bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prelimbic-amygdala overexcitability mediates trait vulnerability in a novel mouse model of acute social defeat stress
Authors: Grossman Yael S. , Fillinger Clementine , Manganaro Alessia , Voren George , Waldman Rachel , Zou Tiffany , Janssen William , Kenny Paul , Dumitriu Dani 
Published: June 2020

BACKGROUNDDepression is a debilitating neuropsychiatric disorder with 20% lifetime prevalence in the developed world but only approximately half of afflicted individuals respond to currently available therapies. While there is growing understanding of the neurobiological underpinnings of the depressed brain, much less is known about the preexisting circuitry leading to selective vulnerability versus resilience. Elucidating these networks could lead to novel preventative approaches.METHODSWe developed a model of acute social defeat stress (ASDS) that allows classification of male mice into “susceptible” (socially avoidant) versus “resilient” (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic to basolateral amygdala (PL→BLA) circuit in resilient versus susceptible mice. To test the functional relevance of identified structure/function differences to divergent behavioral responses, we used an intersectional chemogenetic approach to inhibit the PL→BLA circuit during or prior to ASDS.RESULTSSusceptible mice had greater PL→BLA recruitment during ASDS and activated PL→BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. Inhibition of the PL→BLA circuit led to a population shift towards resilience.CONCLUSIONPreexisting PL→BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support the PL→BLA circuit as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.
Fourier-transform-based attribution priors improve the interpretability and stability of deep learning models for genomics
Authors: Tseng Alex M. , Shrikumar Avanti , Kundaje Anshul 
Published: June 2020

AbstractDeep learning models can accurately map genomic DNA sequences to associated functional molecular readouts such as protein–DNA binding data. Base-resolution importance (i.e. “attribution”) scores inferred from these models can highlight predictive sequence motifs and syntax. Unfortunately, these models are prone to overfitting and are sensitive to random initializations, often resulting in noisy and irreproducible attributions that obfuscate underlying motifs. To address these shortcomings, we propose a novel attribution prior, where the Fourier transform of input-level attribution scores are computed at training-time, and high-frequency components of the Fourier spectrum are penalized. We evaluate different model architectures with and without attribution priors trained on genome-wide binary or continuous molecular profiles. We show that our attribution prior dramatically improves models’ stability, interpretability, and performance on held-out data, especially when training data is severely limited. Our attribution prior also allows models to identify biologically meaningful sequence motifs more sensitively and precisely within individual regulatory elements. The prior is agnostic to the model architecture or predicted experimental assay, yet provides similar gains across all experiments. This work represents an important advancement in improving the reliability of deep learning models for deciphering the regulatory code of the genome.
Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens
Authors: Dobaño Carlota , Vidal Marta , Santano Rebeca , Jiménez Alfons , Chi Jordi , Barrios Diana , Ruiz-Olalla Gemma , Melero Natalia Rodrigo , Carolis Carlo , Parras Daniel , Serra Pau , de Aguirre Paula Martínez , Carmona-Torre Francisco , Reina Gabriel , Santamaria Pere , Mayor Alfredo , García-Basteiro Alberto , Izquierdo Luis , Aguilar Ruth , Moncunill Gemma 
Published: June 2020

ABSTRACTReliable serological tests are required to determine the prevalence of antibodies against SARS-CoV-2 antigens and to characterise immunity to the disease in order to address key knowledge gaps in the context of the COVID-19 pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and ELISA with their higher precision, dynamic range, throughput, miniaturization, cost-efficacy and multiplexing capacity. We developed three qSAT assays to detect IgM, IgA and IgG to a panel of eight SARS-CoV-2 antigens including spike (S), nucleoprotein (N) and membrane (M) protein constructs. The assays were optimized to minimize processing time and maximize signal to noise ratio. We evaluated the performance of the assays using 128 plasmas obtained before the COVID-19 pandemic (negative controls) and 115 plasmas from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 8 were asymptomatic, 58 had mild symptoms and 49 were hospitalized. Pre-existing IgG antibodies recognizing N, M and S2 proteins were detected in negative controls suggestive of cross-reactive to common cold coronaviruses. The best performing antibody isotype/antigen signatures had specificities of 100% and sensitivities of 94.94% at ≥14 days since the onset of symptoms and 96.08% at ≥21 days since the onset of symptoms, with AUC of 0.992 and 0.999, respectively. Combining multiple antibody markers as assessed by qSAT assays has the highest efficiency, breadth and versatility to accurately detect low-level antibody responses for obtaining reliable data on prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity required for vaccine development to combat pandemics like the COVID-19.
Amyotrophic lateral sclerosis associated mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex
Authors: Dyer MS , Lewis KE , Walker AK , Dickson TC , Woodhouse A , Blizzard CA 
Published: June 2020

AbstractAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA binding protein TAR-DNA binding protein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changes occurring in people with ALS and mouse models of disease. To investigate the effect of mislocalized TDP-43 on the function of motor cortex neurons we utilised mouse models that express either human wild-type (TDP-43WT) or nuclear localization sequence-deficient TDP-43 (TDP-43ΔNLS) on an inducible promoter that is restricted to the forebrain. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression TDP-43ΔNLSin adult mice (60 days of age) does not cause any changes in the number of NeuN positive nor CTIP2 positive neurons in the motor cortex. However at this time-point the expression of TDP-43ΔNLSdrives intrinsic hyperexcitability in layer V excitatory neurons of the motor cortex. This hyperexcitability occurs concomitantly with a decrease in excitatory synaptic input to these cells. This pathophysiology is not present when TDP-43WTexpression is driven, demonstrating that the localisation of TDP-43 to the cytoplasm is crucial for the altered excitability phenotype. This study has important implications for the mechanisms of toxicity of one of the most notorious proteins linked to ALS, TDP-43. We provide the first evidence that TDP-43 mislocalization causes aberrant synaptic function and a hyperexcitability phenotype in the motor cortex, linking some of the earliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.
Computational Investigation Of Blood Flow And Flow-mediated Transport In Arterial Thrombus Neighborhood
Authors: Teeraratkul Chayut , Irwin Zachariah , Shadden Shawn C. , Mukherjee Debanjan 
Published: June 2020

AbstractA pathologically formed blood clot or thrombus is central to major cardiovascular diseases like heart attack and stroke. Detailed quantitative evaluation of flow and flow-mediated transport processes in the thrombus neighborhood within large artery hemodynamics is crucial for understanding disease progression and assessing treatment efficacy. This, however, remains a challenging task owing to the complexity of pulsatile viscous flow interactions with arbitrary shape and heterogeneous microstructure of realistic thrombi. Here, we address this challenge by conducting a systematic parametric simulation based study on characterizing unsteady hemodynamics and flow-mediated transport in the neighborhood of an arterial thrombus. We use a hybrid particle-continuum based finite element approach to handle arbitrary thrombus shape and microstructural variations. Results from a cohort of 50 different unsteady flow scenarios are presented, including unsteady vortical structures, pressure-gradient across the thrombus boundary, finite time Lyapunov exponents, and dynamic coherent structures that organize advective transport. We clearly illustrate the combined influence of three key parameters - thrombus shape, microstructure, and extent of wall disease - in terms of: (a) determining hemodynamic features in the thrombus neighborhood; and (b) governing the balance between advection, permeation, and diffusion to regulate transport processes in the thrombus neighborhood.
Hot droughts compromise interannual survival across all group sizes in a cooperatively breeding bird
Authors: Bourne Amanda R. , Cunningham Susan J. , Spottiswoode Claire N. , Ridley Amanda R. 
Published: June 2020

AbstractIncreasingly harsh and unpredictable climate regimes are affecting animal populations around the world as climate change advances. One relatively unexplored aspect of species vulnerability to climate change is whether and to what extent responses to environmental stressors might be mitigated by variation in group size in social species. We used a 15-year dataset for a cooperatively-breeding bird, the southern pied babblerTurdoides bicolor, to determine the impact of temperature, rainfall, and group size on body mass change and interannual survival in both juveniles and adults. Hot and dry conditions were associated with reduced juvenile growth, mass loss in adults, and compromised survival between years in both juveniles (−86%) and adults (−60%). Individuals across all group sizes experienced similar effects of climatic conditions. Larger group sizes may not buffer individual group members against the impacts of hot and dry conditions, which are expected to increase in frequency and severity in future.
Sensitivity of commercial Anti-SARS-CoV-2 serological assays in a high-prevalence setting
Authors: Müller Lisa , Ostermann Philipp N. , Walker Andreas , Wienemann Tobias , Mertens Alexander , Adams Ortwin , Andree Marcel , Hauka Sandra , Lübke Nadine , Keitel Verena , Drexler Ingo , Di Cristanziano Veronica , Hermsen Derik Franz , Kaiser Rolf , Boege Friedrich , Klein Florian , Schaal Heiner , Timm Jörg , Senff Tina 
Published: June 2020

AbstractWe analysed SARS-CoV-2 specific antibody responses in 42 social and working contacts of a super-spreader from the Heinsberg area in Germany. Consistent with a high-prevalence setting 26 individuals had SARS-CoV-2 antibodies determined by in-house neutralisation testing. These results were compared with four commercial assays, suggesting limited sensitivity of the assays in such a high-prevalence setting. Although SARS-CoV-2 nucleocapsid-restricted tests showed a better sensitivity, spike-based assays had a stronger correlation with neutralisation capacity.
The actin networks of chytrid fungi reveal evolutionary loss of cytoskeletal complexity in the fungal kingdom
Authors: Prostak Sarah M. , Robinson Kristyn A. , Titus Margaret A. , Fritz-Laylin Lillian K. 
Published: June 2020

ABSTRACTCells from across the eukaryotic tree use actin polymers and a number of conserved regulators for a wide variety of functions including endocytosis, cytokinesis, and cell migration. Despite this conservation, the actin cytoskeleton has undergone significant evolution and diversification, highlighted by the differences in the actin cytoskeletal networks of mammalian cells and yeast. Chytrid fungi diverged before the emergence of the Dikarya (multicellular fungi and yeast), and therefore provide a unique opportunity to study the evolution of the actin cytoskeleton. Chytrids have two life stages: zoospore cells that can swim with a flagellum, and sessile sporangial cells that, like multicellular fungi, are encased in a chitinous cell wall. Here we show that zoospores of the amphibian-killing chytrid Batrachochytrium dendrobatidis (Bd) build dynamic actin structures that resemble those of animal cells, including pseudopods, an actin cortex, and filopodia-like actin spikes. In contrast, Bd sporangia assemble actin patches similar to those of yeast, as well as perinuclear actin shells. Our identification of actin cytoskeletal elements in the genomes of five species of chytrid fungi indicate that these actin structures are controlled by both fungal-specific components as well as actin regulators and myosin motors found in animals but not other fungal lineages. The use of specific small molecule inhibitors indicate that nearly all of Bd’s actin structures are dynamic and use distinct nucleators: while pseudopods and actin patches are Arp2/3-dependent, the actin cortex appears formin-dependent, and actin spikes require both nucleators. The presence of animal- and yeast-like actin cytoskeletal components in the genome combined with the intermediate actin phenotypes in Bd suggests that the simplicity of the yeast cytoskeleton may be due to evolutionary loss.
The genetic organization of subcortical volumetric change is stable throughout the lifespan
Authors: Fjell Anders M , Grydeland Håkon , Wang Yunpeng , Amlien Inge , Bartrés-Faz David , Brandmaier Andreas M. , Düzel Sandra , Elman Jeremy , Franz Carol , Håberg Asta K. , Kietzmann Tim C. , Kievit Rogier A. , Kremen William S , Krogsrud Stine K , Kühn Simone , Lindenberger Ulman , Macià Didac , Mowinckel Athanasia M. , Nyberg Lars , Panizzon Matthew S. , Solé-Padullés Cristina , Sørensen Øystein , Westerhausen René , Walhovd Kristine B 
Published: June 2020

AbstractWhile development and aging of the cerebral cortex show a similar topographic organization and are mainly governed by the same genes, it is unclear whether the same is true for subcortical structures, which follow fundamentally different ontogenetic and phylogenetic principles than the cerebral cortex. To test the hypothesis that genetically governed neurodevelopmental processes can be traced in subcortical structures throughout life, we analyzed a longitudinal magnetic resonance imaging dataset (n = 974, age 4-89 years), identifying five clusters of longitudinal change in development. With some exceptions, these clusters followed placement along the cranial axis in embryonic brain development, suggesting continuity in the pattern of change from prenatal stages. Developmental change patterns were conserved through the lifespan and predicted general cognitive function in an age-invariant manner. The results were replicated in longitudinal data from the Lifebrain consortium (n = 756, age 19-83 years). Genetic contributions to longitudinal brain changes were calculated from the Vietnam Era Twin Study of Aging (n = 331 male twins, age 51-60 years), revealing that distinct sets of genes tended to govern change for each developmental cluster. This finding was confirmed with single nucleotide polymorphisms and cross-sectional MRI data from the UK Biobank (n = 20,588, age 40-69), demonstrating significantly higher co-heritability among structures belonging to the same developmental clusters. Together, these results suggest that coordination of subcortical change adheres to fundamental principles of lifespan continuity, genetic organization and age-invariant relationships to cognitive function.Significance statementHere we show that subcortical change during childhood development is organized in clusters. These clusters tend to follow the main gradient of embryonic brain development, and are stable across life. This means that subcortical regions changing together in childhood also change together throughout the rest of life, in accordance with a lifespan perspective on brain development and aging. Twin and single nucleotide polymorphism-based heritability analyses in middle-aged and older adults showed that volume and volume change of regions within each developmental cluster tended to be governed by the same sets of genes. Thus, volumetric changes across subcortical regions are tightly organized, and the coordinated change can be described in a lifespan perspective according to ontogenetic and genetic influences.
Oscillating and stable genome topologies underlie hepatic physiological rhythms during the circadian cycle
Authors: Mermet Jérôme , Yeung Jake , Naef Félix 
Published: June 2020

AbstractThe circadian clock drives extensive temporal gene expression programs controlling daily changes in behavior and physiology. In mouse liver, transcription factors dynamics, chromatin modifications, and RNA Polymerase II (PolII) activity oscillate throughout the 24-hour (24h) day, regulating the rhythmic synthesis of thousands of transcripts. Also, 24h rhythms in gene promoter-enhancer chromatin looping accompany rhythmic mRNA synthesis. However, how chromatin organization impinges on temporal transcription and liver physiology remains unclear. Here, we applied time-resolved chromosome conformation capture (4C-seq) in livers of WT and arrhythmicBmal1knockout mice. In WT, we observed 24h oscillations in promoter-enhancer contact at multiple loci including the core-clock genesPeriod1, Period2andBmal1. In addition, we detected rhythmic PolII activity, chromatin modifications and transcription involving stable chromatin loops at gene promoters representing key liver function such as glucose and lipid metabolism and detoxification. Intriguingly, these contacts persisted in clock-impaired mice in which both PolII activity and chromatin marks no longer oscillated. Finally, we observed chromatin interaction hubs connecting neighbouring genes showing coherent transcription regulation across genotypes. Thus, both clock-controlled and clock-independent chromatin topology underlie rhythmic regulation of liver physiology.
Exosite inhibition of A Disintegrin And Metalloproteinase with Thrombospondin motif (ADAMTS)-5 by a glycoconjugated arylsulfonamide
Authors: Salvatore Santamaria , Cuffaro Doretta , Nuti Elisa , Ciccone Lidia , Tuccinardi Tiziano , Liva Francesca , D’Andrea Felicia , de Groot Rens , Rossello Armando , Ahnström Josefin 
Published: June 2020

AbstractADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Its aggrecanase activity has been directly linked to the etiology of osteoarthritis (OA), identifying ADAMTS-5 as a pharmaceutical target for OA treatment. However, most existing ADAMTS-5 inhibitors target its active site and therefore suffer from poor selectivity. Here, using a novel approach, we have designed a new class of sugar-based arylsulfonamide inhibitors, which are selective for ADAMTS-5 through binding to a previously unknown substrate-binding site (exosite). Docking calculations combined with molecular dynamics simulations demonstrated that our lead compound is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Targeted mutagenesis identified disintegrin-like domain residues K532 and K533 as an exosite which is critical for substrate recognition. Furthermore, we show that this exosite acts as major determinant for inhibitor binding and, therefore, can be targeted for development of selective ADAMTS-5 inhibitors.
Late ESCRT Machinery Mediates The Recycling And Rescue of Invariant Surface Glycoprotein 65 inTrypanosoma brucei
Authors: Umaer Khan , Bangs James D. 
Published: June 2020

ABSTRACTTheEndosomalSortingComplexRequired forTransport machinery consists of four protein complexes (ESCRT 0-IV) and the post ESCRT ATPase Vps4. ESCRT mediates cargo delivery for lysosomal degradation via formation of multivesicular bodies.Trypanosoma bruceicontains orthologues of ESCRT I-III and Vps4. Trypanosomes also have a ubiquitinylated invariant surface glycoprotein (ISG65) that is delivered to the lysosome by ESCRT, however, we previously implicated TbVps4 in rescue and recycling of ISG65. Here we use conditional silencing to investigate the role of TbVps24, a phosphoinositide-binding ESCRT III component, on protein trafficking. TbVps24 localizes to the TbRab7+late endosome, and binds PI(3,5)P2, the product of the TbFab1 kinase, both of which also localize to late endosomes. TbVps24 silencing is lethal, and negatively affects biosynthetic trafficking of the lysosomal markers p67 and TbCathepsin L. However, the major phenotype of silencing is accelerated degradation and depletion of the surface pool of ISG65. Thus, TbVps24 silencing phenocopies that of TbVps4 in regard to ISG65 trafficking. This presents a paradox since we have previously found that depletion of TbFab1 completely blocks ISG65 turnover. We propose a model in which late ESCRT components operate at two sites, one PI(3,5)P2-dependent (degradation) and one PI(3,5)P2-independent (recycling), to regulate ISG65 homeostasis.