bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression in African Americans and Latinos reveals ancestry-specific patterns of genetic architecture
Authors: Kachuri Linda , Mak Angel C.Y. , Hu Donglei , Eng Celeste , Huntsman Scott , Elhawary Jennifer R. , Gupta Namrata , Gabriel Stacey , Xiao Shujie , Keys Kevin L. , Oni-Orisan Akinyemi , Rodríguez-Santana José R. , LeNoir Michael , Borrell Luisa N. , Zaitlen Noah A. , Williams L. Keoki , Gignoux Christopher R. , Burchard Esteban González , Ziv Elad 
Published: August 2021

ABSTRACTWe analyzed whole genome and RNA sequencing data from 2,733 African American and Hispanic/Latino children to explore ancestry- and heterozygosity-related differences in the genetic architecture of whole blood gene expression. We found that heritability of gene expression significantly increases with greater proportion of African genetic ancestry and decreases with higher levels of Indigenous American ancestry, consistent with a relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of statistically significant ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most of the anc-eQTLs (89%) were driven by population differences in allele frequency, demonstrating the importance of measuring gene expression across multiple populations. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait pairs using models trained in our admixed population than models trained in GTEx. Our study highlights the importance of large and ancestrally diverse genomic studies for enabling new discoveries of complex trait architecture and reducing disparities.
Loneliness is linked to specific subregional alterations in hippocampus-default network co-variation
Authors: Zajner Chris , Spreng Nathan , Bzdok Danilo 
Published: August 2021

AbstractSocial interaction complexity makes humans unique. But in times of social deprivation this strength risks to expose important vulnerabilities. Human social neuroscience studies have placed a premium on the default network (DN). In contrast, hippocampus (HC) subfields have been intensely studied in rodents and monkeys. To bridge these two literatures, we here quantified how DN subregions systematically co-vary with specific HC subfields in the context of subjective social isolation (i.e., loneliness). By co-decomposition using structural brain scans of ∼40,000 UK Biobank participants, loneliness was specially linked to midline subregions in the uncovered DN patterns. These association cortex signatures coincided with concomitant HC patterns implicating especially CA1 and molecular layer. These patterns also showed a strong affiliation with the fornix white-matter tract and the nucleus accumbens. In addition, separable signatures of structural HC-DN co-variation had distinct associations with the genetic predisposition for loneliness at the population level.
High-throughput phenotyping of leaf discs infected with grapevine downy mildew using shallow convolutional neural networks
Authors: Zendler Daniel , Malagol Nagarjun , Schwandner Anna , Töpfer Reinhard , Hausmann Ludger , Zyprian Eva 
Published: August 2021

AbstractObjective and standardized recording of disease severity in mapping crosses and breeding lines is a crucial step in characterizing resistance traits utilized in breeding programs and to conduct QTL or GWAS studies. Here we report a system for automated high-throughput scoring of disease severity on inoculated leaf discs. As proof of concept, we used leaf discs inoculated with Plasmopara viticola causing grapevine downy mildew (DM). This oomycete is one of the major grapevine pathogens and has the potential to reduce grape yield dramatically if environmental conditions are favorable. Breeding of DM resistant grapevine cultivars is an approach for a novel and more sustainable viticulture. This involves the evaluation of several thousand inoculated leaf discs from mapping crosses and breeding lines every year. Therefore, we trained a shallow convolutional neural-network (SCNN) for efficient detection of leaf disc segments showing P. viticola sporangiophores. We could illustrate a high and significant correlation with manually scored disease severity used as ground truth data for evaluation of the SCNN performance. Combined with an automated imaging system, this leaf disc-scoring pipeline has the potential to reduce the amount of time during leaf disc phenotyping considerably. The pipeline with all necessary documentation for adaptation to other pathogens is freely available.
CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis
Authors: Mohanty Sibasish , Mohapatra Pallavi , Shriwas Omprakash , Ansari Shamima Azma , Priyadarshini Manashi , Priyadarsini Swatismita , Rath Rachna , Sultania Mahesh , Das Majumdar Saroj Kumar , Swain Rajeeb Kumar , Dash Rupesh 
Published: August 2021

AbstractCisplatin, 5FU and docetaxel (TPF) are the most common chemotherapy regimen used for advanced OSCC. However, many cancer patients experience relapse, continued tumor growth, and spread due to drug resistance, which leads to treatment failure and metastatic disease. Here, using a CRISPR/Cas9 based kinome knockout screening, Misshapen-like kinase 1 (MINK1) is identified as an important mediator of 5FU resistance in OSCC. Analysis of clinical samples demonstrated significantly higher MINK1 expression in the tumor tissues of chemotherapy non-responder as compared to chemotherapy responders. The nude mice and zebrafish xenograft experiments indicate that knocking out MINK1 restores 5FU mediated cell death in chemoresistant OSCC. An antibody based phosphorylation array screen revealed MINK1 as a negative regulator of p53. Mechanistically, MINK1 modulates AKT phosphorylation at Ser473, which enables p-MDM2 (Ser 166) mediated degradation of p53. We also identified lestaurtinib as a potent inhibitor of MINK1 kinase activity. The patient derived TPF resistant cell based xenograft data suggest that lestaurtinib restores 5FU sensitivity and facilitates a significant reduction of tumor burden. Overall, our study suggests that MINK1 is a major driver of 5FU resistance in OSCC. The novel combination of MINK1 inhibitor lestaurtinib and 5FU needs further clinical investigation in advanced OSCC.
A novel lineage-tracing mouse model for MmuPV1 infection enables in vivo studies in the absence of cytopathic effects
Authors: Yilmaz Vural , Louka Panayiota , Strati Katerina 
Published: August 2021

AbstractHuman papillomaviruses (HPVs) are DNA viruses that ubiquitously infect humans and have been associated with hyperproliferative lesions. The recently discovered mouse specific papillomavirus, MmuPV1, provides the opportunity to study papillomavirus infections in vivo in the context of a common laboratory mouse model (Mus musculus). To date, a major challenge in the field has been the lack of tools to identify, observe and characterize individually the papillomavirus hosting cells and also trace the progeny of these cells over time.Here, we present the successful generation of an in vivo lineage-tracing model of MmuPV1-harboring cells and their progeny by means of genetic reporter activation. Following the validation of the system both in vitro and in vivo, we used it to provide a proof-of-concept of its utility. Using flow-cytometry analysis, we observed increased proliferation dynamics and decreased MHC-I cell surface expression in MmuPV1-treated tissues which could have implications in tissue regenerative capacity and ability to clear the virus. This model is a novel tool to study the biology of the MmuPV1 host-pathogen interactions.
Audiovisual integration in the Mauthner cell enhances escape probability and reduces response latency
Authors: Martorell Nicolás , Medan Violeta 
Published: August 2021

SUMMARYFast and accurate threat detection is critically important for animal survival. Reducing perceptual ambiguity by integrating multiple sources of sensory information can enhance threat detection and reduce response latency. However, studies showing a direct link between behavioral correlates of multisensory integration and its underlying neural basis are rare. In fish, an explosive escape behavior known as C-start is driven by an identified neural circuit centered on the Mauthner cell. The Mauthner cell can trigger C-starts in response to visual and auditory stimuli allowing to investigate how multisensory integration in a single neuron affects behavioral outcome after threat detection. Here we demonstrate that in goldfish visual looms and brief auditory stimuli can be integrated to increase C-start probability and that this enhancement is inversely correlated to the saliency of the cues with weaker auditory cues producing a proportionally stronger multisensory effect. We also show that multisensory stimuli reduce response latency locked to the presentation of the auditory cue. Finally, we make a direct link between behavioral data and its underlying neural mechanism by reproducing empirical data with an integrate-and-fire computational model of the Mauthner cell.
Oculomotor freezing indicates conscious detection free of decision bias
Authors: White Alex L. , Moreland James C. , Rolfs Martin 
Published: August 2021

AbstractThe appearance of a salient stimulus rapidly inhibits saccadic eye movements. Curiously, this “oculomotor freezing” reflex is triggered only by stimuli that the observer reports seeing. It remains unknown, however, if oculomotor freezing is linked to the observer’ssensory experience, or theirdecisionthat a stimulus was present. To dissociate between these possibilities, we manipulated decision criterion via monetary payoffs and stimulus probability in a detection task. These manipulations greatly shifted observers’ decision criteria but did not affect the degree to which microsaccades were inhibited by stimulus presence. Moreover, the link between oculomotor freezing and explicit reports of stimulus presence was stronger when the criterion was conservative rather than liberal. We conclude that the sensory threshold for oculomotor freezing is independent of decision bias. Provided that conscious experience is also unaffected by such bias, oculomotor freezing is an implicit indicator of sensory awareness.New & NoteworthySometimes a visual stimulus reaches awareness, and sometimes it does not. To understand why, we need objective, bias-free measures of awareness. We discovered that a reflexive freezing of small eye movements indicates when an observer detects a stimulus. Furthermore, when we biased observers’ decisions to report seeing the stimulus, the oculomotor reflex was unaltered. This suggests that the threshold for conscious perception is independent of the decision criterion and is revealed by oculomotor freezing.
Dynamic representation of space in the hippocampus: spatial novelty detection and consolidation in CA1 and CA2
Authors: Bhasin Guncha 
Published: August 2021

AbstractHippocampal place cells are the functional units of spatial navigation and are present in all subregions-CA1, CA2, CA3 and CA4. Recent studies on CA2 have indicated its role in social and contextual memory, but its contribution towards spatial novelty detection and consolidation remains largely unknown. The current study aims to uncover how CA1 and CA2 detect, process, assimilate and consolidate spatial novelty. Accordingly, a novel 3-day paradigm was designed where the animal was introduced to a completely new environment on the first day and to varying degrees of familiarity and novelty on subsequent days, as the track was extended in length and modified in shape, keeping other environmental constraints fixed. Detection of spatial novelty was found to be a dynamic and complex phenomenon, characterized by different responses from hippocampal place cells, depending on when novelty was introduced. Therefore, the study concludes that early novelty detection (the first time a novel space is introduced in a relatively familiar environment) and subsequent novelty detection are not processed in the same way. Additionally, while neuronal responses to spatial novelty detection (early and subsequent) were found to be the same in CA1 and CA2 ensembles, their responses differed in spatial consolidation mechanisms during subsequent sleep replays. For CA1, spatial coverage of prior behaviour was found to be closely reflected in subsequent sleep for that particular day, but CA2 showed no such ‘coherent response’, highlighting mnemonic processing differences between CA2 and CA1 with respect to spatial novelty.
Diverse Genotype-by-Weather Interactions in Switchgrass
Authors: MacQueen Alice H. , Zhang Li , Smith Samuel Pattillo , Bonnette Jason E. , Boe Arvid R. , Fay Philip A. , Fritschi Felix B. , Lowry David B. , Mitchell Robert B. , Rouquette Francis M. , Wu Yanqi , Harpak Arbel , Juenger Thomas E. 
Published: August 2021

AbstractThe timing of vegetative and reproductive growth in plants (“phenological timings”) depend on genetic effects (G), environmental (e.g., weather) cues, and their interaction. Here, we measure phenological timings in two highly divergent switchgrass (Panicum virgatum) subpopulations using repeated plantings of cloned individuals at eight sites across the central United States. The timing of vegetative growth for the two subpopulations reversed between their two natural ranges and had strong negative correlations between these regions; in contrast, the timing of flowering was positively correlated between gardens. We expect that these phenotypic correlations consist of polygenic effects on phenology which have distinct patterns of GxE segregating at different mapped loci. Thus, we infer the mixture of ways genetic effects impact phenological timings, such as across common gardens (GxE) or with weather cues (GxWeather). We demonstrate that we can identify genetic variation with GxWeather and assign genetic loci to specific weather-based cues or other patterns. For example, in the Gulf subpopulation, 65% of genetic effects on the timing of vegetative growth covary with daylength 14 days prior to green-up date, and 33% of genetic effects on the timing of flowering covary with cumulative rainfall in the week prior to flowering. However, most variation in genetic effects cannot be attributed to variation in weather variables. Selective breeding for particular alleles at GxWeather loci could alter flowering responsiveness in a photoperiod or rainfall-specific way. More broadly, our approach refines the characterization of genotype-by-environment interactions and can be implemented in any species phenotyped in multiple environments.
Somatic mutation rates scale with lifespan across mammals
Authors: Cagan Alex , Baez-Ortega Adrian , Brzozowska Natalia , Abascal Federico , Coorens Tim H. H. , Sanders Mathijs A. , Lawson Andrew R. J. , Harvey Luke M. R. , Bhosle Shriram , Jones David , Alcantara Raul E. , Butler Timothy M. , Hooks Yvette , Roberts Kirsty , Anderson Elizabeth , Lunn Sharna , Flach Edmund , Spiro Simon , Januszczak Inez , Wrigglesworth Ethan , Jenkins Hannah , Dallas Tilly , Masters Nic , Perkins Matthew W. , Deaville Robert , Druce Megan , Bogeska Ruzhica , Milsom Michael D. , Neumann Björn , Gorman Frank , Constantino-Casas Fernando , Peachey Laura , Bochynska Diana , John Smith Ewan St. , Gerstung Moritz , Campbell Peter J. , Murchison Elizabeth P. , Stratton Michael R. , Martincorena Iñigo 
Published: August 2021

AbstractThe rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Remarkably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied displaying a comparable association. Despite widely different life histories among the species surveyed, including ∼30-fold variation in lifespan and ∼40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of ∼3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.
A flexible point and variance estimator to assess bird/bat fatality from carcass searches
Authors: Mercker Moritz 
Published: August 2021

AbstractEstimation of bird and bat fatalities due to collision with anthropogenic structures (such as power lines or wind turbines) is an important ecological issue. However, searching for collision victims usually only detects a proportion of the true number of collided individuals. Various mortality estimators have previously been proposed to correct for this incomplete detection, based on regular carcass searches and additional field experiments. However, each estimator implies specific assumptions/restrictions, which may easily be violated in practice. In this study, we extended previous approaches and developed a versatile algorithm to compute point and variance estimates for true carcass numbers. The presented method allows for maximal flexibility in the data structure. Using simulated data, we showed that our point and variance estimators ensured unbiased estimates under various challenging data conditions. The presented method may improve the estimation of true collision numbers, as an important pre-condition for calculating collision rates and evaluating measures to reduce collision risks, and may thus provide a basis for management decisions and/or compensation actions with regard to planned or existing wind turbines and power lines.
Learning the local landscape of protein structures with convolutional neural networks
Authors: Kulikova Anastasiya V. , Diaz Daniel J. , Loy James M. , Ellington Andrew D. , Wilke Claus O. 
Published: August 2021

AbstractThe fundamental problem of protein biochemistry is to predict protein structure from amino acid sequence. The inverse problem, predicting either entire sequences or individual mutations that are consistent with a given protein structure, has received much less attention even though it has important applications in both protein engineering and evolutionary biology. Here, we ask whether 3D convolutional neural networks (3D CNNs) can learn the local fitness landscape of protein structure to reliably predict either the wild-type amino acid or the consensus in a multiple sequence alignment from the local structural context surrounding a site of interest. We find that the network can predict wild type with good accuracy, and that network confidence is a reliable measure of whether a given prediction is likely going to be correct or not. Predictions of consensus are less accurate, and are primarily driven by whether or not the consensus matches the wild type. Our work suggests that high-confidence mis-predictions of the wild type may identify sites that are primed for mutation and likely targets for protein engineering.
Corticostriatal suppression of appetitive Pavlovian conditioned responding
Authors: Villaruel Franz R. , Martins Melissa , Chaudhri Nadia 
Published: August 2021

ABSTRACTThe capacity to suppress learned responses is essential for animals to adapt in dynamic environments. Extinction is a process by which animals learn to suppress conditioned responding when an expected outcome is omitted. The infralimbic cortex (IL) to nucleus accumbens shell (NAcS) neural circuit is implicated in suppressing conditioned responding after extinction, especially in the context of operant cocaine-seeking behaviour. However, the role of the IL-to-NAcS neural circuit in the extinction of responding to appetitive Pavlovian cues is unknown and the psychological mechanisms involved in response suppression following extinction are unclear. We trained rats to associate a 10 s auditory conditioned stimulus (CS; 14 trials per session) with a sucrose unconditioned stimulus (US; 0.2 mL per CS) in a specific context and then, following extinction in a different context, precipitated a renewal of CS responding by presenting the CS alone in the original Pavlovian conditioning context. Unilateral, optogenetic stimulation of the IL-to-NAcS circuit selectively during CS trials suppressed renewal. In a separate experiment, IL-to-NAcS stimulation suppressed CS responding regardless of prior extinction and impaired extinction retrieval. Finally, IL-to-NAcS stimulation during the CS did not suppress the acquisition of Pavlovian conditioning but was required for the subsequent expression of CS responding. These results are consistent with multiple studies showing that the IL-to-NAcS neural circuit is involved in the suppression of operant cocaine-seeking, extending these findings to appetitive Pavlovian cues. The suppression of appetitive Pavlovian responding following IL-to-NAcS circuit stimulation does not, however, appear to require an extinction-dependent process.SIGNIFICANCE STATEMENTExtinction is a form of inhibitory learning through which animals learn to suppress conditioned responding in the face of non-reinforcement. We investigated the role of infralimbic (IL) cortex inputs to the nucleus accumbens shell (NAcS) in the extinction of responding to appetitive Pavlovian cues and the psychological mechanisms involved in response suppression following extinction. Using in vivo optogenetics, we found that stimulating the IL-to-NAcS neural circuit suppressed context-induced renewal of conditioned responding after extinction. In a separate experiment, stimulating the IL-to-NAcS circuit suppressed conditioned responding in an extinction-independent manner. These findings can be leveraged by future research aimed at understanding how corticostriatal circuits contribute to behavioural flexibility and mental disorders that involve the suppression of learned behaviours.