and results
Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr‐Glu‐Tyr) motif (−28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte‐specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6‐fold, P < 0.05) and protein level (3.1‐fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice.
Conclusions
VO‐induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte‐specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
Objective
The aim of this study was to determine the prevalence of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, group A Streptococcus (GAS), and Staphylococcus aureus in asymptomatic elderly people and to unravel risk factors leading to colonization.
Methods
A multi-centre cross-sectional study was conducted including 677 asymptomatic adults aged 65 years or more, living at home or in nursing homes. Study areas were Greater Aachen (North-Rhine-Westphalia) and Wuerzburg (Bavaria), both regions with medium to high population density. Nasal and oropharyngeal swabs as well as questionnaires were collected from October 2012 to May 2013. Statistical analysis included multiple logistic regression models.
Results
The carriage rate was 1.9% ([95%CI: 1.0–3.3%]; 13/677) for H. influenzae, 0.3% ([95%CI: 0–1.1%]; 2/677) for N. meningitidis and 0% ([95% CI: 0–0.5%]; 0/677) for S. pneumoniae and GAS. Staphylococcus aureus was harboured by 28.5% of the individuals ([95% CI: 25.1–32.1%]; 193/677) and 0.7% ([95% CI: 0.2–1.7%]; 5/677) were positive for methicillin-resistant S. aureus. Among elderly community-dwellers colonization with S. aureus was significantly associated with higher educational level (adjusted OR: 1.905 [95% CI: 1.248–2.908]; p = 0.003). Among nursing home residents colonization was associated with being married (adjusted OR: 3.367 [1.502–7.546]; p = 0.003).
Conclusion
The prevalence of N. meningitidis, H. influenzae, S. pneumoniae and GAS was low among older people in Germany. The S. aureus rate was expectedly high, while MRSA was found in less than 1% of the individuals.
The FDA approval of targeted therapy with BRAFV600E inhibitors like vemurafenib and dabrafenib in 2011 has been the first major breakthrough in the treatment of metastatic melanoma since almost three decades. Despite increased progression free survival and elevated overall survival rates, complete responses are scarce due to resistance development approximately six months after the initial drug treatment. It was previously shown in our group that melanoma cells under vemurafenib pressure in vitro and in vivo exhibit features of drug-induced senescence. It is known that some cell types, which undergo this cell cycle arrest, develop a so-called senescence associated secretome and it has been reported that melanoma cell lines also upregulate the expression of different factors after senescence induction. This work describes the effect of the vemurafenib-induced secretome on cells. Conditioned supernatants of vemurafenib-treated cells increased the viability of naive fibroblast and melanoma cell lines. RNA analysis of donor melanoma cells revealed elevated transcriptional levels of FGF1, MMP2 and CCL2 in the majority of tested cell lines under vemurafenib pressure, and I could confirm the secretion of functional proteins. Similar observations were also done after MEK inhibition as well as in a combined BRAF and MEK inhibitor treatment situation. Interestingly, the transcription of other FGF ligands (FGF7, FGF17) was also elevated after MEK/ERK1/2 inhibition. As FGF receptors are therapeutically relevant, I focused on the analysis of FGFR-dependent processes in response to BRAF inhibition. Recombinant FGF1 increased the survival rate of melanoma cells under vemurafenib pressure, while inhibition of the FGFR pathway diminished the viability of melanoma cells in combination with vemurafenib and blocked the stimulatory effect of vemurafenib conditioned medium. The BRAF inhibitor induced secretome is regulated by active PI3K/AKT signaling, and the joint inhibition of mTor and BRAFV600E led to decreased senescence induction and to a diminished induction of the secretome-associated genes. In parallel, combined inhibition of MEK and PI3K also drastically decreased mRNA levels of the relevant secretome components back to basal levels.
In summary, I could demonstrate that BRAF inhibitor treated melanoma cell lines acquire a specific PI3K/AKT dependent secretome, which is characterized by FGF1, CCL2 and MMP2. This secretome is able to stimulate other cells such as naive melanoma cells and fibroblasts and contributes to a better survival under drug pressure. These data are therapeutically highly relevant, as they imply the usage of novel drug combinations, especially specific FGFR inhibitors, with BRAF inhibitors in the clinic.
Background
Autologous hematopoietic stem cell transplantation (aHSCT) is performed in patients with aggressive forms of systemic sclerosis (SSc). The profile of B cell reconstitution after aHSCT is not fully understood. The aim of this study was to investigate changes of B cell subsets and cytokine production of B cells in patients with SSc after aHSCT.
Methods
Peripheral blood of six patients with SSc was collected at defined intervals up to 16 months after aHSCT. Immunophenotyping was performed, and B cell function was determined by measuring cytokine secretion in supernatants of stimulated B cell cultures.
Results
Within 1 month after aHSCT, a peak in the percentage of CD38\(^{++}\)/CD10\(^+\)/IgD\(^+\) transitional B cells and CD38\(^{++}\)/CD27\(^{++}\)/IgD\(^−\) plasmablasts was detected. Long-term changes persisted up to 14 months after aHSCT and showed an increased percentage of total B cells; the absolute B cell number did not change significantly. Within the B cell compartment, an increased CD27/IgD\(^+\) naïve B cell percentage was found whereas decreased percentages of CD27\(^+\)/IgD\(^+\) pre-switched memory, CD27\(^+\)/IgD\(^−\) post-switched memory, and CD27\(^−\) /IgD\(^−\) double-negative B cells were seen after aHSCT. Cytokine secretion in B cell cultures showed significantly increased IL-10 concentrations 13 to 16 months after aHSCT.
Conclusion
A changed composition of the B cell compartment is present for up to 14 months after aHSCT indicating positive persisting effects of aHSCT on B cell homeostasis. The cytokine secretion profile of B cells changes in the long term and shows an increased production of the immune regulatory cytokine IL-10 after aHSCT. These findings might promote the clinical improvements after aHSCT in SSc patients.
Sea level rise contribution from the Antarctic ice sheet is influenced by changes in glacier and ice shelf front position. Still, little is known about seasonal glacier and ice shelf front fluctuations as the manual delineation of calving fronts from remote sensing imagery is very time-consuming. The major challenge of automatic calving front extraction is the low contrast between floating glacier and ice shelf fronts and the surrounding sea ice. Additionally, in previous decades, remote sensing imagery over the often cloud-covered Antarctic coastline was limited. Nowadays, an abundance of Sentinel-1 imagery over the Antarctic coastline exists and could be used for tracking glacier and ice shelf front movement. To exploit the available Sentinel-1 data, we developed a processing chain allowing automatic extraction of the Antarctic coastline from Seninel-1 imagery and the creation of dense time series to assess calving front change. The core of the proposed workflow is a modified version of the deep learning architecture U-Net. This convolutional neural network (CNN) performs a semantic segmentation on dual-pol Sentinel-1 data and the Antarctic TanDEM-X digital elevation model (DEM). The proposed method is tested for four training and test areas along the Antarctic coastline. The automatically extracted fronts deviate on average 78 m in training and 108 m test areas. Spatial and temporal transferability is demonstrated on an automatically extracted 15-month time series along the Getz Ice Shelf. Between May 2017 and July 2018, the fronts along the Getz Ice Shelf show mostly an advancing tendency with the fastest moving front of DeVicq Glacier with 726 ± 20 m/yr.
Automated real-time monitoring of human pluripotent stem cell aggregation in stirred tank reactors
(2019)
The culture of human induced pluripotent stem cells (hiPSCs) at large scale becomes feasible with the aid of scalable suspension setups in continuously stirred tank reactors (CSTRs). Innovative monitoring options and emerging automated process control strategies allow for the necessary highly defined culture conditions. Next to standard process characteristics such as oxygen consumption, pH, and metabolite turnover, a reproducible and steady formation of hiPSC aggregates is vital for process scalability. In this regard, we developed a hiPSC-specific suspension culture unit consisting of a fully monitored CSTR system integrated into a custom-designed and fully automated incubator. As a step towards cost-effective hiPSC suspension culture and to pave the way for flexibility at a large scale, we constructed and utilized tailored miniature CSTRs that are largely made from three-dimensional (3D) printed polylactic acid (PLA) filament, which is a low-cost material used in fused deposition modelling. Further, the monitoring tool for hiPSC suspension cultures utilizes in situ microscopic imaging to visualize hiPSC aggregation in real-time to a statistically significant degree while omitting the need for time-intensive sampling. Suitability of our culture unit, especially concerning the developed hiPSC-specific CSTR system, was proven by demonstrating pluripotency of CSTR-cultured hiPSCs at RNA (including PluriTest) and protein level.
Automation in Software Performance Engineering Based on a Declarative Specification of Concerns
(2019)
Software performance is of particular relevance to software system design, operation, and evolution because it has a significant impact on key business indicators. During the life-cycle of a software system, its implementation, configuration, and deployment are subject to multiple changes that may affect the end-to-end performance characteristics. Consequently, performance analysts continually need to provide answers to and act based on performance-relevant concerns. To ensure a desired level of performance, software performance engineering provides a plethora of methods, techniques, and tools for measuring, modeling, and evaluating performance properties of software systems. However, the answering of performance concerns is subject to a significant semantic gap between the level on which performance concerns are formulated and the technical level on which performance evaluations are actually conducted. Performance evaluation approaches come with different strengths and limitations concerning, for example, accuracy, time-to-result, or system overhead. For the involved stakeholders, it can be an elaborate process to reasonably select, parameterize and correctly apply performance evaluation approaches, and to filter and interpret the obtained results. An additional challenge is that available performance evaluation artifacts may change over time, which requires to switch between different measurement-based and model-based performance evaluation approaches during the system evolution. At model-based analysis, the effort involved in creating performance models can also outweigh their benefits.
To overcome the deficiencies and enable an automatic and holistic evaluation of performance throughout the software engineering life-cycle requires an approach that: (i) integrates multiple types of performance concerns and evaluation approaches, (ii) automates performance model creation, and (iii) automatically selects an evaluation methodology tailored to a specific scenario. This thesis presents a declarative approach —called Declarative Performance Engineering (DPE)— to automate performance evaluation based on a humanreadable specification of performance-related concerns. To this end, we separate the definition of performance concerns from their solution. The primary scientific contributions presented in this thesis are:
A declarative language to express performance-related concerns and a corresponding processing framework:
We provide a language to specify performance concerns independent of a concrete performance evaluation approach. Besides the specification of functional aspects, the language allows to include non-functional tradeoffs optionally. To answer these concerns, we provide a framework architecture and a corresponding reference implementation to process performance concerns automatically. It allows to integrate arbitrary performance evaluation approaches and is accompanied by reference implementations for model-based and measurement-based performance evaluation.
Automated creation of architectural performance models from execution traces:
The creation of performance models can be subject to significant efforts outweighing the benefits of model-based performance evaluation. We provide a model extraction framework that creates architectural performance models based on execution traces, provided by monitoring tools.The framework separates the derivation of generic information from model creation routines. To derive generic information, the framework combines state-of-the-art extraction and estimation techniques. We isolate object creation routines specified in a generic model builder interface based on concepts present in multiple performance-annotated architectural modeling formalisms. To create model extraction for a novel performance modeling formalism, developers only need to write object creation routines instead of creating model extraction software from scratch when reusing the generic framework.
Automated and extensible decision support for performance evaluation approaches:
We present a methodology and tooling for the automated selection of a performance evaluation approach tailored to the user concerns and application scenario. To this end, we propose to decouple the complexity of selecting a performance evaluation approach for a given scenario by providing solution approach capability models and a generic decision engine. The proposed capability meta-model enables to describe functional and non-functional capabilities of performance evaluation approaches and tools at different granularities. In contrast to existing tree-based decision support mechanisms, the decoupling approach allows to easily update characteristics of solution approaches as well as appending new rating criteria and thereby stay abreast of evolution in performance evaluation tooling and system technologies.
Time-to-result estimation for model-based performance prediction:
The time required to execute a model-based analysis plays an important role in different decision processes. For example, evaluation scenarios might require the prediction results to be available in a limited period of time such that the system can be adapted in time to ensure the desired quality of service. We propose a method to estimate the time-to-result for modelbased performance prediction based on model characteristics and analysis parametrization. We learn a prediction model using performancerelevant features thatwe determined using statistical tests. We implement the approach and demonstrate its practicability by applying it to analyze a simulation-based multi-step performance evaluation approach for a representative architectural performance modeling formalism.
We validate each of the contributions based on representative case studies. The evaluation of automatic performance model extraction for two case study systems shows that the resulting models can accurately predict the performance behavior. Prediction accuracy errors are below 3% for resource utilization and mostly less than 20% for service response time. The separate evaluation of the reusability shows that the presented approach lowers the implementation efforts for automated model extraction tools by up to 91%. Based on two case studies applying measurement-based and model-based performance evaluation techniques, we demonstrate the suitability of the declarative performance engineering framework to answer multiple kinds of performance concerns customized to non-functional goals. Subsequently, we discuss reduced efforts in applying performance analyses using the integrated and automated declarative approach. Also, the evaluation of the declarative framework reviews benefits and savings integrating performance evaluation approaches into the declarative performance engineering framework. We demonstrate the applicability of the decision framework for performance evaluation approaches by applying it to depict existing decision trees. Then, we show how we can quickly adapt to the evolution of performance evaluation methods which is challenging for static tree-based decision support systems. At this, we show how to cope with the evolution of functional and non-functional capabilities of performance evaluation software and explain how to integrate new approaches. Finally, we evaluate the accuracy of the time-to-result estimation for a set of machinelearning algorithms and different training datasets. The predictions exhibit a mean percentage error below 20%, which can be further improved by including performance evaluations of the considered model into the training data. The presented contributions represent a significant step towards an integrated performance engineering process that combines the strengths of model-based and measurement-based performance evaluation. The proposed performance concern language in conjunction with the processing framework significantly reduces the complexity of applying performance evaluations for all stakeholders. Thereby it enables performance awareness throughout the software engineering life-cycle. The proposed performance concern language removes the semantic gap between the level on which performance concerns are formulated and the technical level on which performance evaluations are actually conducted by the user.
Auxin is a molecule, which controls many aspects of plant development through both transcriptional and non-transcriptional signaling responses. AUXIN BINDING PROTEIN1 (ABP1) is a putative receptor for rapid non-transcriptional auxin-induced changes in plasma membrane depolarization and endocytosis rates. However, the mechanism of ABP1-mediated signaling is poorly understood. Here we show that membrane depolarization and endocytosis inhibition are ABP1-independent responses and that auxin-induced plasma membrane depolarization is instead dependent on the auxin influx carrier AUX1. AUX1 was itself not involved in the regulation of endocytosis. Auxin-dependent depolarization of the plasma membrane was also modulated by the auxin efflux carrier PIN2. These data establish a new connection between auxin transport and non-transcriptional auxin signaling.
An efficient foraging strategy is one of the most important traits for the fitness of animals. The theory of optimal foraging tries to predict foraging behaviour through the overarching question: how animals should forage so as to minimize costs while maximizing profits? Social insects, having occupied nearly every natural niche through widely different strategies, offer themselves as an ideal group to study how well optimal foraging theory can explain their behaviour and success.
Specialization often leads to unique adaptations in morphology and behaviour. I therefore decided to investigate the behaviour of Megaponera analis. This ponerine ant species is specialized on hunting only termites of the subfamily Macrotermitinae at their foraging sites. Their foraging behaviour is regulated by a handful of individual scouts (10-20) that search for termite foraging sites before returning to the nest to recruit a large number of nestmates (200-500 ants). These ants then follow the scout in a column formation to the termites and after the hunt return together to the nest, these raids occur two to five times per day.
Predators of highly defensive prey likely develop cost reducing adaptations. The evolutionary arms race between termites and ants led to various defensive mechanisms in termites, e.g. a caste specialized in fighting predators. As M. analis incurs high injury/mortality risks when preying on termites, some risk mitigating adaptations have evolved. I show that a unique rescue behaviour in M. analis, consisting of injured nestmates being carried back to the nest, reduces combat mortality. These injured ants “call for help” with pheromones present in their mandibular gland reservoirs. A model accounting for this rescue behaviour identifies the drivers favouring its evolution and estimates that rescuing allows for maintaining a 29% larger colony size. Heavily injured ants that lost too many legs during the fight on the other hand are not helped. Interestingly, this was regulated not by the helper but by the uncooperativeness of the injured ant. I further observed treatment of the injury by nestmates inside the nest through intense allogrooming directly at the wound. Lack of treatment increased mortality from 10% to 80% within 24 hours, with the cause of death most likely being infections.
Collective decision-making is one of the main mechanisms in social insects through which foraging is regulated. However, individual decision-making can also play an important role, depending on the type of foraging behaviour. In M. analis only a handful of individuals (the scouts) hold all the valuable information about foraging sites. I therefore looked at predictions made by optimal foraging theory to better understand the interplay between collective and individual decision-making in this obligate group-raiding predator. I found a clear positive relation between raid size and termite abundance at the foraging site. Furthermore, selectivity of the food source increased with distance. The confirmation of optimal foraging theory suggests that individual scouts must be the main driver behind raid size, choice and raiding behaviour. Therefore most central place foraging behaviours in M. analis were not achieved by collective decisions but rather by individual decisions of scout ants. Thus, 1% of the colony (10–20 scouts) decided the fate and foraging efficiency of the remaining 99%.
Division of labour is one of the main reasons for the success of social insects. Worker polymorphism, age polyethism and work division in more primitive ants, like the ponerines, remain mostly unexplored though. Since M. analis specializes on a defensive prey, adaptations to reduce their foraging costs can be expected. I found that the work division, task allocation and column-formation during the hunt were much more sophisticated than was previously thought. The column-formation was remarkably stable, with the same ants resuming similar positions in subsequent raids and front ants even returning to their positions if displaced in the same raid. Most of the raid tasks were not executed by predetermined members of the raid but were filled out as need arose during the hunt, with a clear preference for larger ants to conduct most tasks.
I show that specialization towards a highly defensive prey can lead to very unique adaptations in the foraging behaviour of a species. I explored experimentally the adaptive value of rescue behaviour focused on injured nestmates in social insects. This was not only limited to selective rescuing of lightly injured individuals by carrying them back (thus reducing predation risk) but moreover includes a differentiated treatment inside the nest. These observations will help to improve our understanding of the evolution of rescue behaviour in animals. I further show that most optimal foraging predictions are fulfilled and regulated by a handful of individuals in M. analis. Lastly, I propose that the continuous allometric size polymorphism in M. analis allows for greater flexibility in task allocation, necessary due to the unpredictability of task requirements in an irregular system such as hunting termites in groups. All of my observations help to further understand how a group-hunting predator should forage so as to minimize costs while maximizing profits.
Disruptions in brain serotonin (5-hydroxytryptamine, 5-HT) signaling pathways have been associated with etiology and pathogenesis of various neuropsychiatric disorders, but specific neural mechanisms of 5-HT function are yet to be fully elucidated. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme for brain 5-HT synthesis. Therefore, in this study a tamoxifen (Tam)-inducible cre-mediated conditional gene (Tph2) knockout in adult mouse brain (Tph2icKO) has been established to decipher the specific role of brain 5-HT in the regulation of behavior in adulthood.
Immunohistochemistry and high-performance liquid chromatography (HPLC) were used first to test the efficacy of Tam-inducible inactivation of Tph2 and consequential reduction of 5-HT in adult mouse brain. Tam treatment resulted in ≥90% reduction in the number of 5-HT immuno-reactive cells in the anterior raphe nuclei. HPLC revealed a significant reduction in concentration of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in selected brain regions of Tph2icKO, indicating the effectiveness of the protocol used.
Second, standard behavioral tests were used to assess whether reduced brain 5-HT concentrations could alter anxiety-, fear- and depressive-like behavior in mice. No altered anxiety- and depressive-like behaviors were observed in Tph2icKO compared to control mice (Tph2CON) in all indices measured, but Tph2icKO mice exhibited intense and sustained freezing during context-dependent fear memory retrieval. Tph2icKO mice also exhibited locomotor hyperactivity in the aversive environments, such as the open field, and consumed more food and fluid than Tph2CON mice.
Lastly, the combined effect of maternal separation (MS) stress and adult brain 5-HT depletion on behavior was assessed in male and female mice. Here, MS stress, 5-HT depletion and their interaction elicited anxiety-like behavior in a sex-dependent manner. MS reduced exploratory behavior in both male and female mice. Reduced 5-HT enhanced anxiety in female, but not in male mice.
Furthermore, expression of genes related to the 5-HT system and emotionality (Tph2, Htr1a, Htr2a, Maoa and Avpr1a) was assessed by performing a quantitative real-time PCR. In Tph2icKO mice there was a reduction in expression of Tph2 in the raphe nuclei of both male and female mice. Interaction between MS stress and 5-HT deficiency was detected showing increased Htr2a and Maoa expression in raphe and hippocampus respectively of female mice. In male mice, MS stress and 5-HT depletion interaction effects reduced Avpr1a expression in raphe, while the expression of Htr1a, Htr2a and Maoa was differentially altered by 5-HT depletion and MS in various brain regions.
Beneficial effects of vitamin D treatment in an obese mouse model of non-alcoholic steatohepatitis
(2019)
Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut–liver axis.
This paper provides a critical analysis of the subadditivity axiom, which is the key condition for coherent risk measures. Contrary to the subadditivity assumption, bank mergers can create extra risk. We begin with an analysis how a merger affects depositors, junior or senior bank creditors, and bank owners. Next it is shown that bank mergers can result in higher payouts having to be made by the deposit insurance scheme. Finally, we demonstrate that if banks are interconnected via interbank loans, a bank merger could lead to additional contagion risks. We conclude that the subadditivity assumption should be rejected, since a subadditive risk measure, by definition, cannot account for such increased risks.
In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.
Cosmology often uses intricate formulas and mathematics to derive new theories and concepts. We do something different in this paper: We look at biological processes and derive from these heuristics so that the revised cosmology agrees with astronomical observations but does also agree with standard biological observations. We show that we then have to replace any type of singularity at the start of the universe by a condensation nucleus and that the very early period of the universe usually assumed to be inflation has to be replaced by a period of rapid crystal growth as in Weiss magnetization domains.
Impressively, these minor modifications agree well with astronomical observations including removing the strong inflation perturbations which were never observed in the recent BICEP2 experiments. Furthermore, looking at biological principles suggests that such a new theory with a condensation nucleus at start and a first rapid phase of magnetization-like growth of the ordered, physical laws obeying lattice we live in is in fact the only convincing theory of the early phases of our universe that also is compatible with current observations.
We show in detail in the following that such a process of crystal creation, breaking of new crystal seeds and ultimate evaporation of the present crystal readily leads over several generations to an evolution and selection of better, more stable and more self-organizing crystals. Moreover, this explains the “fine-tuning” question why our universe is fine-tuned to favor life: Our Universe is so self-organizing to have enough offspring and the detailed physics involved is at the same time highly favorable for all self-organizing processes including life.
This biological theory contrasts with current standard inflation cosmologies. The latter do not perform well in explaining any phenomena of sophisticated structure creation or self-organization. As proteins can only thermodynamically fold by increasing the entropy in the solution around them we suggest for cosmology a condensation nucleus for a universe can form only in a “chaotic ocean” of string-soup or quantum foam if the entropy outside of the nucleus rapidly increases. We derive an interaction potential for 1 to n-dimensional strings or quantum-foams and show that they allow only 1D, 2D, 4D or octonion interactions. The latter is the richest structure and agrees to the E8 symmetry fundamental to particle physics and also compatible with the ten dimensional string theory E8 which is part of the M-theory. Interestingly, any other interactions of other dimensionality can be ruled out using Hurwitz compositional theorem. Crystallization explains also extremely well why we have only one macroscopic reality and where the worldlines of alternative trajectories exist: They are in other planes of the crystal and for energy reasons they crystallize mostly at the same time, yielding a beautiful and stable crystal. This explains decoherence and allows to determine the size of Planck´s quantum h (very small as separation of crystal layers by energy is extremely strong).
Ultimate dissolution of real crystals suggests an explanation for dark energy agreeing with estimates for the “big rip”. The halo distribution of dark matter favoring galaxy formation is readily explained by a crystal seed starting with unit cells made of normal and dark matter.
That we have only matter and not antimatter can be explained as there may be right handed mattercrystals and left-handed antimatter crystals. Similarly, real crystals are never perfect and we argue that exactly such irregularities allow formation of galaxies, clusters and superclusters. Finally, heuristics from genetics suggest to look for a systems perspective to derive correct vacuum and Higgs Boson energies.
Gonorrhea is the second most common sexually transmitted infection in the world and is caused by Gram-negative diplococcus Neisseria gonorrhoeae. Since N. gonorrhoeae is a human-specific pathogen, animal infection models are only of limited use. Therefore, a suitable in vitro cell culture model for studying the complete infection including adhesion, transmigration and transport to deeper tissue layers is required. In the present study, we generated three independent 3D tissue models based on porcine small intestinal submucosa (SIS) scaffold by co-culturing human dermal fibroblasts with human colorectal carcinoma, endometrial epithelial, and male uroepithelial cells. Functional analyses such as transepithelial electrical resistance (TEER) and FITC-dextran assay indicated the high barrier integrity of the created monolayer. The histological, immunohistochemical, and ultra-structural analyses showed that the 3D SIS scaffold-based models closely mimic the main characteristics of the site of gonococcal infection in human host including the epithelial monolayer, the underlying connective tissue, mucus production, tight junction, and microvilli formation. We infected the established 3D tissue models with different N. gonorrhoeae strains and derivatives presenting various phenotypes regarding adhesion and invasion. The results indicated that the disruption of tight junctions and increase in interleukin production in response to the infection is strain and cell type-dependent. In addition, the models supported bacterial survival and proved to be better suitable for studying infection over the course of several days in comparison to commonly used Transwell® models. This was primarily due to increased resilience of the SIS scaffold models to infection in terms of changes in permeability, cell destruction and bacterial transmigration. In summary, the SIS scaffold-based 3D tissue models of human mucosal tissues represent promising tools for investigating N. gonorrhoeae infections under close-to-natural conditions.
While polysulfones constitute a class of well‐established, highly valuable applied materials, knowledge about polymers based on the related sulfoximine group is very limited. We have employed functionalized diaryl sulfoximines and a p ‐phenylene bisborane as building blocks for unprecedented BN‐ and BO‐doped alternating inorganic–organic hybrid copolymers. While the former were accessed by a facile silicon/boron exchange protocol, the synthesis of polymers with main‐chain B–O linkages was achieved by salt elimination.
A 1,4,2,3‐diazadiborinine derivative was found to form Lewis adducts with strong two‐electron donors such as N‐heterocyclic and cyclic (alkyl)(amino)carbenes. Depending on the donor, some of these Lewis pairs are thermally unstable, converting to sole B,N‐embedded products upon gentle heating. The products of these reactions, which have been fully characterized by NMR spectroscopy, elemental analysis, and single‐crystal X‐ray diffraction, were identified as B,N‐heterocycles with fused 1,5,2,4‐diazadiborepine and 1,4,2‐diazaborinine rings. Computational modelling of the reaction mechanism provides insight into the formation of these unique structures, suggesting that a series of B−H, C−N, and B−B bond activation steps are responsible for these “intercalation” reactions between the 1,4,2,3‐diazadiborinine and NHCs.
Background
Several recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene.
Methods
221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205).
Results
There were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression.
Conclusions
These results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder.
Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function.
C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells
(2019)
A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV–Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C\(_{60}\) binding in an aqueous solution. Complexation with C\(_{60}\) was found to promote Ber intracellular uptake. By increasing C\(_{60}\) concentration, the C\(_{60}\)-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C\(_{60}\)-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C\(_{60}\) improved its in vitro efficiency against cancer cells.
Bone graft substitutes in orthopedic applications have to fulfill various demanding requirements. Most calcium phosphate (CaP) bone graft substitutes are highly porous to achieve bone regeneration, but typically lack mechanical stability. This study presents a novel approach, in which a scaffold structure with appropriate properties for bone regeneration emerges from the space between specifically shaped granules. The granule types were tetrapods (TEPO) and pyramids (PYRA), which were compared to porous CaP granules (CALC) and morselized bone chips (BC). Bulk materials of the granules were mechanically loaded with a peak pressure of 4 MP; i.e., comparable to the load occurring behind an acetabular cup. Mechanical loading reduced the volume of CALC and BC considerably (89% and 85%, respectively), indicating a collapse of the macroporous structure. Volumes of TEPO and PYRA remained almost constant (94% and 98%, respectively). After loading, the porosity was highest for BC (46%), lowest for CALC (25%) and comparable for TEPO and PYRA (37%). The pore spaces of TEPO and PYRA were highly interconnected in a way that a virtual object with a diameter of 150 µm could access 34% of the TEPO volume and 36% of the PYRA volume. This study shows that a bulk of dense CaP granules in form of tetrapods and pyramids can create a scaffold structure with load capacities suitable for the regeneration of an acetabular bone defect
Infectious diseases are still a significant cause of morbidity and mortality worldwide. Despite the progress in drug development, the occurrence of microbial resistance is still a significant concern. Alternative therapeutic strategies are required for non-responding or relapsing patients. Chimeric antigen receptor (CAR) T cells has revolutionized cancer immunotherapy, providing a potential therapeutic option for patients who are unresponsive to standard treatments. Recently two CAR T cell therapies, Yescarta® (Kite Pharma/Gilead) and Kymriah® (Novartis) were approved by the FDA for the treatments of certain types of non-Hodgkin lymphoma and B-cell precursor acute lymphoblastic leukemia, respectively. The success of adoptive CAR T cell therapy for cancer has inspired researchers to develop CARs for the treatment of infectious diseases. Here, we review the main achievements in CAR T cell therapy targeting viral infections, including Human Immunodeficiency Virus, Hepatitis C Virus, Hepatitis B Virus, Human Cytomegalovirus, and opportunistic fungal infections such as invasive aspergillosis.
Major advances in the chemistry of 5th and 6th row heavy p-block element compounds have recently uncovered intriguing reactivity patterns towards small molecules such as H\(_2\), CO\(_2\), and ethylene. However, well-defined, homogeneous insertion reactions with carbon monoxide, one of the benchmark substrates in this field, have not been reported to date. We demonstrate here, that a cationic bismuth amide undergoes facile insertion of CO into the Bi–N bond under mild conditions. This approach grants direct access to the first cationic bismuth carbamoyl species. Its characterization by NMR, IR, and UV/vis spectroscopy, elemental analysis, single-crystal X-ray analysis, cyclic voltammetry, and DFT calculations revealed intriguing properties, such as a reversible electron transfer at the bismuth center and an absorption feature at 353 nm ascribed to a transition involving σ- and π-type orbitals of the bismuth-carbamoyl functionality. A combined experimental and theoretical approach provided insight into the mechanism of CO insertion. The substrate scope could be extended to isonitriles.
Virtual reality plays an increasingly important role in research and therapy of pathological fear. However, the mechanisms how virtual environments elicit and modify fear responses are not yet fully understood. Presence, a psychological construct referring to the ‘sense of being there’ in a virtual environment, is widely assumed to crucially influence the strength of the elicited fear responses, however, causality is still under debate. The present study is the first that experimentally manipulated both variables to unravel the causal link between presence and fear responses. Height-fearful participants (N = 49) were immersed into a virtual height situation and a neutral control situation (fear manipulation) with either high versus low sensory realism (presence manipulation). Ratings of presence and verbal and physiological (skin conductance, heart rate) fear responses were recorded. Results revealed an effect of the fear manipulation on presence, i.e., higher presence ratings in the height situation compared to the neutral control situation, but no effect of the presence manipulation on fear responses. However, the presence ratings during the first exposure to the high quality neutral environment were predictive of later fear responses in the height situation. Our findings support the hypothesis that experiencing emotional responses in a virtual environment leads to a stronger feeling of being there, i.e., increase presence. In contrast, the effects of presence on fear seem to be more complex: on the one hand, increased presence due to the quality of the virtual environment did not influence fear; on the other hand, presence variability that likely stemmed from differences in user characteristics did predict later fear responses. These findings underscore the importance of user characteristics in the emergence of presence.
Monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic MDSCs (G-MDSCs) have been found to be massively induced in TB patients as well in murine Mtb infection models. However, the interaction of mycobacteria with MDSCs and its role in TB infection is not well studied. Here, we investigated the role of Cav-1 for MDSCs infected with Mycobacterium bovis Bacille-Calmette-Guerín (BCG). MDSCs that were generated from murine bone marrow (MDSCs) of wild-type (WT) or Cav1\(^{−/−}\) mice upregulated Cav-1, TLR4 and TLR2 expression after BCG infection on the cell surface. However, Cav-1 deficiency resulted in a selective defect of intracellular TLR2 levels predominantly in the M-MDSC subset. Further analysis indicated no difference in the phagocytosis of BCG by M-MDSCs from WT and Cav1\(^{−/−}\) mice or caveosome formation, but a reduced capacity to up-regulate surface markers, to secrete various cytokines, to induce iNOS and NO production required for suppression of T cell proliferation, whereas Arg-1 was not affected. Among the signaling pathways affected by Cav-1 deficiency, we found lower phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Together, our findings implicate that (i) Cav-1 is dispensable for the internalization of BCG, (ii) vesicular TLR2 signaling in M-MDSCs is a major signaling pathway induced by BCG, (iii) vesicular TLR2 signals are controlled by Cav-1, (iv) vesicular TLR2/Cav-1 signaling is required for T cell suppressor functions.
We analyze the processing of cereals and its role at Early Neolithic Göbekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. Göbekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and–in some cases–have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at Göbekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into Göbekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts.
Background:
Cerebellar liponeurocytoma is an extremely rare tumour entity of the central nervous system. It is histologically characterised by prominent neuronal/neurocytic differentiation with focal lipidisation and corresponding histologically to WHO grade II. It typically develops in adults, and usually shows a low proliferative potential. Recurrences have been reported in almost 50% of cases, and in some cases the recurrent tumour may display increased mitotic activity and proliferation index, vascular proliferations and necrosis. Thus pathological diagnosis of liponeurocytoma is challenging. This case presentation highlights the main clinical, radiographic and pathological features of a cerebellar liponeurocytoma.
Case presentation:
A 59-year-old, right-handed woman presented at our department with a short history of persistent headache, vertigo and gait disturbances. Examination at presentation revealed that the patient was awake, alert and fully oriented. The cranial nerve status was normal. Uncertainties were noted in the bilateral finger-to-nose testing with bradydiadochokinesis on both sides. Strength was full and no pronator drift was observed. Sensation was intact. No signs of pyramidal tract dysfunction were detected. Her gait appeared insecure. The patient underwent surgical resection. Afterward no further disturbances could be detected.
Conclusions:
To date >40 cases of liponeurocytoma have been reported, including cases with supratentorial location. A review of the 5 published cases of recurrent cerebellar. Liponeurocytoma revealed that the median interval between the first and second relapse was rather short, indicating uncertain malignant potential. The most recent WHO classification of brain tumours (2016) classifies the cerebellar liponeurocytoma as a separate entity and assigns the tumour to WHO grade II. Medulloblastoma is the most important differential diagnosis commonly seen in children and young adults. In contrast, cerebellar liponeurocytoma is typically diagnosed in adults. The importance of accurate diagnosis should not be underestimated especially in the view of possible further therapeutic interventions and for the determination of the patient's prognosis.
In recent years, the midlatitudes are characterized by more intense heatwaves in summer and sometimes severe cold spells in winter that might emanate from changes in atmospheric circulation, including synoptic‐scale and planetary wave activity in the midlatitudes. In this study, we investigate the heat and momentum exchange between the mean flow and atmospheric waves in the North Atlantic sector and adjacent continents by means of the physically consistent Eliassen–Palm flux diagnostics applied to reanalysis and forced climate model data. In the long‐term mean, momentum is transferred from the mean flow to atmospheric waves in the northwest Atlantic region, where cyclogenesis prevails. Further downstream over Europe, eddy fluxes return momentum to the mean flow, sustaining the jet stream against friction. A global climate model is able to reproduce this pattern with high accuracy. Atmospheric variability related to atmospheric wave activity is much more expressed at the intraseasonal rather than the interannual time‐scale. Over the last 40 years, reanalyses reveal a northward shift of the jet stream and a weakening of intraseasonal weather variability related to synoptic‐scale and planetary wave activity. This pertains to the winter and summer seasons, especially over central Europe, and correlates with changes in the North Atlantic Oscillation as well as regional temperature and precipitation. A very similar phenomenon is found in a climate model simulation with business‐as‐usual scenario, suggesting an anthropogenic trigger in the weakening of intraseasonal weather variability in the midlatitudes.
Methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for the clinical course of patients. In recent years, there have been observations of patients changing their MGMT promoter methylation from primary tumor to relapse. Still, data on this topic are scarce. Studies often consist of only few patients and provide rather contrasting results, making it hard to draw a clear conclusion on clinical implications. Here, we summarize the previous publications on this topic, add new cases of changing MGMT status in relapse and finally combine all reports of more than ten patients in a statistical analysis based on the Wilson score interval. MGMT promoter methylation changes are seen in 115 of 476 analyzed patients (24%; CI: 0.21–0.28). We discuss potential reasons like technical issues, intratumoral heterogeneity and selective pressure of therapy. The clinical implications are still ambiguous and do not yet support a change in clinical practice. However, retesting MGMT methylation might be useful for future treatment decisions and we encourage clinical studies to address this topic
Since Channelrhodopsins has been described first and introduced successfully in freely moving animals (Nagel et al., 2003 and 2005), tremendous impact has been made in this interesting field of neuroscience. Subsequently, many different optogenetic tools have been described and used to address long-lasting scientific issues. Furthermore, beside the ‘classical’ Channelrhodopsin-2 (ChR2), basically a cation-selective ion channel, also altered ChR2 descendants, anion selective channels and light-sensitive metabotropic proteins have expanded the optogenetic toolbox. However, in spite of this variety of different tools most researches still pick Channelrhodopsin-2 for their optogenetic approaches due to its well-known kinetics. In this thesis, an improved Channelrhodopsin, Channelrhodopsin2-XXM (ChR2XXM), is described, which might become an useful tool to provide ambitious neuroscientific approaches by dint of its characteristics. Here, ChR2XXM was chosen to investigate the functional consequences of Drosophila larvae lacking latrophilin in their chordotonal organs. Finally, the functionality of GtACR, was checked at the Drosophila NMJ. For a in-depth characterisation, electrophysiology along with behavioural setups was employed. In detail, ChR2XXM was found to have a better cellular expression pattern, high spatiotemporal precision, substantial increased light sensitivity and improved affinity to its chromophore retinal, as compared to ChR2. Employing ChR2XXM, effects of latrophilin (dCIRL) on signal transmission in the chordotonal organ could be clarified with a minimum of side effects, e.g. possible heat response of the chordotonal organ, due to high light sensitivity. Moreover, optogenetic activation of the chordotonal organ, in vivo, led to behavioural changes. Additionally, GtACR1 was found to be effective to inhibit motoneuronal excitation but is accompanied by unexpected side effects. These results demonstrate that further improvement and research of optogenetic tools is highly valuable and required to enable researchers to choose the best fitting optogenetic tool to address their scientific questions.
Mammalian haloacid dehalogenase (HAD)-type phosphatases are a large and ubiquitous family of at least 40 human members. Many of them have important physiological functions, such as the regulation of intermediary metabolism and the modulation of enzyme activities, yet they are also linked to diseases such as cardiovascular or metabolic disorders and cancer.
Still, most of the mammalian HAD phosphatases remain functionally uncharacterized.
This thesis reveals novel cell biological and physiological functions of the phosphoglycolate phosphatase PGP, also referred to as AUM. To this end, PGP was functionally characterized by performing analyses using purified recombinant proteins to investigate potential protein substrates of PGP, cell biological studies using the spermatogonial cell line GC1, primary mouse lung endothelial cells and lymphocytes, and a range of biochemical techniques to characterize Pgp-deficient mouse embryos.
To characterize the cell biological functions of PGP, its role downstream of RTK- and integrin signaling in the regulation of cell migration was investigated. It was shown that PGP inactivation elevates integrin- and RTK-induced circular dorsal ruffle (CDR) formation, cell spreading and cell migration. Furthermore, PGP was identified as a negative regulator of directed lymphocyte migration upon integrin- and GPCR activation.
The underlying mechanisms were analyzed further. It was demonstrated that PGP regulates CDR formation and cell migration in a PLC- and PKC-dependent manner, and that Src family kinase activities are required for the observed cellular effects. Upon integrin- and RTK activation, phosphorylation levels of tyrosine residues 1068 and 1173 of the EGF receptor were elevated and PLCγ1 was hyper-activated in PGP-deficient cells. Additionally, PGP-inactivated lymphocytes displayed elevated PKC activity, and PKC-mediated cytoskeletal remodeling was accelerated upon loss of PGP activity. Untargeted lipidomic analyses revealed that the membrane lipid phosphatidylserine (PS) was highly upregulated in PGP-depleted cells.
These data are consistent with the hypothesis that the accumulation of PS in the plasma membrane leads to a pre-assembly of signaling molecules such as PLCγ1 or PKCs that couple the activation of integrins, EGF receptors and GPCRs to accelerated cytoskeletal remodeling.
Thus, this thesis shows that PGP can affect cell spreading and cell migration by acting as a PG-directed phosphatase.
To understand the physiological functions of PGP, conditionally PGP-inactivated mice were analyzed. Whole-body PGP inactivation led to an intrauterine growth defect with developmental delay after E8.5, resulting in a gradual deterioration and death of PgpDN/DN embryos between E9.5 and E11.5. However, embryonic lethality upon whole-body PGP inactivation was not caused by a primary defect of the (cardio-) vascular system. Rather, PGP inactivated embryos died during the intrauterine transition from hypoxic to normoxic conditions.
Therefore, the potential impact of oxygen on PGP-dependent cell proliferation was investigated. Analyses of mouse embryonic fibroblasts (MEFs) generated from E8.5 embryos and GC1 cells cultured under normoxic and hypoxic conditions revealed that normoxia (~20% O2) causes a proliferation defect in PGP-inactivated cells, which can be rescued under
hypoxic (~1% O2) conditions. Mechanistically, it was found that the activity of triosephosphate isomerase (TPI), an enzyme previously described to be inhibited by phosphoglycolate (PG) in vitro, was attenuated in PGP-inactivated cells and embryos. TPI constitutes a critical branch point between carbohydrate- and lipid metabolism because it catalyzes the isomerization of the glycolytic intermediates dihydroxyacetone phosphate (DHAP, a precursor of the glycerol backbone required for triglyceride biosynthesis) and glyceraldehyde 3’-phosphate (GADP).
Attenuation of TPI activity, likely explains the observed elevation of glycerol 3-phosphate levels and the increased TG biosynthesis (lipogenesis). Analyses of ATP levels and oxygen consumption rates (OCR) showed that mitochondrial respiration rates and ATP production were elevated in PGP-deficient cells in a lipolysis-dependent manner. However under hypoxic conditions (which corrected the impaired proliferation of PGP-inactivated cells), OCR and ATP production was indistinguishable between PGP-deficient and PGP-proficient cells. We therefore propose that the inhibition of TPI activity by PG accumulation due to loss of PGP activity shifts cellular bioenergetics from a pro-proliferative, glycolytic metabolism to a lipogenetic/lipolytic metabolism.
Taken together, PGP acts as a metabolic phosphatase involved in the regulation of cell migration, cell proliferation and cellular bioenergetics. This thesis constitutes the basis for further studies of the interfaces between these processes, and also suggests functions of PGP for glucose and lipid metabolism in the adult organism.
Characterization of novel rhodopsins with light-regulated cGMP production or cGMP degradation
(2019)
Photoreceptors are widely occurring in almost all kingdoms of life. They mediate the first step in sensing electromagnetic radiation of different wavelength. Absorption spectra are found within the strongest radiation from the sun and absorption usually triggers downstream signaling pathways. Until now, mainly 6 classes of representative photoreceptors are known: five water-soluble proteins, of these three classes of blue light-sensitive proteins including LOV (light-oxygen-voltage), BLUF (blue-light using FAD), and cryptochrome modules with flavin (vitamin B-related) nucleotides as chromophore; while two classes of yellow and red light-sensitive proteins consist of xanthopsin and phytochrome, respectively. Lastly, as uniquely integral membrane proteins, the class of rhodopsins can usually sense over a wide absorption spectrum, ranging from ultra-violet to green and even red light. Rhodopsins can be further divided into two types, i.e., microbial (type I) and animal (type II) rhodopsins. Rhodopsins consist of the protein opsin and the covalently bound chromophore retinal (vitamin A aldehyde). In this thesis, I focus on identification and characterization of novel type I opsins with guanylyl cyclase activity from green algae and a phosphodiesterase opsin from the protist Salpingoeca rosetta.
Until 2014, all known type I and II rhodopsins showed a typical structure with seven transmembrane helices (7TM), an extracellular N-terminus and a cytosolic C-terminus. The proven function of the experimentally characterized type I rhodopsins was membrane transport of ions or the coupling to a transducer which enables phototaxis via a signaling chain. A completely new class of type I rhodopsins with enzymatic activity was identified in 2014. A light-activated guanylyl cyclase opsin was discovered in the fungus Blastocladiella emersonii which was named Cyclop (Cyclase opsin) by Gao et al. (2015), after heterologous expression and rigorous in-vitro characterization. BeCyclop is the first opsin for which an 8 transmembrane helices (8TM) structure was demonstrated by Gao et al. (2015). Earlier (2004), a novel class of enzymatic rhodopsins was predicted to exist in C. reinhardtii by expressed sequence tag (EST) and genome data, however, no functional data were provided up to now. The hypothetical rhodopsin included an N-terminal opsin domain, a fused two-component system with histidinekinase and response regulator domain, and a C-terminal guanylyl cyclase (GC) domain. This suggested that there could be a biochemical signaling cascade, integrating light-induction and ATP-dependent phosphate transfer, and as output the light-sensitive cGMP production.
One of my projects focused on characterizing two such opsins from the green algae Chlamydomonas reinhardtii and Volvox carteri which we then named 2c-Cyclop (two-component Cyclase opsin), Cr2c-Cyclop and Vc2c-Cyclop, respectively. My results show that both 2c-Cyclops are light-inhibited GCs. Interestingly, Cr2c-Cyclop and Vc2c-Cyclop are very sensitive to light and ATP-dependent, whereby the action spectra of Cr2c-Cyclop and Vc2c-Cyclop peak at ~540 nm and ~560 nm, respectively. More importantly, guanylyl cyclase activity is dependent on continuous phosphate transfer between histidine kinase and response regulator. However, green light can dramatically block phosphoryl group transfer and inhibit cyclase activity. Accordingly, mutation of the retinal-binding lysine in the opsin domain resulted in GC activity and lacking light-inhibition.
A novel rhodopsin phosphodiesterase from the protist Salpingoeca rosetta (SrRhoPDE) was discovered in 2017. However, the previous two studies of 2017 claimed a very weak or absent light-regulation. Here I give strong evidence for light-regulation by studying the activity of SrRhoPDE, expressed in Xenopus laevis oocytes, in-vitro at different cGMP concentrations. Surprisingly, hydrolysis of cGMP shows a ~100-fold higher turnover than that of cAMP. Light can enhance substrate affinity by decreasing the Km value for cGMP from 80 μM to 13 μM, but increases the maximum turnover only by ~30%. In addition, two key single mutants, SrRhoPDE K296A or K296M, can abolish the light-activation effect by interrupting a covalent bond of Schiff base type to the chromophore retinal. I also demonstrate that SrRhoPDE shows cytosolic N- and C- termini, most likely via an 8-TM structure. In the future, SrRhoPDE can be a potentially useful optogenetic tool for light-regulation of cGMP concentration, possibly after further improvements by genetic engineering.
A fundamental question in current biology concerns the translational mechanisms leading from genetic variability to phenotypes. Technologies have evolved to the extent that they can efficiently and economically determine an individual’s genomic composition, while at the same time big data on clinical profiles and diagnostics have substantially accumulated. Genome-wide association studies linking genomic loci to certain traits, however, remain limited in their capacity to explain the cellular mechanisms that underlie the given association. For most associations, gene expression has been blamed; yet given that transcript and protein abundance oftentimes do not correlate, that finding does not necessarily decrypt the underlying mechanism. Thus, the integration of further information is crucial to establish a model that could prove more accurate in predicting genotypic effects on the human organism.
In this work we describe the so-called proteotype as a feature of the cell that could provide a substantial link between genotype and phenotype. Rather than looking at the proteome as a set of independent molecules, we demonstrate a consistent modular architecture of the proteome that is driven by molecular cooperativity. Functional modules, especially protein complexes, can be further interrogated for differences between individuals and tackled as imprints of genetic and environmental variability. We also show that subtle stoichiometric changes of protein modules could have broader effects on the cellular system, such as the transport of specific molecular cargos.
The presented work also delineates to what extent temporal events and processes influence the stoichiometry of protein complexes and functional modules. The re-wiring of the glycolytic pathway for example is illustrated as a potential cause for an increased Warburg effect during the ageing of the human bone marrow. On top of analyzing protein abundances we also interrogate proteome dynamics in terms of stability and solubility transitions during the short temporal progression of the cell cycle. One of our main observations in the thesis encompass the delineation of protein complexes into respective sub-complexes according to distinct stability patterns during the cell cycle. This has never been demonstrated before, and is functionally relevant for our understanding of the dis- and assembly of large protein modules.
The insights presented in this work imply that the proteome is more than the sum of its parts, and primarily driven by variability in entire protein ensembles and their cooperative nature. Analyzing protein complexes and functional modules as molecular reflections of genetic and environmental variations could indeed prove to be a stepping stone in closing the gap between genotype and phenotype and customizing clinical treatments in the future.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Chimeric Antigen Receptor Library Screening Using a Novel NF-kappa B/NFAT Reporter Cell Platform
(2019)
Chimeric antigen receptor (CAR)-T cell immunotherapy is under intense preclinical and clinical investigation, and it involves a rapidly increasing portfolio of novel target antigens and CAR designs. We established a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells derived from the T cell lymphoma line Jurkat. Reporter cells were equipped with nuclear factor kappa B (NF kappa B) and nuclear factor of activated T cells (NFAT) reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs. The reporter data were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary CAR-T cells (21 days). We challenged the reporter platform to a large-scale screening campaign on a ROR1-CAR library, and we showed that reporter cells retrieved a functional CAR variant that was present with a frequency of only 6 in 1.05 x 10(6). The data illustrate the potential to implement this reporter platform into the preclinical development path of novel CAR-T cell products and to inform and accelerate the selection of lead CAR candidates for clinical translation.