bluuebunny/crossref_metadata_2025_split huggingface dataset:
AURTHO: autoregulation as facilitator of cis-acting element discovery of orthologous transcription factors
Authors: Anderssen Sinaeda , Naômé Aymeric , Jadot Cédric , Brans Alain , Tocquin Pierre , Rigali Sébastien 
Published: April 2022

ABSTRACTTranscriptional regulation is key in bacteria for providing an adequate response in time and space to changing environmental conditions. However, despite decades of research, the binding sites and therefore the target genes and the function of most transcription factors (TFs) remain unknown. Filling this gap in knowledge through conventional methods represents a colossal task which we demonstrate here can be significantly facilitated by a widespread feature in transcriptional control: the autoregulation of TFs implying that the yet unknown transcription factor binding site (TFBS) is neighbouring the TF itself. In this work, we describe the “AURTHO” methodology (AUtoregulation of oRTHOlogous transcription factors), consisting of analyzing upstream regions of orthologous TFs in order to uncover their associated TFBSs. AURTHO enabled the de novo identification of novel TFBSs with an unprecedented improvement in terms of quantity and reliability. DNA-protein interaction studies on a selection of candidate cis-acting elements yielded an >90% success rate, demonstrating the efficacy of AURTHO at highlighting true TF-TFBS couples and confirming the identification in a near future of a plethora of TFBSs across all bacterial species.Key pointsTranscription factor (TF) autoregulation implies that their binding site (TFBS) is in their close vicinityWe developed and assessed the AURTHO methodology (AUtoregulation of oRTHOlogous TFs) for TFBS discoveryOur results shows that AURTHO greatly facilitates the identification of highly reliable novel TFBSs
Thresholding Gini Variable Importance with a single trained Random Forest: An Empirical Bayes Approach
Authors: Dunne Robert , Reguant Roc , Ramarao-Milne Priya , Szul Piotr , Sng Letitia , Lundberg Mischa , Twine Natalie A. , Bauer Denis C. 
Published: April 2022

AbstractBackgroundRandom Forests (RF) are a widely used modelling tool, enabling feature-selection via a variable importance measure. For this, a threshold is required that separates label-associated features from false positives. In the absence of a good understanding of the characteristics of the variable importance measures, current approaches attempt to select features by training multiple RFs to generate statistical power via a permutation null, employ recursive feature elimination or a combination of both. However, for high-dimensional datasets, such as genome data with millions of variables, this is computationally infeasible.MethodWe present RFlocalfdr, a statistical approach for thresholding that identifies which features are significantly associated with the prediction label and reduces false positives. It builds on the empirical Bayes argument of Efron (2005) and models the variable importance as mixture of two distributions – null and non-null “genes.”ResultWe demonstrate on synthetic data that RFlocalfdr has an equivalent accuracy to computationally more intensive approaches, while being up to 100 times faster. RFlocalfdr is the only tested method able to successfully threshold a dataset with 6 Million features and 10,000 samples. RFlocalfdr performs analysis in real-time and is compatible with any RF implementation that returns variable importance and counts, such as ranger or VariantSpark.ConclusionRFlocalfdr allows for robust feature selection by placing a confidence value on the predicted importance score. It does so without repeated fitting of the RF or the use of additional shadow variables and is thus usable for data sets with very large numbers of variables.
ERPs responses to dominance features from human faces
Authors: Miao Chengguo , Li Xiaojun , Derrington Edmund , Li Yansong , Dreher Jean-Claude 
Published: April 2022

AbstractSocial dominance is an important feature of social life. Dominance has been proposed to be one of two trait dimensions underpinning social judgments of human faces. Yet, the neural bases of the ability to identify different dominance levels in others based on facial features remains poorly understood. Here, we used event-related potentials (ERPs) to determine the temporal dynamics of facial dominance evaluation based on facial features signaling physical strength/weakness in humans. Twenty-seven participants performed a dominance perception task where they passively viewed faces with different dominance levels. Dominance levels did not modulate an early component of face processing, known as the N170 component, but did modulate the Late Positive Potential (LPP) component. These findings indicate that participants inferred dominance levels at a late stage of face evaluation. Furthermore, the highest level of dominant faces and the lowest level of submissive faces both elicited higher LPP amplitudes than faces with a neutral dominance level. Taken together, the present study provides new insights regarding the dynamics of the neurocognitive processes underlying facial dominance evaluation.
Hazel dormouse in managed woodland select for young, dense, and species-rich tree stands
Authors: Mortensen Rasmus Mohr , Fuller Michelle Fyrstelin , Dalby Lars , Berg Thomas Bjørneboe , Sunde Peter 
Published: April 2022

AbstractIn fragmented forest landscapes, population persistence of arboreal species with limited dispersal ability may strongly depend on the quality of the remaining forest habitat. Using the hazel dormouse (Muscardinus avellanarius) as a model species, we studied habitat selection at two spatial scales (home range and within home range) in intensely managed woodlands at its northern distributional range in Denmark. We modelled selection at home range level as the conditional probability of occupancy of 588 nest boxes and nest tubes in 15 managed forests relative to habitat variables measured within 25 m radius. Habitat selection within home ranges was modelled by comparing habitat variables within 3 m radius of triangulated locations by 19 radio-tracked individuals (12 M, 7 F) when active at night with regularly distributed available locations within their home ranges.At both spatial scales, hazel dormice strongly selected sites with high abundance-weighted species richness and high vegetation density of woody plants. On home range level, they furthermore selected for young tree vegetation, while they within home ranges selected for intermediate aged tree stands (maximum trunk circumference: 1.50 m). The predicted probability of presence in nest boxes or nest tubes varied from less than 1% to more than 99% as a combined function of three habitat variables. From May to October, selection for abundance-weighted species richness of woody plants of radio-tagged individuals decreased with date and body weight, suggesting that a diverse food base is particularly important early in their season of activity and for lean and small (growing) individuals. Selection for dense vegetation increased with body mass and mean available vegetation density within home ranges, indicating behavioural variability related to changes in energy expenditure and need for safety among individuals.The study demonstrates that the hazel dormouse has specific habitat requirements related to food and safety that can be accommodated with relatively simple means in managed forests.Graphical abstract
PhenoComb: A discovery tool to assess complex phenotypes in high-dimension, single-cell datasets
Authors: Burke Paulo E. P. , Strange Ann , Monk Emily , Thompson Brian , Amato Carol M. , Woods David M. 
Published: April 2022

AbstractMotivationHigh-dimension cytometry assays can simultaneously measure dozens of markers, enabling the investigation of complex phenotypes. However, as manual gating relies on previous biological knowledge, few marker combinations are often assessed. This results in complex phenotypes with potential for biological relevance being overlooked. Here we present PhenoComb, an R package that allows agnostic exploration of phenotypes by assessing all combinations of markers.DesignPhenoComb uses signal intensity thresholds to assign markers to discrete states (e.g. negative, low, high) and then counts the number of cells per sample from all possible marker combinations in a memory-safe manner. Time and disk space are the only constraints on the number of markers evaluated. PhenoComb also provides several approaches to perform statistical comparisons, evaluate the relevance of phenotypes, and assess the independence of identified phenotypes. PhenoComb allows users to guide analysis by adjusting several function arguments such as identifying parent populations of interest, filtering of low-frequency populations, and defining a maximum complexity of phenotypes to evaluate. We have designed PhenoComb to be compatible with local computer or server-based use.ResultsIn testing of PhenoComb’s performance on synthetic datasets, computation on 16 markers was completed in the scale of minutes and up to 26 markers in hours. We applied PhenoComb to two publicly available datasets: an HIV flow cytometry dataset (12 markers and 421 samples) and the COVIDome CyTOF dataset (40 markers and 99 samples). In the HIV dataset, PhenoComb identified immune phenotypes associated with HIV seroconversion, including those highlighted in the original publication. In the COVID dataset, we identified several immune phenotypes with altered frequencies in infected individuals relative to healthy individuals. Collectively, PhenoComb represents a powerful discovery tool for agnostically assessing high-dimension, single-cell data.AvailabilityThe PhenoComb R package can be downloaded from https://github.com/SciOmicsLab/PhenoComb
A Novel Caenorhabditis elegans Gene Network Uncovers Mechanisms of Mitochondrial Maintenance
Authors: Moreno Armando , Taffet Allison , Tjahjono Elissa , Kirienko Natalia V. 
Published: April 2022

AbstractMitochondria play key roles in cellular health and metabolism and are a critical determinant of the activation of multiple cell death processes. Although several pathways for regulating and re-establishing mitochondrial homeostasis have been identified within the past twenty years, large gaps remain in our understanding of how cells keep mitochondria healthy.To address this limitation, have developed a network of genes that underlie mitochondrial health. We began by compiling a list of frequently mutated genes using publicly available data from multiple human cancer cell lines. RNAi was used to disrupt orthologous genes in the model organism Caenorhabditis elegans in a series of assays to evaluate these genes’ ability to support mitochondrial health, as evidenced by precocious activation of mitochondrial autophagy and sensitivity to acute mitochondrial damage. Iterative screening of ~1000 genes yielded a network of 139 genes showing significant connectivity.Functional validation of a panel of genes from the network indicated that disruption of each gene triggered at least one phenotype consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of ATP, NADH, or ROS, and altered oxygen consumption. Importantly, RNAi-mediated knockdown of these genes often exacerbated α-synuclein aggregation in a C. elegans model of Parkinson’s disease, indicating significant changes to cellular health. Additionally, human orthologs of the final mitochondrial health gene network showed enrichment for roles in a number of human disorders identified in the OMIM database. This gene network provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis.
Genotype error biases trio-based estimates of haplotype phase accuracy
Authors: Browning Brian L. , Browning Sharon. R. 
Published: April 2022

AbstractHaplotypes can be estimated from unphased genotype data using statistical methods. When parent-offspring data are available for inferring true phase from Mendelian inheritance rules, the accuracy of statistical phasing is usually measured by the switch error rate, which is the proportion of pairs of consecutive heterozygotes that are incorrectly phased. We present a method for estimating the genotype error rate from parent-offspring trios and a method for estimating the bias in the observed switch error rate that is caused by genotype error. We apply these methods to 485,301 genotyped UK Biobank samples that include 899 White British trios and to 38,387 sequenced TOPMed samples that include 217 African Caribbean trios and 669 European American trios. We show that genotype error inflates the observed switch error rate and that the relative bias increases with sample size. For the UK Biobank White British trios, we estimate that the observed switch error rate in the trio offspring is 2.4 times larger than the true switch error rate (1.41 × 10−3 vs 5.79 × 10−4) and that the average distance between phase errors is 64 megabases.
Mouse brain-wide transgene expression by systemic injection of genetically engineered exosomes: CAP-Exosomes
Authors: Sarkar Saumyendra N , Corbin Debora , Simpkins James W 
Published: April 2022

AbstractThe bottleneck in drug discovery for central nervous system diseases is the absence of effective systemic drug delivery technology for delivering therapeutic drugs into the brain. Although some Adeno Associated Virus (AAV) serotype can cross blood brain barrier and deliver virus genome packaged therapeutic DNA (gene) or RNA molecules to brain cells along with other organs, several hurdles have emerged in the AAV9 vector gene transfer technology in both preclinical studies and clinical trials. In order to overcome some of the hurdles, we have developed a workflow to generate a novel brain targeted drug delivery system (DDS) that involves generation of genetically engineering exosomes by first selecting various functional AAV capsid specific peptides (collectively called CAP) known to be involved in brain targeted high expression gene delivery, and then expressing the CAP in frame with lysosome-associated membrane glycoprotein (Lamp2b) followed by expressing CAP-Lamp2b fusion protein on the surface of mesenchymal stem cell derived exosomes, generating CAP-exosomes. Intravenous injection of green fluorescent protein (GFP) gene loaded CAP-exosomes in mice transfer GFP gene throughout the CNS as measured by monitoring brain sections for GFP expression with confocal microscopy. GFP gene transfer efficiency is at least 20-fold greater than that of control Lamp2b-exosomes. GFP gene transduction to mouse liver was low. CAP-exosome has advantage over AAV-vector including, 1) no restriction in gene size to be delivered, 2) expected reduced production of neutralizing antibody, and 3) can be used separately for drug repurposing and/or in combination with therapeutic genes.Graphical Abstract
Analysis of flavonol regulator evolution in the Brassicaceae reveals MYB12, MYB111 and MYB21 duplications associated with MYB11 and MYB24 gene loss
Authors: Schilbert Hanna M. , Glover Beverley J. 
Published: April 2022

BackgroundFlavonols are the largest subgroup of flavonoids, possessing multiple functions in plants including protection against ultraviolet radiation, antimicrobial activities, and flower pigmentation together with anthocyanins. They are of agronomical and economical importance because the major off-taste component in rapeseed protein isolates is a flavonol derivative, which limits rapeseed protein use for human consumption. Flavonol production in Arabidopsis thaliana is mainly regulated by the subgroup 7 (SG7) R2R3-MYB transcription factors MYB11, MYB12, and MYB111. Recently, the SG19 MYBs MYB21, MYB24, and MYB57 were shown to regulate flavonol accumulation in pollen and stamens. The members of each subgroup are closely related, showing gene redundancy and tissue-specific expression in A. thaliana. However, the evolution of these flavonol regulators inside the Brassicaceae, especially inside the Brassiceae, which include the rapeseed crop species, is not fully understood.ResultsWe studied the SG7 and SG19 MYBs in 44 species, including 31 species of the Brassicaceae, by phylogenetic analyses followed by synteny and gene expression analyses. Thereby we identified a deep MYB12 and MYB111 duplication inside the Brassicaceae, which likely occurred before the divergence of Brassiceae and Thelypodieae. These duplications of SG7 members were followed by the loss of MYB11 after the divergence of Eruca vesicaria from the remaining Brassiceae species. Similarly, MYB21 experienced duplication before the emergence of the Brassiceae family, where the gene loss of MYB24 is also proposed to have happened. Due to the overlapping spatio-temporal expression patterns of the SG7 and SG19 MYB members in B. napus, the loss of MYB11 and MYB24 is likely to be compensated by the remaining homologs.ConclusionsWe identified a duplication of MYB12, MYB111, and MYB21 inside the Brassicaceae which is associated with MYB11 and MYB24 gene loss inside the tribe Brassiceae. We propose that gene redundancy and meso-polyploidization events have shaped the evolution of the flavonol regulators in the Brassicaceae, especially in the Brassiceae.
The effects of environmental heterogeneity within a city on the evolution of clines
Authors: Santangelo James S. , Roux Cindy , Johnson Marc T. J. 
Published: April 2022

AbstractThere is increasing evidence that environmental change associated with urbanization can drive rapid adaptation. However, most studies of urban adaptation have focused on coarse urban vs. rural comparisons or sampled along a single urban-rural environmental gradient, thereby ignoring the role that within-city environmental heterogeneity might play in adaptation to urban environments.In this study, we examined fine-scale variation in the presence of HCN—a potent anti-herbivore defense—and its two underlying genes (Ac and Li) between park green spaces and surrounding suburban habitats for five city parks in the Greater Toronto Area.We show that fine-scale urbanization has driven the formation of micro-clines in HCN on a scale of < 2 km, though the presence and strength of micro-clines varied across parks. Interestingly, these micro-clines were driven by lower HCN frequencies inside park green spaces, and are therefore in the opposite direction to that predicted based on previously described patterns of HCN frequency change along urban-rural gradients.Synthesis: These results suggest larger scale, adaptive urban-rural clines occur across a complex matrix of environmental heterogeneity within cities that drives fine-scale adaptive microclines of varying strengths and directions.
Experimental identification of individual insect visual tracking delays in free flight and their effects on visual swarm patterns
Authors: Islam Md. Saiful , Faruque Imraan A. 
Published: April 2022

AbstractInsects are model systems for swarming robotic agents, yet engineered descriptions do not fully explain the mechanisms by which they provide onboard sensing and feedback to support such motions; in particular, the exact value and population distribution of visuomotor processing delays are not yet quantified, nor the effect of such delays on a visually-interconnected swarm. This study measures untethered insects performing a solo in-flight visual tracking task and applies system identification techniques to build an experimentally-consistent model of the visual tracking behaviors, and then integrates the measured experimental delay and its variation into a visually interconnected swarm model to develop theoretical and simulated solutions and stability limits. The experimental techniques include the development of a moving visual stimulus and real-time multi camera based tracking system called VISIONS1 providing the capability to recognize and simultaneously track both a visual stimulus (input) and an insect at a frame rate of 60-120 Hz. A frequency domain analysis of honeybee tracking trajectories is conducted via fast Fourier and Chirp Z transforms, identifying a coherent linear region and its model structure. The model output is compared in time and frequency domain simulations. The experimentally measured delays are then related to probability density functions, and both the measured delays and their distribution are incorporated as inter-agent interaction delays in a second order swarming dynamics model. Linear stability and bifurcation analysis on the long range asymptotic behavior is used to identify delay distributions leading to a family of solutions with stable and unstable swarm center of mass (barycenter) locations. Numerical simulations are used to verify these results with both continuous and modeled distributions.The results of this experiment quantify a model structure and temporal lag (transport delay) in the closed loop dynamics, and show that this delay varies across 50 individuals from 5-110ms, with an average delay of 22ms and a standard deviation of 40ms. When analyzed within the swarm model, the measured delays support a diversity of solutions and indicate an unstable barycenter.
Beyond control: experimental control protocol slightly affects prepubescent mice behavior in a sex-specific manner
Authors: Moraes Muiara A , Árabe Laila Blanc , Resende Bruna Lopes , Codo Beatriz Campos , Reis Ana Luíza A. L. , Souza Bruno Rezende 
Published: April 2022

AbstractStudy design and experimental tools are crucial for good quality science, and an important part of it is the choice of control groups to best test the hypothesis. Two of the most common control groups in research are needle prickling without substance injection (Sham) and/or vehicle injection (Saline). Very few studies investigated the behavioral effects of a single intraperitoneal (i.p) Sham and/or single i.p. Saline administration in mice, mostly using adult males. In this study, we investigated if a single i.p. Sham and/or i.p. Saline administration affects female and male prepubertal (4-weeks-old) mice behavior. After Sham or Saline injection, we examined exploratory/motor behavior (open field test – OFT), anxiety-like behavior (elevated plus-maze – EPM), and behavioral despair/depressive-like behavior (forced swimming test – FST). We observed that both Sham prepubertal females and males showed minor behavioral alterations in OFT and EPM, and Saline males showed behavioral alterations in OFT and FST. On the other hand, prepubertal Saline females showed an increase in exploratory behavior, risk assessment/anxiety-like behavior, and behavioral despair/depressive-like behavior. Thus, we observed that the experimental procedures used as control have mild (but not insignificant) consequences on prepubescent mice behavior. However, the consequences of control protocols in prepubescent females are stronger than in males. To the best of our knowledge, this is the first study investigating the consequences of Sham and Saline protocols in prepubertal mice. This study highlights how important is to include Naïve animals (Negative control) together with Sham and/or Vehicle for a better and more honest interpretation of the data.