bluuebunny/crossref_metadata_2025_split huggingface dataset:
NeuroML-DB: Sharing and characterizing data-driven neuroscience models described in NeuroML
Authors: Birgiolas Justas , Haynes Vergil , Gleeson Padraig , Gerkin Richard C. , Dietrich Suzanne W. , Crook Sharon M. 
Published: September 2021

AbstractAs researchers develop computational models of neural systems with increasing sophistication and scale, it is often the case that fullyde novomodel development is impractical and inefficient. Thus arises a critical need to quickly find, evaluate, re-use, and build upon models and model components developed by other researchers. We introduce the NeuroML Database (NeuroML-DB.org), which has been developed to address this need and to complement other model sharing resources. NeuroML-DB stores over 1,500 previously published models of ion channels, cells, and networks that have been translated to the modular NeuroML model description language. The database also provides reciprocal links to other neuroscience model databases (ModelDB, Open Source Brain) as well as access to the original model publications (PubMed). These links along with Neuroscience Information Framework (NIF) search functionality provide deep integration with other neuroscience community modeling resources and greatly facilitate the task of finding suitable models for reuse.Serving as an intermediate language, NeuroML and its tooling ecosystem enable efficient translation of models to other popular simulator formats. The modular nature also enables efficient analysis of a large number of models and inspection of their properties. Search capabilities of the database, together with web-based, programmable online interfaces, allow the community of researchers to rapidly assess stored model electrophysiology, morphology, and computational complexity properties. We use these capabilities to perform a database-scale analysis of neuron and ion channel models and describe a novel tetrahedral structure formed by cell model clusters in the space of model properties and features.Author SummaryComputational models of neurons and their circuits are increasingly used by neuroscience researchers as a tool to probe fundamental aspects of brain function. Here we describe a database of computational models of neurons and networks that makes it easier to evaluate and reuse these models. The models in the database are available in a standard format, called NeuroML, that makes it easier to extend and reuse the models in simulation studies using a wide range of simulation software platforms. The use of this standard format also makes it easier to characterize models in an automated way and analyze relationships across the features of simulated data from model simulations.Striking Image
Interplay between the Genetics of Personality Traits, severe Psychiatric Disorders, and COVID-19 Host Genetics in the Susceptibility to SARS-CoV-2 Infection
Authors: Heilbronner Urs , Streit Fabian , Vogl Thomas , Senner Fanny , Schaupp Sabrina K. , Reich-Erkelenz Daniela , Papiol Sergi , Kohshour Mojtaba Oraki , Klöhn-Saghatolislam Farahnaz , Kalman Janos L. , Heilbronner Maria , Gade Katrin , Comes Ashley L. , Budde Monika , Andlauer Till F. M. , Anderson-Schmidt Heike , Adorjan Kristina , Stürmer Til , Loerbroks Adrian , Amelang Manfred , Poisel Eric , Foo Jerome , Heilmann-Heimbach Stefanie , Forstner Andreas J. , Degenhardt Franziska , Zimmermann Jörg , Wiltfang Jens , von Hagen Martin , Spitzer Carsten , Schmauss Max , Reininghaus Eva , Reimer Jens , Konrad Carsten , Juckel Georg , Lang Fabian U. , Jäger Markus , Figge Christian , Fallgatter Andreas J. , Dietrich Detlef E. , Dannlowski Udo , Baune Bernhardt T. , Arolt Volker , Anghelescu Ion-George , Nöthen Markus M. , Witt Stephanie H. , Andreassen Ole A. , Chen Chi-Hua , Falkai Peter , Rietschel Marcella , Schulze Thomas G. , Schulte Eva C. 
Published: September 2021

ABSTRACTBackgroundThe SARS-CoV-2 pandemic, with all its impacts on our way of life, is affecting our experiences and mental health. Notably, individuals with mental disorders have been reported to have a higher risk of contracting SARS-CoV-2. Personality traits could represent an important determinant of preventative health behavior and, therefore, the risk of contracting the virus.AimsWe examined overlapping genetic underpinnings between major psychiatric disorders, personality traits, and susceptibility to SARS-CoV-2 infection.MethodsLinkage disequilibrium score regression was used to explore the genetic correlations of COVID-19 susceptibility with psychiatric disorders and personality traits based on data from the largest available respective genome-wide association studies (GWAS). In two cohorts (the PsyCourse (n=1346) and the HeiDE (n=3266) study), polygenic risk scores were used to analyze if a genetic association between, psychiatric disorders, personality traits, and COVID-19 susceptibility exists in individual-level data.ResultsWe observed no significant genetic correlations of COVID-19 susceptibility with psychiatric disorders. For personality traits, there was a significant genetic correlation for COVID-19 susceptibility with extraversion (p=1.47×10-5; rg=0.284). Yet, this was not reflected in individual-level data from the PsyCourse and HeiDE studies.ConclusionsWe identified no significant correlation between genetic risk factors for severe psychiatric disorders and genetic risk for COVID-19 susceptibility. Among the personality traits, extraversion showed evidence for a positive genetic association with COVID-19 susceptibility, in one but not in another setting. Overall, these findings highlight a complex contribution of genetic and non-genetic components in the interaction between COVID-19 susceptibility and personality traits or mental disorders.
PAOX1expression in mixed-substrate continuous cultures ofKomagataella phaffii(Pichia pastoris) is completely determined by methanol consumption regardless of the secondary carbon source
Authors: Singh Anamika , Narang Atul 
Published: September 2021

AbstractThe expression of recombinant proteins by theAOX1promoter ofKomagataella phaffiiis typically induced by adding methanol to the cultivation medium. Since growth on methanol imposes a high oxygen demand, the medium is often supplemented with an additional secondary carbon source which serves to reduce the consumption of methanol, and hence, oxygen. Early research recommended the use of glycerol as the secondary carbon source, but more recent studies recommend the use of sorbitol because glycerol represses PAOX1expression. To assess the validity of this recommendation, we measured the steady state concentrations of biomass, residual methanol, and LacZ expressed from PAOX1over a wide range of dilution rates (0.02–0.20 h−1) in continuous cultures of the Mut+strain fed with methanol + glycerol (repressing) and methanol + sorbitol (non-repressing). We find that under these conditions, the specific PAOX1expression rate is completely determined by the specific methanol consumption rate regardless of the type (repressing/non-repressing) of the secondary carbon source. In both cultures, the specific PAOX1expression rate is proportional to the specific methanol consumption rate provided that the latter is below 0.15 g/(gdw-h); beyond this threshold consumption rate, the specific PAOX1expression rate of both cultures saturates to the same value. Analysis of the data in the literature shows that the same phenomenon also occurs in continuous cultures ofEscherichia colifed with mixtures of lactose plus repressing/non-repressing carbon sources. The specific Placexpression rate is completely determined by the specific lactose consumption rate regardless of the type of secondary carbon source, glycerol or glucose.Key pointsPAOX1expression rate is completely determined by the methanol consumption rate.Sorbitol is not necessarily superior secondary carbon source than glycerol.
Layered Feedback Control Overcomes Performance Trade-off in Synthetic Biomolecular Networks
Authors: Hu Chelsea Y. , Murray Richard M. 
Published: September 2021

AbstractLayered feedback is an optimization strategy in feedback control designs widely used in electrical and mechanical engineering. Layered control theory suggests that the performance of controllers is bound by the universal robustness-efficiency tradeoff limit, which could be overcome by layering two or more feedbacks together. In natural biological networks, genes are often regulated with redundancy and layering to adapt to environmental perturbations. Control theory hypothesizes that this layering architecture is also adopted by nature to overcome this performance trade-off. In this work, we validated this property of layered control with a synthetic network in living E. coli cells. We performed system analysis on a node-based design to confirm the tradeoff properties before proceeding to simulations with an effective mechanistic model, which guided us to the best performing design to engineer in cells. Finally, we interrogated its system dynamics experimentally with eight sets of perturbations on chemical signals, nutrient abundance, and growth temperature. For all cases, we consistently observed that the layered control overcomes the robustness-efficiency trade-off limit. This work experimentally confirmed that layered control could be adopted in synthetic biomolecular networks as a performance optimization strategy. It also provided insights in understanding genetic feedback control architectures in nature.Abstract Figure
Phase separation of +TIP-networks regulates microtubule dynamics
Authors: Miesch Julie , Wimbish Robert T. , Velluz Marie-Claire , Aumeier Charlotte 
Published: September 2021

SUMMARYRegulation of microtubule dynamics is essential for diverse cellular functions, and proteins that bind to dynamic microtubule ends can regulate network dynamics. Here we show that two conserved microtubule end-binding proteins, CLIP-170 and EB3, undergo phase separation and form dense liquid-networks. When CLIP-170 and EB3 act together the multivalency of the network increases, which synergistically increases the amount of protein in the dense phase. In vitro and in cells these liquid networks can condense tubulin. In vitro in the presence of microtubules, EB3/CLIP-170 phase separation can co-condense tubulin all along the microtubule. At this condition microtubule growth speed increases up to two-fold and depolymerization events are strongly reduced, compared to conditions with phase separation deficient networks. Our data show that phase separated EB3/CLIP-170 networks impact microtubule growth dynamics beyond direct protein-microtubule interactions.
Integrated molecular analysis identifies a conserved pericyte gene signature in zebrafish
Authors: Shih Yu-Huan , Portman Daneal , Idrizi Feston , Grosse Ann , Lawson Nathan D. 
Published: September 2021

ABSTRACTPericytes reside in capillary beds where they share a basement membrane with endothelial cells and regulate their function. However, little is known about embryonic pericyte development, in part, due to lack of specific molecular markers and genetic tools. Here, we applied single cell RNA-sequencing (scRNA-seq) of platelet derived growth factor beta (pdgfrb)-positive cells to molecularly characterize pericytes in zebrafish larvae. scRNA-seq revealed zebrafish cells expressing mouse pericyte gene orthologs while comparison to bulk RNA-seq from wild type and pdgfrb mutant larvae further refined a pericyte geneset. Subsequent integration with mouse pericyte scRNA-seq profiles revealed a core set of conserved pericyte genes. Using transgenic reporter lines, we validated pericyte expression of two genes identified in our analysis: NDUFA4 mitochondrial complex associated like 2a (ndufa4l2a), and potassium voltage-gated channel, Isk-related family, member 4 (kcne4). Both reporter lines exhibited pericyte expression in multiple anatomical locations, while kcne4 was also detected in a subset of vascular smooth muscle cells. Thus, our integrated molecular analysis revealed a molecular profile for zebrafish pericytes and allowed us to develop new tools to observe these cells in vivo.SUMMARY STATEMENTAn integrated molecular analysis in zebrafish identifies new molecular markers for pericytes.
Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage
Authors: Cao Kai , Riley Joel S , Cloix Catherine , Elmasry Yassmin , Ichim Gabriel , Campbell Kirsteen J , Tait Stephen WG 
Published: September 2021

SummaryMitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centres upon the control of minority MOMP, a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP, and its associated DNA damage, by enabling homogenous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.
Cell-based and cell-free firefly luciferase complementation assay to quantify Human Immunodeficiency Virus type 1 Rev-Rev interaction
Authors: Hansen Tucker , Baris Jodie , Zhao Min , Sutton Richard 
Published: September 2021

AbstractRev is an essential regulatory protein of Human Immunodeficiency Virus type 1 (HIV) that is found in the nucleus of infected cells. Rev multimerizes on the Rev-response element (RRE) of HIV RNA to facilitate the export of intron-containing HIV mRNAs from the nucleus to the cytoplasm, and, as such, HIV cannot replicate in the absence of Rev. We have developed cell-intact and cell-free assays based upon a robust firefly split-luciferase complementation system, both of which quantify Rev-Rev interaction. Using the cell-based system we show that additional Crm1 did not impact the interaction whereas excess Rev reduced it. Furthermore, when a series of mutant Revs were tested, there was a strong correlation between the results of the cell-based assay and the results of a functional Rev trans-complementation infectivity assay. Of interest, a camelid nanobody (NB) that was known to inhibit Rev function enhanced Rev-Rev interaction in the cell-based system. We observed a similar increase in Rev-Rev interaction in a cell-free system, when cell lysates expressing NLUC-Rev or CLUC-Rev were simply mixed. In the cell-free system Rev-Rev interaction occurred within minutes and was inhibited by excess Rev. The levels of interaction between the mutant Revs tested varied by mutant type. Treatment of Rev lysates with RNAse minimally reduced the degree of interaction whereas addition of HIV RRE RNA enhanced the interaction. Purified GST-Rev protein inhibited the interaction. The Z-factor (Z’) for the cell-free system was ~0.85 when tested in 96-well format, and anti-Rev NB enhanced the interaction in the cell-free system. Thus, we have developed both cell-intact and cell-free systems that can reliably, rapidly, and reproducibly quantify Rev-Rev interaction. These assays, particularly the cell-free one, may be useful in screening and identifying compounds that inhibit Rev function on a high throughput basis.
Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer’s disease synapse model
Authors: Hori Tetsuya , Eguchi Kohgaku , Wang Han-Ying , Miyasaka Tomohiro , Guillaud Laurent , Taoufiq Zacharie , Yamada Hiroshi , Takei Kohji , Takahashi Tomoyuki 
Published: September 2021

AbstractElevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer’s disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in brainstem slices. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10-20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin-1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.Significance StatementWild-type human recombinant tau loaded in rodent presynaptic terminals inhibited vesicle endocytosis, thereby causing activity-dependent rundown of excitatory transmission. This endocytic block is caused by a sequestration of dynamin by excess microtubules newly assembled by tau and can be rescued by a peptide inhibiting the microtubules-dynamin interaction, or by the microtubule disassembler nocodazole. Thus, synaptic dysfunction can be induced by pathological increase of endogenous soluble tau in Alzheimer disease slice model.
CTCF and cohesin promote focal detachment of DNA from the nuclear lamina
Authors: van Schaik Tom , Liu Ning Qing , Manzo Stefano G. , Peric-Hupkes Daan , de Wit Elzo , van Steensel Bas 
Published: September 2021

AbstractLamina associated domains (LADs) are large genomic regions that are positioned at the nuclear lamina (NL). It has remained largely unclear what drives the positioning and demarcation of LADs. Because the insulator protein CTCF is enriched at LAD borders, it was postulated that CTCF binding could position a subset of LAD boundaries, possibly through its function in stalling cohesin and hence preventing cohesin to invade into the LAD. To test this, we mapped genome – NL interactions in mouse embryonic stem cells after rapid depletion of CTCF and other perturbations of cohesin dynamics. CTCF and cohesin contribute to a sharp transition in NL interactions at LAD borders, whilst LADs are maintained after depletion of these proteins, also at borders marked by CTCF. CTCF and cohesin may thus reinforce LAD borders, but do not position these. CTCF binding sites within LADs are locally detached from the NL and enriched for accessible DNA and active histone modifications. Remarkably, even though NL positioning is strongly correlated with genome inactivity, this DNA remains accessible after the local detachment is lost following CTCF depletion. At a chromosomal scale, cohesin depletion and cohesin stabilization (depletion of the unloading factor WAPL) quantitatively affect NL interactions, indicative of perturbed chromosomal positioning in the nucleus. Finally, while H3K27me3 is locally enriched at CTCF-marked LAD borders, we find no evidence for an interplay between CTCF and H3K27me3 on NL interactions. Combined, these findings illustrate that CTCF and cohesin do not shape LAD patterns. Rather, these proteins mediate fine-tuning of NL interactions.
Glycosaminoglycans Modulate Long-Range Mechanical Communication Between Cells in Collagen Networks
Authors: Chen Xingyu , Chen Dongning , Ban Ehsan , Janmey Paul A. , Wells Rebecca G. , Shenoy Vivek B. 
Published: September 2021

AbstractCells can sense and respond to mechanical forces in fibrous extracellular matrices (ECM) over distances much greater than their size. This phenomenon, termed long-range force transmission, is enabled by the realignment (buckling) of collagen fibers along directions where the forces are tensile (compressive). However, whether other key structural components of the ECM, in particular glycosaminoglycans (GAGs), can affect the efficiency of cellular force transmission remains unclear. Here we developed a theoretical model of force transmission in collagen networks with interpenetrating GAGs, capturing the competition between tension-driven collagen-fiber alignment and the swelling pressure induced by GAGs. Using this model, we show that the swelling pressure provided by GAGs increases the stiffness of the collagen network by stretching the fibers in an isotropic manner. We found that the GAG-induced swelling pressure can help collagen fibers resist buckling as the cells exert contractile forces. This mechanism impedes the alignment of collagen fibers and decreases long-range cellular mechanical communication. We experimentally validated the theoretical predictions by comparing collagen fiber alignment between cellular spheroids cultured on collagen gels versus collagen-GAG co-gels. We found significantly less alignment of collagen in collagen-GAG co-gels, consistent with the prediction that GAGs can prevent collagen fiber alignment. The roles of GAGs in modulating force transmission uncovered in this work can be extended to understand pathological processes such as the formation of fibrotic scars and cancer metastasis, where cells communicate in the presence of abnormally high concentrations of GAGs.Statement of significanceGlycosaminoglycans (GAGs) are carbohydrates that are expressed ubiquitously in the human body and are among the key macromolecules that influence development, homeostasis, and pathology of native tissues. Abnormal accumulation of GAGs has been observed in metabolic disorders, solid tumors, and fibrotic tissues. Here we theoretically and experimentally show that tissue swelling caused by the highly polar nature of GAGs significantly affects the mechanical interactions between resident cells by altering the organization and alignment of the collagenous extracellular matrix. The roles of GAGs in modulating cellular force transmission revealed here can guide the design of biomaterial scaffolds in regenerative medicine and provides insights on the role of cell-cell communication in tumor progression and fibrosis.
The N terminus of adhesion G protein-coupled receptor GPR126/ADGRG6 as allosteric force integrator
Authors: Mitgau Jakob , Franke Julius , Schinner Camilla , Stephan Gabriele , Berndt Sandra , Placantonakis Dimitris G. , Kalwa Hermann , Spindler Volker , Wilde Caroline , Liebscher Ines 
Published: September 2021

AbstractThe adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown.In this study we provide this information by combining classic second messenger detection with single cell atomic force microscopy. We establish a monoclonal antibody targeting the N terminus to stimulate GPR126 and compare it to the activation through its known ECM ligands collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be viewed as an allosteric module that can fine-tune receptor activation in a context-specific manner.