bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
Authors: Tanzer Maria C , Bludau Isabell , Stafford Che A , Hornung Veit , Mann Matthias 
Published: November 2020

SummaryTumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. We reasoned that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Combining phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis identifies functional modules of phosphorylations. The majority of regulated phosphorylations could be assigned to an upstream kinase by inhibiting master kinases and spatial proteomics revealed phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovered a key role for transcriptional cyclin-dependent kinase (CDK) activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. Our comprehensive interrogation of TNF induced pathways and sites can be explored athttp://tnfviewer.biochem.mpg.de/.Highlights-Distinct phosphorylation events mark early and late TNF signaling-Inhibition of master kinases reveals TNF stimulation dependent kinase-substrate relations-TNF induces phosphorylation-dependent spatial rearrangement of hundreds of proteins-CDK kinase activity promotes TNF-induced cytokine expression and inhibits cell death-CDK12/13 inhibitors have potential as anti-inflammatory agents
Ligand-induced motions in pentameric ligand-gated ion channels revealed by EPR spectroscopy
Authors: Tiwari Varun , Borchardt Jennifer , Schuh Abby , Klug Candice S. , Czajkowski Cynthia 
Published: November 2020

AbstractSignaling in the brain depends on rapid opening and closing of pentameric ligand-gated ion channels (pLGICs). These proteins are the targets of various clinical drugs and, defects in their function is linked to a variety of diseases including myasthenia, epilepsy and sleep-disorders. While recent high-resolution structures of prokaryotic and eukaryotic pLGICs have shed light on the molecular architecture of these proteins, describing their conformational dynamics in physiological lipids is essential for understanding their function. Here, we used site-directed spin labeling electron paramagnetic resonance (SDSL EPR) spectroscopy and functional channels reconstituted in liposomes to reveal ligand-induced structural changes in the extracellular domain (ECD) of GLIC. Proton-activation caused an inward motion of labeled sites at the top of β-strands (β1, 2, 5, 6, 8) towards the channel lumen, consistent with an agonist-induced inward tilting motion of the ECD. Similar proton-dependent GLIC ECD motions were detected in the presence of a non-activating (gating deficient) mutation, suggesting that the inward tilting of the ECD does not accompany channel opening but is associated with an agonist-induced closed pre-activated channel state. These findings provide new insights into the protein dynamics underlying pLGIC gating transitions.
Cell wall damage impairs root hair cell patterning and tissue morphogenesis mediated by the Arabidopsis receptor kinase STRUBBELIG
Authors: Chaudhary Ajeet , Chen Xia , Leśniewska Barbara , Gao Jin , Wolf Sebastian , Schneitz Kay 
Published: November 2020

AbstractCell wall remodeling is essential for the control of growth and development as well as the regulation of stress responses. However, the underlying cell wall monitoring mechanisms remain poorly understood. Regulation of root hair fate and flower development inArabidopsis thalianarequires signaling mediated by the atypical receptor kinase STRUBBELIG (SUB). Furthermore, SUB is involved in cell wall integrity signaling and regulates the cellular response to reduced levels of cellulose, a central component of the cell wall. Here, we show that continuous exposure to sub-lethal doses of the cellulose biosynthesis inhibitor isoxaben results in altered root hair patterning and floral morphogenesis. Genetically impairing cellulose biosynthesis also results in root hair patterning defects. We further show that isoxaben exerts its developmental effects through the attenuation of SUB signaling. Our evidence indicates that down-regulation of SUB is a multi-step process and involves changes in SUB complex architecture at the plasma membrane, enhanced removal of SUB from the cell surface, and downregulation ofSUBtranscript levels. The results provide molecular insight into how the cell wall regulates cell fate and tissue morphogenesis.
Precision medicine for the rescue of specific impairments in social behavior associated with the A350VIqsec2mutation
Authors: Jabarin Renad , Levy Nina , Abergel Yasmin , Berman Joshua H. , Zag Amir , Netser Shai , Levy Andrew P. , Wagner Shlomo 
Published: November 2020

AbstractIn this study we tested the hypothesis that precision medicine guided therapy targeting glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in theIqsec2gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in theIQSEC2gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. We found that A350VIqsec2mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with PF-4778574. We conclude that social behavior deficits associated with the A350VIqsec2mutation may be rescued by enhancing AMPAR mediated synaptic transmission.
Landmark-Centered Coding in Frontal Cortex Visual Responses
Authors: Schütz Adrian , Bharmauria Vishal , Yan Xiaogang , Wang Hongying , Bremmer Frank , Crawford J. Douglas 
Published: November 2020

SummaryVisual landmarks influence spatial cognition [1–3], navigation [4,5] and goal-directed behavior [6–8], but their influence on visual coding in sensorimotor systems is poorly understood [6,9–11]. We hypothesized that visual responses in frontal cortex control gaze areas encode potential targets in an intermediate gaze-centered / landmark-centered reference frame that might depend on specific target-landmark configurations rather than a global mechanism. We tested this hypothesis by recording neural activity in the frontal eye fields (FEF) and supplementary eye fields (SEF) while head-unrestrained macaques engaged in a memory-delay gaze task. Visual response fields (the area of visual space where targets modulate activity) were tested for each neuron in the presence of a background landmark placed at one of four oblique configurations relative to the target stimulus. 102 of 312 FEF and 43 of 256 SEF neurons showed spatially tuned response fields in this task. We then fit these data against a mathematical continuum between a gaze-centered model and a landmark-centered model. When we pooled data across the entire dataset for each neuron, our response field fits did not deviate significantly from the gaze-centered model. However, when we fit response fields separately for each target-landmark configuration, the best fits shifted (mean 37% / 40%) toward landmark-centered coding in FEF / SEF respectively. This confirmed an intermediate gaze / landmark-centered mechanism dependent on local (configuration-dependent) interactions. Overall, these data show that external landmarks influence prefrontal visual responses, likely helping to stabilize gaze goals in the presence of variable eye and head orientations.HighlightsPrefrontal visual responses recorded in the presence of visual landmarksResponse fields showed intermediate gaze / landmark-centered organizationThis influence depended on specific target-landmark configurations
Advanced Biophysical Model to Capture Channel Variability for EQS Capacitive HBC
Authors: Datta Arunashish , Nath Mayukh , Yang David , Sen Shreyas 
Published: November 2020

AbstractHuman Body Communication (HBC) has come up as a promising alternative to traditional radio frequency (RF) Wireless Body Area Network (WBAN) technologies. This is essentially due to HBC providing abroadbandcommunication channel with enhanced signal security in the physical layer due to lower radiation from the human body as compared to its RF counterparts. An in-depth understanding of the mechanism for the channel loss variability and associated biophysical model needs to be developed before EQS-HBC can be used more frequently in WBAN consumer and medical applications. Biophysical models characterizing the human body as a communication channel didn’t exist in literature for a long time. Recent developments have shown models that capture the channel response for fixed transmitter and receiver positions on the human body. These biophysical models do not capture the variability in the HBC channel for varying positions of the devices with respect to the human body. In this study, we provide a detailed analysis of the change in path loss in a capacitive-HBC channel in the electroquasistatic (EQS) domain. Causes of channel loss variability namely: inter-device coupling and effects of fringe fields due to body’s shadowing effects are investigated. FEM based simulation results are used to analyze the channel response of human body for different positions and sizes of the device which are further verified using measurement results to validate the developed biophysical model. Using the bio-physical model, we develop a closed form equation for the path loss in a capacitive HBC channel which is then analyzed as a function of the geometric properties of the device and the position with respect to the human body which will help pave the path towards future EQS-HBC WBAN design.
A Polynomial-Time Algorithm for Minimizing the Deep Coalescence Cost for Level-1 Species Networks
Authors: LeMay Matthew , Libeskind-Hadas Ran , Wu Yi-Chieh 
Published: November 2020

AbstractPhylogenetic analyses commonly assume that the species history can be represented as a tree. However, in the presence of hybridization, the species history is more accurately captured as a network. Despite several advances in modeling phylogenetic networks, there is no known polynomial-time algorithm for parsimoniously reconciling gene trees with species networks while accounting for incomplete lineage sorting. To address this issue, we present a polynomial-time algorithm for the case of level-1 networks, in which no hybrid species is the direct ancestor of another hybrid species. This work enables more efficient reconciliation of gene trees with species networks, which in turn, enables more efficient reconstruction of species networks.
Relaxed 3D genome conformation facilitates the pluripotent to totipotent state transition in embryonic stem cells
Authors: Yu Jiali , Zhu Yezhang , Gu Jiahui , Xue Chaoran , Zhang Long , Chen Jiekai , Shen Li 
Published: November 2020

SUMMARYThe 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastmeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq, and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotency-to-totipotency transition in mouse embryonic stem cells (ESCs). The totipotent 2-cell-embro-like cells (2CLCs) exhibit more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former leads to inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter may facilitate contacts between the new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin loops by depleting CTCF or cohesin promotes ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.HIGHLIGHTSGlobal weakening of the 3D genome conformation during ESC to 2CLC transitionLoss of enhancer-promoter loops and down-regulation of pluripotent genes in 2CLCsInactivation of ESC enhancers and formation of new enhancers in 2CLCsDisruption of chromatin loops by depleting CTCF or cohesin promotes 2CLC emergence
Genomic Characterization of Tissue Invasive Klebsiella pneumoniae Complex in a Hospital System with a Focus on Species Distribution and Hypervirulence
Authors: Bohrhunter Jessica , Taffner Samantha , Wang Jun , Hardy Dwight , Pecora Nicole 
Published: November 2020

AbstractKlebsiella pneumoniae is an opportunistic pathogen known for multidrug resistance. Current research indicates that K. pneumoniae is a complex of closely related organisms (K. pneumoniae sensu stricto, K. quasipneumoniae, K. variicola, K. quasivariicola, and K. africana). Additionally, some strains of K. pneumoniae sensu stricto, known as hypervirulent K. pneumoniae (hvKp), cause severe infections in healthy members of the community. There is a paucity of research into rates of hvKp in the United States, the distribution of K. pneumoniae complex members in clinical specimens, and the pathogenic potential of complex members other than K. pneumoniae sensu stricto. We assessed the rates of hvKp and K. pneumoniae complex members in our 886 bed tertiary care facility in Rochester, New York. We performed whole genome sequencing on all inpatient, sterile-source isolates identified by routine culture work-up as K. pneumoniae from October 2018 – October 2019 (n=35). We additionally sequenced all K. pneumoniae liver isolates available in our collection, spanning 2017-2019 (n=18). In the yearlong collection of K. pneumoniae complex isolates, we found that 92.4% were K. pneumoniae sensu stricto (n=32), 5.7% were K. quasipneumoniae (n=2), and 2.9% were K. variicola (n=1). Five hvKp isolates were found, representing 5.7% (n=2) of K. pneumoniae sensu stricto isolates in the yearlong collection and 27.7% (n=5) of the liver isolate collection. All hvKp isolates were from liver; 60% were not associated with prior international residence.
gene.iobio: an interactive web tool for versatile, clinically-driven variant interrogation and prioritization
Authors: Di Sera Tonya , Velinder Matt , Ward Alistair , Qiao Yi , Georges Stephanie , Miller Chase , Pitman Anders , Richards Will , Ekawade Aditya , Viskochil David , Carey John C , Pace Laura , Bale Jim , Clardy Stacey L , Andrews Ashley , Botto Lorenzo , Marth Gabor 
Published: November 2020

AbstractWith increasing utilization of comprehensive genomic data to guide clinical care, anticipated to become the standard of care in many clinical settings, the practice of diagnostic medicine is undergoing a notable shift. However, the move from single-gene or panel-based genetic testing to exome and genome sequencing has not been matched by the development of tools to enable diagnosticians to interpret increasingly complex genomic findings. A new paradigm has emerged, where genome-based tests are often evaluated by a large multi-disciplinary collaborative team, typically including a diagnostic pathologist, a bioinformatician, a genetic counselor, and often a subspeciality clinician. This team-based approach calls for new computational tools to allow every member of the clinical care provider team, at varying levels of genetic knowledge and diagnostic expertise, to quickly and easily analyze and interpret complex genomic data. Here, we presentgene.iobio, a real-time, intuitive and interactive web application for clinically-driven variant interrogation and prioritization. We showgene.iobiois a novel and effective approach that significantly improves upon and reimagines existing methods. In a radical departure from existing methods that present variants and genomic data in text and table formats,gene.iobioprovides an interactive, intuitive and visually-driven analysis environment. We demonstrate that adoption ofgene.iobioin clinical and research settings empowers clinical care providers to interact directly with patient genomic data both for establishing clinical diagnoses and informing patient care, using sophisticated genomic analyses that previously were only accessible via complex command line tools.
Ecological dynamics of the almond floral microbiome in relation to crop management and pollination
Authors: Schaeffer Robert N. , Crowder David W. , Illán Javier Gutiérrez , Beck John J. , Fukami Tadashi , Williams Neal M. , Vannette Rachel L. 
Published: November 2020

AbstractCrop tissues harbor microbiomes that can affect host health and yield. However, processes driving microbiome assembly, and resulting effects on ecosystem services, remain poorly understood. This is particularly true of flowering crops that rely on pollinators for yield.We assessed effects of orchard management tactics and landscape context on the flower microbiome in almond,Prunus dulcis. Fourteen orchards (5 conventional, 4 organic, 5 habitat augmentation) were sampled at two bloom stages to characterize bacterial and fungal communities associated with floral tissues. The surveys were complemented byin vitroexperiments to assess effects of arrival order and fungicides on nectar microbial communities, and effects of fungicides and microbes on honey bee foraging. Finally, a field trial was conducted to test effects of fungicides and microbes on pollination.As bloom progressed, bacterial and fungal abundance and diversity increased, across all floral tissue types and management strategies. The magnitude by which microbial abundance and diversity were affected varied, with host proximity to apiaries and orchard management having notable effects on bacteria and fungi, respectively.Experiments showed immigration history and fungicides affected the composition of nectar microbial communities, but only fungicides affected pollinator foraging through reduced nectar removal. Neither treatment affected pollination services.Synthesis and applications. Our results shed light on routes through which management practices can shape microbiota associated with flowers of a pollinator-dependent crop. With growing appreciation for the role of floral-associated microbes in affecting biotic interactions at the floral interface, understanding such drivers can potentially inform microbial-derived ecosystem services in agricultural landscapes, including pollination and biocontrol.
Identification of a novel fold type in CPA/AT transporters by ab-initio structure prediction
Authors: Bassot Claudio , Govindarajan Sudha , Lamb John , Elofsson Arne 
Published: November 2020

AbstractMembers of the CPA/AT transporter superfamily show significant structural variability. All previously known members consist of an inverted duplicated repeat unit that folds into two separate domains, the core and the scaffold domain. Crucial for its transporting function, the central helix in the core domain is a noncanonical transmembrane helix, which can either be in the form of a broken helix or a reentrant helix. Here, we expand the structural knowledge of the CPA/AT family by using contact-prediction-based protein modelling. We show that the N-terminal domains of the Pfam families; PSE (Cons_hypoth698 PF03601), Lysine exporter (PF03956) and LrgB (PF04172) families have a previously unseen reentrant-helix-reentrant fold. The close homology between PSE and the Sodium-citrate symporter (2HCT) suggests that the new fold originates from the truncation of an ancestral reentrant protein, caused by the loss of the C-terminal reentrant helix. To compensate for the lost reentrant helix one external loop moves into the membrane to form the second reentrant helix, highlighting the adaptability of the CPA/AT transporters. This study also demonstrates that the most recent deep-learning-based modelling methods have become a useful tool to gain biologically relevant structural, evolutionary and functional insights about protein families.
Gene-corrected Parkinson’s disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function
Authors: Barbuti Peter A. , Santos Bruno FR. , Antony Paul M. , Massart Francois , Cruciani Gérald , Dording Claire M. , Pavelka Lukas , Kwon Yong-Jun , Krüger Rejko 
Published: November 2020

AbstractParkinson’s disease is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. In a patient-derived stem cell model, we have generated dopaminergic neurons from an individual harbouring the p.A30P SNCA mutation and compared those neurons against gene-corrected isogenic control cell lines. We have used confocal microscopy to assess the neuronal network, specifically segmenting dopaminergic neurons and have identified image-based phenotypes showing axonal impairment and reduced neurite branching. We show using multi-electrode array (MEA) technology that the neurons carrying the endogenous p.A30P alpha-synuclein mutation are functionally impaired and identified mitochondrial dysfunction as a pathogenic cellular phenotype. We report that against gene-corrected isogenic control cell lines the neurons carrying the p.A30P SNCA mutation have a deficit and are susceptible to the mitochondrial toxin and environmental pesticide Rotenone. Our data supports the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease modifying compound screenings and drug discovery strategies.