bluuebunny/crossref_metadata_2025_split huggingface dataset:
An integral genomic signature approach for tailored cancer targeted therapy using genome-wide sequencing data
Authors: Wang Xiaosong , Lee Sanghoon , Tang Gong , Wang Yue 
Published: February 2021

ABSTRACTWith the advent of low-cost sequencing, transcriptome and genome sequencing is expected to become clinical routine and transform precision oncology within next decade. However, viable genome-wide modeling methods that can facilitate rational selection of patients for tailored intervention while tolerating sequencing biases are far lacking. Here we propose an integral genomic signature (iGenSig) analysis as a new class of transparent, interpretable, and resilient methods for precision oncology based on multiple types of genome-wide sequencing data. We postulate that the redundant high-dimensional genomic features, which are typically eliminated during multi-omics modeling, may help overcome the sequencing biases. We thus conceive a novel method that models the therapeutic response using the high-dimensional transcriptional and mutational features predictive of tumor response, which we termed as an integral genomic signature (iGenSig), and then algorithmically resolve the feature redundancy tailored for each patient subject. Using genomic dataset of chemical perturbations, we developed the iGenSig models for predicting targeted therapy responses, and applied selected models to independent datasets for cancer cell lines, patient-derived xenografts, and patient subjects. iGenSig models exhibit outstanding cross-dataset performance compared to artificial intelligence methods, with exceptional resilience against simulated errors in genomic features. In particular, the iGenSig model for the EGFR inhibitor Erlotinib significantly predicted the responses of patient-derived xenografts and patients from a clinical trial, biological interpretation of which led to new insights into the predictive signature pathways with clinical relevance. Together, iGenSig will provide a computational infrastructure to empower tailored cancer intervention based on genome-wide sequencing data.
Predators affect a plant virus through direct and trait-mediated indirect effects on vectors
Authors: Lee Benjamin W. , Clark Robert E. , Basu Saumik , Crowder David W. 
Published: February 2021

AbstractArthropods that vector plant pathogens often interact with predators within food webs. Predators affect vectors by eating them (consumptive effects) and by inducing antipredator behaviors (non-consumptive effects), and these interactions may affect transmission of vector-borne pathogens. However, it has proven difficult to experimentally tease apart the effects of predators on vector fitness and behavior as they are often correlated. We addressed this problem by assessing how both aphids and an aphid-borne pathogen were affected by variable predation risk. Specifically, we experimentally manipulated ladybeetle predators’ mouthparts to isolate consumptive, and non-consumptive, effects of predators on aphid fitness, movement, and virus transmission. We show that although lethal predators decreased aphid vector abundance, they increased pathogen transmission by increasing aphid movement among hosts. Moreover, aphids responded to risk of predation by moving to younger plant tissue that was more susceptible to the pathogen. Aphids also responded to predator risk through compensatory reproduction, which offset direct consumptive effects. Our results support predictions of disease models showing alterations of vector movement due to predators can have greater effects on transmission of pathogens than vector consumption. Broadly, our study shows isolating direct and indirect predation effects can reveal novel pathways by which predators affect vector-borne pathogens.
The Serine Protease HtrA2 mediates radiation-induced senescence in cancer cells
Authors: Hammer Liat , Levin-Salomon Vered , Yaeli-Slonim Naama , Weiss Moria , Dekel-Bird Naama P. , Olender Tsviya , Porat Ziv , Winograd-Katz Sabina , Savidor Alon , Levin Yishai , Bialik Shani , Geiger Benjamin , Kimchi Adi 
Published: February 2021

AbstractRadiation therapy can induce cellular senescence in cancer cells leading to short-term tumor growth arrest, yet increased long-term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation-induced senescence in cultured cancer cells, which exhibited a typical senescent phenotype, including upregulation of p53 and its target p21, followed by sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence-associated beta-galactosidase activity. A functional siRNA screen using a cell death-related library identified the mitochondrial Ser protease HtrA2 as necessary for senescence development. Mass spectrometry-based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy, while irradiation with HtrA2 inhibition upregulated cell proliferation components. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus HtrA2, contributes to several hallmarks of senescence and is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence.SummaryHere the authors identify the Ser protease HtrA2 as a novel mediator of radiation-induced senescence, necessary for sustained proliferation arrest and reorganization of the vimentin filament network.
Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits
Authors: Yao Heng Kang , Guet-McCreight Alexandre , Mazza Frank , Chameh Homeira Moradi , Prevot Thomas D. , Griffiths John , Tripathy Shreejoy J. , Valiante Taufik A. , Sibille Etienne , Hay Etay 
Published: February 2021

AbstractCortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.
A cell atlas of chromatin accessibility across 25 adult human tissues
Authors: Zhang Kai , Hocker James D. , Miller Michael , Hou Xiaomeng , Chiou Joshua , Poirion Olivier B. , Qiu Yunjiang , Li Yang E. , Gaulton Kyle J. , Wang Allen , Preissl Sebastian , Ren Bing 
Published: February 2021

SUMMARYCurrent catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of human gene regulatory elements in diverse cell types and tissues in the human body, we applied single cell chromatin accessibility assays to 25 distinct human tissue types from multiple donors. The resulting chromatin maps comprising ∼500,000 nuclei revealed the status of open chromatin for over 750,000 candidatecis-regulatory elements (cCREs) in 54 distinct cell types. We further delineated cell type-specific and tissue-context dependent gene regulatory programs, and developmental stage specificity by comparing with a recent human fetal chromatin accessibility atlas. We finally used these chromatin maps to interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues and organ systems.
Heparan Sulfated Glypican-4 is Released from Astrocytes Predominantly by Proteolytic Shedding
Authors: Huang Kevin , Park Sungjin 
Published: February 2021

AbstractAstrocytes provide neurons with diffusible factors that promote synapse formation and maturation. In particular, glypican-4/GPC4 released from astrocytes promotes the maturation of excitatory synapses. Unlike other secreted factors, GPC4 contains the C-terminal GPI-anchorage signal. However, the mechanism by which membrane-tethered GPC4 is released from astrocytes is unknown. Using primary astrocyte cultures and a quantitative luciferase-based release assay, we show that GPC4 is expressed on the astrocyte surface exclusively via a GPI-anchorage. Soluble GPC4 is robustly released from the astrocytes predominantly by proteolytic shedding and, to a lesser extent, by GPI-anchor cleavage, but not by vesicular release. Pharmacological, overexpression, and loss of function screens showed that ADAM9 in part mediates the release of GPC4 from astrocytes. The released GPC4 contains the heparan sulfate side chain, suggesting that these release mechanisms provide the active form that promotes synapse maturation and function. Overall, our studies identified the release mechanisms and the major releasing enzyme of GPC4 in astrocytes and will provide insights into understanding how astrocytes regulate synapse formation and maturation.Significance StatementAstrocyte-derived diffusible factors regulate synapse development and function. However, the regulatory mechanism underlying the release of astrocyte-derived factors is poorly understood. Noting that, unlike many other secreted factors, glypican-4/GPC4 is GPI-anchored, we characterized the release mechanism of GPI-anchored GPC4 from astrocytes and identified the releasing enzyme. Heparan sulfated GPC4 is robustly released from the astrocytes predominantly by proteolytic shedding. In particular, ADAM9 in part mediates the release of GPC4 from astrocytes. Our study provides an enzymatic mechanism for releasing GPC4 from astrocytes and will provide a novel opportunity to understand the regulatory mechanism of neuron-glia communication for synaptogenesis.
The temporal balance between self-renewal and differentiation of human neural stem cells requires the Amyloid Precursor Protein
Authors: Shabani Khadijeh , Pigeon Julien , Touil Zariouh Marwan Benaissa , Liu Tengyuan , Saffarian Azadeh , Komatsu Jun , Liu Elise , Danda Natasha , Limame Ridha , Bohl Delphine , Parras Carlos , Hassan Bassem A. 
Published: February 2021

AbstractThe approximately 16 billion neurons of the human neocortex are derived from a relatively limited number of developmental neural stem cells (NSCs). During embryogenesis, human cortical NSCs initially generate neurons at a particularly slow rate while preserving their progenitor state for a relatively long time. How this balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. Here we show that the characteristic potential of human NSCs to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the Amyloid Precursor Protein (APP). In contrast, APP is dispensable in mouse NSCs, which undergo neurogenesis at a much faster rate. Mechanistically, loss of APP cell-autonomously accelerates neurogenesis through activation of the AP1 transcription factor and repression of WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.
Caffeinated soda intake in children is associated with neurobehavioral risk factors for substance misuse
Authors: Kwon Mina , Kim Hyeonjin , Yang Jaeyeong , Lee Yoseph , Hur Jihyun K. , Lee Tae-Ho , Bjork James M. , Ahn Woo-Young 
Published: February 2021

AbstractBackground and ObjectivesUse of psychotropic substances in childhood has been associated with both impulsivity and other manifestations of poor executive function as well as escalation over time to use of progressively stronger substances. However, how this relationship may start in earlier childhood has not been well explored. Here, we investigated the neurobehavioral correlates of daily caffeinated soda consumption in preadolescent children and examined whether caffeinated soda intake is associated with a higher risk of subsequent alcohol initiation.MethodsUsing Adolescent Brain Cognitive Development study data, we first investigated cross-sectional relationships between frequent caffeinated soda intake and well-known risk factors of substance misuse: impaired working memory, high impulsivity, and aberrant reward processing. We then examined whether caffeinated soda intake at baseline predicts more alcohol sipping at 12 months follow-up using a machine learning algorithm.ResultsDaily consumption of caffeinated soda was cross-sectionally associated with neurobehavioral risk factors for substance misuse such as higher impulsivity scores and lower working memory performance. Furthermore, caffeinated soda intake predicted greater alcohol sipping after 12 months even after controlling for rates of baseline alcohol sipping; children who drink caffeinated soda daily are twice as likely to start sipping alcohol after one year compared to those who do not drink caffeinated soda at all.ConclusionsThese findings suggest that previous linkages between caffeine and substance use in adolescence also extend to younger initiation, and may stem from core neurocognitive features thought conducive to substance initiation.
A Programmable Toolkit to Dynamically Signal Cells using Peptide Strand Displacement
Authors: Riker Kyle D. , Daly Margaret L. , Papanikolas Micah J. , Jian Tengyue , Klawa Stephen J. , Sahin Jacqueline (Yalin) S. , Liu Dingyuan , Singh Anamika , Miller A. Griffin , Freeman Ronit 
Published: February 2021

AbstractThe native extracellular matrix communicates and interacts with cells by dynamically displaying signals to control their behavior. Mimicking this dynamic environmentin vitrois essential in order to unravel how cell-matrix interactions guide cell fate. Here, we present a synthetic platform for the temporal display of cell adhesive signals using coiled-coil peptides. By designing an integrin-engaging coiled-coil pair to have a toehold (unpaired domain), we were able to use a peptide strand displacement reaction to remove the cell cue from the surface. This allowed us to test how the on-demand display of RGDS ligands at variable duration and periodicity of ligand exposure influence cell spreading degree and kinetics. Transient display of αVβ3selective ligands instructed fibroblast cells to reversibly spread and contract in response to changes in ligand exposure over multiple cycles, exhibiting a universal kinetic response. Also, cells that were triggered to spread and contract repeatedly exhibited greater enrichment of integrins in focal adhesions versus cells cultured on persistent RGDS-displaying surfaces. This dynamic platform will allow us to uncover the molecular code by which cells sense and respond to changes in their environment and will provide insights into ways to program cellular behavior.
Quantifying Viscous Damping and Stiffness in Parkinsonism Using Data-Driven Model Estimation
Authors: Werning Alec , Umbarila Daniel , Fite Maxwell , Fergus Sinta , Zhang Jianyu , Molnar Gregory F. , Johnson Luke A. , Wang Jing , Vitek Jerrold L. , Sanabria David Escobar 
Published: February 2021

AbstractRigidity of upper and lower limbs in Parkinson’s disease (PD) is typically assessed via a clinical rating scale that is subject to biases inherent to human perception. Methodologies and systems to systematically quantify changes in rigidity associated with angular position (stiffness) or velocity (viscous damping) are needed to enhance our understanding of PD pathophysiology and objectively assess therapies. We developed a robotic system and a model-based approach to estimate viscous damping and stiffness of the elbow. Our methodology enables the subject to freely rotate the elbow, while torque perturbations tailored to identify the arm dynamics are delivered. The viscosity and stiffness are calculated based on the experimental data using least-squares optimization. We validated our technique using computer simulations of the arm dynamics and experiments with a nonhuman animal model of PD in the presence and absence of deep brain stimulation (DBS) therapy. Computer simulations of the arm demonstrate that the proposed approach can accurately estimate viscous damping and stiffness. The experimental data show that both viscosity and stiffness significantly decreased when DBS was delivered. Computer simulations and experiments showed that stiffness and viscosity measurements obtained with the proposed methodology could better differentiate changes in rigidity than scores previously used for research, including the work score, impulse score, and modified Unified Parkinson’s Disease Rating Scale (mUPDRS). The proposed estimation method is suitable to quantify the effect of therapies on viscous damping and stiffness and study the pathophysiological mechanisms underlying rigidity in PD.
Singlet oxygen-dependent chloroplast degradation is independent of macroautophagy in theArabidopsis ferrochelatasetwo mutant
Authors: Lemke Matthew D. , Fisher Karen E. , Kozlowska Marta A. , Tano David , Woodson Jesse D. 
Published: February 2021

AbstractBackgroundChloroplasts respond to stress and changes in the environment by producing reactive oxygen species (ROS) that have specific signaling abilities. The ROS singlet oxygen (1O2) is unique in that it can signal to initiate selective degradation of damaged chloroplasts and then cell death. This chloroplast quality control pathway can be monitored in theArabidopsismutantplastid ferrochelatase two(fc2) that conditionally accumulates chloroplast1O2under diurnal light cycling conditions leading to rapid chloroplast degradation and eventual cell death. The cellular machinery involved in such degradation, however, remains unknown. Recently it has been demonstrated that whole damaged chloroplasts can be transported to the central vacuole via a process requiring autophagosomes and core components of the autophagy machinery. The relationship between this process, referred to as chlorophagy, and the degradation of1O2-stressed chloroplasts and cells has remained unexplored.ResultsTo further understand1O2-induced cellular degradation and determine what role autophagy may play, the expression of autophagy-related genes were monitored in1O2-stressedfc2seedlings and found to be induced. Although autophagosomes were present infc2cells, they did not associate with chloroplasts during1O2stress. Mutations blocking the core autophagy machinery (atg5, atg7, andatg10) were unable to suppress1O2-induced chloroplast degradation or cell death in thefc2mutant, suggesting autophagosome formation and macroautophagy are dispensable for1O2–mediated cellular degradation. However, bothatg5andatg7led to specific defects in chloroplast ultrastructure and photosynthetic efficiencies, suggesting macroautophagy may be involved in protecting chloroplasts from photo-oxidative damage. Finally, genes predicted to be involved in microautophagy were shown to be induced in stressedfc2seedlings, indicating a possible role for an alternate form of autophagy in the dismantling of1O2-damaged chloroplasts.ConclusionsOur results support the hypothesis that1O2-dependent chloroplast degradation is independent from autophagosome formation, canonical macroautophagy, and chlorophagy. Instead, ATG-independent microautophagy may be involved in such degradation. However, canonical macroautophagy may still play a role in protecting chloroplasts from1O2-induced photo-oxidative stress. Together, this suggests chloroplast function and degradation is a complex process that utilizes multiple autophagy and degradation machineries, possibly depending on the type of stress or damage incurred.
Functional cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein
Authors: Doyle Michael P. , Kose Nurgun , Borisevich Viktoriya , Binshtein Elad , Amaya Moushimi , Nagel Marcus , Annand Edward J. , Armstrong Erica , Bombardi Robin , Dong Jinhui , Schey Kevin L. , Broder Christopher C. , Zeitlin Larry , Kuang Erin A. , Bornholdt Zachary A. , West Brandyn R. , Geisbert Thomas W. , Cross Robert W. , Crowe James E. 
Published: February 2021

AbstractHendra virus (HeV) and Nipah virus (NiV), the prototypic members of theHenipavirus(HNV) genus, are emerging, zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans (Eaton et al., 2006). While several research groups have made strides in developing candidate vaccines and therapeutics against henipaviruses, such countermeasures have not been licensed for human use, and significant gaps in knowledge about the human immune response to these viruses exist. To address these gaps, we isolated a large panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior occupation-related exposure to the equine HeV vaccine (Equivac® HeV). Competition-binding and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies identified at least six distinct antigenic sites on the HeV/NiV receptor binding protein (RBP) that are recognized by human mAbs. Antibodies recognizing multiple antigenic sites potently neutralized NiV and/or HeV isolatesin vitro.The most potent class of cross-reactive antibodies achieved neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3. Antibodies from this class mimic receptor binding by inducing a receptor-bound conformation to the HeV-RBP protein tetramer, exposing an epitope that appears to lie hidden in the interface between protomers within the HeV-RBP tetramer. Antibodies that recognize this cryptic epitope potently neutralized HeV and NiV. Flow cytometric studies using cell-surface-displayed HeV-RBP protein showed that cross-reactive, neutralizing mAbs from each of these classes cooperate for binding. In a highly stringent hamster model of NiVBinfection, antibodies from both classes reduced morbidity and mortality and achieved synergistic protection in combination and provided therapeutic benefit when combined into two bispecific platforms. These studies identified multiple candidate mAbs that might be suitable for use in a cocktail therapeutic approach to achieve synergistic antiviral potency and reduce the risk of virus escape during treatment.