bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice
Authors: Aarde Shawn M. , Bagley Jared R. , Jentsch J. David 
Published: October 2022

ABSTRACTBackgroundSex differences in ethanol consumption have been reported in both humans and laboratory rodents, but the independent/dependent contributions of genetic and hormonal sex◻biasing mechanisms to these phenotypes have not yet been fully explored.MethodsTo examine the contributions of sex-chromosome complement (SCC) and gonadal sex (GS) to ethanol consumption, we studied adolescent (28-32 days old) four core genotypes (FCG) mice (C57BL/6J background; FCG model allows for independent assortment of GS and SCC) using a modified drinking-in-the-dark (DID) procedure. Mice were offered concurrent access to 20%, 10% and 0% ethanol (in water) in four daily 2-hour sessions. Consumption at the level of individual bouts was recorded.ResultsAlthough all four genotype groups preferred the 20% ethanol over 10% and 0%, and showed similar consumption of the 10% and 0% solutions, the group rankings for consumption of the 20% ethanol solution were XX+testes > XY+testes > XY+ovaries > XX+ovaries. Thus, an interaction was observed between SCC and GS for which the simple effect of SCC was greatest in mice with ovaries (XY > XX) and the simple effect of GS was greatest in XX mice (testes > ovaries). Moreover, these effects varied in magnitude across and within drinking sessions. The behavioral microstructure of ethanol consumption (i.e., parameterization of within-session discriminable drinking bouts) support the validity of our 3-bottle modification of the DID procedure as a model of binge-like consumption as: (1) the consumption rate of the 20% ethanol solution was ~80 g EtOH/kg/hwithin a bout(~12 s/bout, ~3 bouts/session), (2) most of this ethanol consumption was completed in a single bout and (3) within-session ethanol consumption was greater earlier than later, indicating “front loading.”ConclusionsThese results indicate that SCC and GS interact on ethanol consumption in adolescent FCG mice on a C57BL/6J background to affect binge-like consumption from the very initiation of access and that these effects are dynamic as they varied both across and within sessions.HighlightsGonadal sex and sex-chromosome complementinteracton ethanol consumption in adolescent four core genotypes miceIn adolescent four core genotypes mice, mice with testes drink more ethanol than mice with ovaries, particularly in the presence of an XX karyotypeIn adolescent four core genotypes mice, XY mice drink more ethanol than XX mice, but only in mice with ovariesThe effects of sex-biasing biological factors on the patterns of ethanol consumption by adolescent four core genotypes mice that we observed in our 3-bottle Drinking-in-the-Dark procedure showed face validity with some of the sex/gender differences observed in human adolescents
A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma
Authors: Beri Pranjali , Plunkett Christopher , Barbara Joshua , Shih Chien-Cheng , Barnes S. Whitney , Ross Olivia , Choconta Paula , Trinh Ton , Litvin Bella , Walker John , Qiu Minhua , Hammack Scott , Toyama Erin 
Published: October 2022

AbstractAsthma is often characterized by tissue-level mechanical phenotypes that include remodeling of the airway and an increase in airway tightening driven by the underlying smooth muscle. Existing therapies only provide symptom relief and do not improve the baseline narrowing of the airway or halt progression of the disease. To investigate such targeted therapeutics, there is a need for models that can recapitulate the 3D environment present in this tissue, provide phenotypic readouts of contractility, and be easily integrated into existing assay plate designs and laboratory automation used in drug discovery campaigns. To address this, we have developed DEFLCT, a high-throughput plate insert that can be paired with standard labware to easily generate high volumes of microscale tissuesin vitrofor screening applications. Using this platform, we exposed primary human airway smooth muscle cell-derived microtissues to a panel of six of inflammatory cytokines present in the asthmatic niche, identifying TGF-β1 and IL-13 as strong contractile modulators. RNAseq analysis further demonstrated enrichment of contractile and remodeling-relevant pathways in TGF-β1 and IL-13 treated tissues as well as pathways generally associated with asthma. Taken together, these data establish a disease relevant, 3D tissue model for the asthmatic airway which combines niche specific inflammatory cues and complex mechanical readouts that can be utilized in drug discovery efforts.
JINXED: Just in time crystallization for easy structure determination of biological macromolecules
Authors: Henkel Alessandra , Galchenkova Marina , Maracke Julia , Yefanov Oleksandr , Hakanpää Johanna , Mesters Jeroen R. , Chapman Henry N. , Oberthür Dominik 
Published: October 2022

AbstractMacromolecular crystallography is a well-established method in the field of structure biology and has led to the majority of known protein structures to date. After focusing on static structures, the method is now developing towards the investigation of protein dynamics through time-resolved methods. These experiments often require multiple handling steps of the sensitive protein crystals, e.g. for ligand soaking and cryo-protection. These handling steps can cause significant crystal damage, causing a decrease in data quality. Furthermore, in time-resolved experiments based on serial crystallography that use micron-sized crystals for short diffusion times of ligands, certain crystal morphologies with small solvent channels can prevent sufficient ligand diffusion. Described here is a method combining protein crystallization and data collection in a novel one-step-process. Corresponding experiments were successfully performed as a proof-of-principle using hen egg white lysozyme and crystallization times of only a few seconds. This method called JINXED (Justintimecrystallization foreasy structuredetermination) promises to result in high-quality data due the avoidance of crystal handling and has the potential to enable time-resolved experiments with crystals containing small solvent channels by adding potential ligands to the crystallization buffer, simulating traditional co-crystallization approaches.
Different extrapolation of moving object locations in perception, smooth pursuit and saccades
Authors: Lisi Matteo , Cavanagh Patrick 
Published: October 2022

AbstractThe ability to accurately perceive and track moving objects is crucial for many everyday activities. In this study, we use a “double-drift stimulus” Lisi and Cavanagh (2015); Shapiro et al. (2010); Tse and Hsieh (2006) to explore the processing of visual motion signals that underlie perception, pursuit, and saccade responses to a moving object. Participants were presented with peripheral moving apertures filled with noise that either drifted orthogonally to the aperture’s direction or had no net motion. Participants were asked to saccade to and track these targets with their gaze as soon as they appeared, and then to report their direction. In the trials with internal motion, the target disappeared at saccade onset so that the first 100 ms of the post-saccadic pursuit response was driven uniquely by peripheral information gathered before saccade onset. This provided independent measures of perceptual, pursuit, and saccadic responses to the double-drift stimulus on a trial-by-trial basis. Our analysis revealed systematic differences between saccadic responses on one hand and perceptual and pursuit responses on the other. These differences are unlikely to be caused by differences in the processing of motion signals because saccade and pursuit appear to use a common motion processing mechanism (e.g., Erkelens, 2006; Fleuriet and Goffart, 2012). We conclude that our results are instead due to a difference in how the processing mechanisms underlying perception, pursuit, and saccades combine motor signals with target position. These findings advance our understanding of the mechanisms underlying dissociation in visual processing between perception and eye movements.
A Numerical Method to Compute Brain Injury Associated with Concussion
Authors: Bastien C. , Scattina A. , Neal-Sturgess C. , Panno R. , Shrinivas V. 
Published: October 2022

AbstractConcussion can result from various events in everyday life, including falls, sports collisions, and motor vehicle accidents, which could lead to the disruption of neuronal cell membranes and axonal stretching, leading to a neuro-metabolic cascade of molecular changes in the brain. There is currently no agreement on which computational method can assess such low-level injuries. This paper demonstrates for the first time that the Peak Virtual Power (PVP), based on the Clausius-Duhem inequality, assuming that the injury is represented by the irreversible work in a human body, could be a candidate to capture brain distortion related to concussion. The work is based on the evaluation of the PVP via reconstruction of three NFL helmet-to-helmet impacts by means of finite element analysis, using validated Biocore helmet models fitted with calibrated Hybrid III headforms against linear and angular acceleration impact corridors, which were defined as realistic impact conditions for each collision scenario. Once the exact impact parameters were defined, the Hybrid III headform was replaced with a validated THUMS 4.02 human head model in which the PVP was computed for each head at the corpus callosum and midbrain locations. The results indicate that mild and severe concussions could be prevented for lateral collisions and frontal impacts with PVP values lower than 0.928mW and 9.405mW, respectively, and no concussion would happen in the head vertical impact direction for a PVP value of less than 1.184mW. This innovative method proposes a new paradigm to improve helmet designs, assess sports injuries and improve people’s wellbeing.HighlightsPeak Virtual Power method can capture brain distortion related to concussionConcussion is extracted from corpus callosum and midbrain locations of THUMS4.02Peak power in midbrain less than 1.184mW for a vertical impact leads to no concussionPeak power in midbrain more than 0.928mW for a lateral impact leads to concussionPeak power in midbrain more than 9.405mW for a front impact leads to concussion
Concurrent Contribution of Co-contraction to Error Reduction during Dynamic Adaptation of the Wrist
Authors: Farrens Andria J. , Schmidt Kristin , Cohen Hannah , Sergi Fabrizio 
Published: October 2022

AbstractMRI-compatible robots provide a means of studying brain function involved in complex sensorimotor learning processes, such as adaptation. To properly interpret the neural correlates of behavior measured using MRI-compatible robots, it is critical to validate the measurements of motor performance obtained via such devices. Previously, we characterized adaptation of the wrist in response to a force field applied via an MRI-compatible robot, the MR-SoftWrist. Compared to arm reaching tasks, we observed lower end magnitude of adaptation, and reductions in trajectory errors beyond those explained by adaptation. Thus, we formed two hypotheses: that the observed differences were due to measurement errors of the MR-SoftWrist; or that impedance control plays a significant role in control of wrist movements during dynamic perturbations. To test both hypotheses, we performed a two-session counterbalanced study. In both sessions, participants performed wrist pointing in three force field conditions (zero force, constant, random). Participants used either the MR-SoftWrist or the UDiffWrist, a non-MRI-compatible wrist robot, for task execution in session one, and the other device in session two. To measure anticipatory co-contraction associated with impedance control, we collected surface EMG of four forearm muscles. We found no significant effect of device on behavior, validating the measurements of adaptation obtained with the MR-SoftWrist. EMG measures of co-contraction explained a significant portion of the variance in excess error reduction not attributable to adaptation. These results support the hypothesis that for the wrist, impedance control significantly contributes to reductions in trajectory errors in excess of those explained by adaptation.
Genome-Wide Mapping of 5’ Isoforms with 5’-Seq
Authors: Gvozdenov Zlata 
Published: October 2022

ABSTRACTTranscriptome of a genome is appreciated to be more complex than previously assumed. Same gene readouts can differ in terms of transcription start site, transcription end site and splicing. Growing evidence suggests functional importance of distinct transcript isoforms of the same gene. Obtaining these isoforms easily experimentally and processing data is crucial for prompt transcriptome functional characterizations. Here, I describe a quick protocol for generation of capped 5’ isoforms sequencing library and 5’ isoforms data analysis. The protocol relies on utilization of dephosphorylation-decapping method (oligo-capping), and it is a simplification of previously published 5’ isoform studies. The pipeline for data analysis suggests several isoform features to focus on.
The functional impact of 1,570 SNP-accessible missense variants in humanOTC
Authors: Lo Russell S. , Cromie Gareth A. , Tang Michelle , Teng Kevin , Owens Katherine , Sirr Amy , Kutz J. Nathan , McLaughlin Richard N. , Morizono Hiroki , Caldovic Ljubica , Mew Nicholas Ah , Gropman Andrea , Dudley Aimée M. 
Published: October 2022

ABSTRACTDeleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare, but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Neonatal onset patients appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma and death, outcomes ameliorated by rapid diagnosis and treatment. Existing biochemical assays have limitations, including the sensitivity of the citrulline assays used in newborn screening panels. With prior knowledge of variant pathogenicity, DNA sequence-based diagnostics would provide an alternative screening method. Here, we develop a high throughput functional assay for human OTC and measure the impact of 1,570 variants, 84% of all SNP-accessible missense mutations. Our assay scores agree well with existing clinical significance calls, distinguishing known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. Further, use of an intronless expression construct allows us to measure the impact of amino acid changes at splice sites independent of their effect on splicing, thereby separating the contribution of splicing and protein coding changes to aid the analysis of molecular mechanisms underlying pathogenicity. Finally, we assess the utility of our functional data onOTCvariant curation by using the current ACMG/AMP guidelines to reclassify variants. Inclusion of our data as PS3/BS3 substantially improves variant interpretation. Thus, our dataset is of high clinical utility and illustrates the power of functional assays to inform interpretation of existing and novel genetic variation.
Statistically Consistent Rooting of Species Trees under the Multispecies Coalescent Model
Authors: Tabatabaee Yasamin , Roch Sebastien , Warnow Tandy 
Published: October 2022

AbstractRooted species trees are used in several downstream applications of phylogenetics. Most species tree estimation methods produce unrooted trees and additional methods are then used to root these unrooted trees. Recently, Quintet Rooting (QR) (Tabatabaee et al., ISMB and Bioinformatics 2022), a polynomial-time method for rooting an unrooted species tree given unrooted gene trees under the multispecies coalescent, was introduced. QR, which is based on a proof of identifiability of rooted 5-taxon trees in the presence of incomplete lineage sorting, was shown to have good accuracy, improving over other methods for rooting species trees when incomplete lineage sorting was the only cause of gene tree discordance, except when gene tree estimation error was very high. However, the statistical consistency of QR was left as an open question. Here, we present QR-STAR, a polynomial-time variant of QR that has an additional step for determining the rooted shape of each quintet tree. We prove that QR-STAR is statistically consistent under the multispecies coalescent model. Our simulation study under a variety of model conditions shows that QR-STAR matches or improves on the accuracy of QR. QR-STAR is available in open source form athttps://github.com/ytabatabaee/Quintet-Rooting.
Targeting IRS-1/2 in uveal melanoma inhibitsin vitrocell growth, survival and migration, andin vivotumor growth
Authors: Chattopadhyay Chandrani , Bhattacharya Rajat , Roszik Jason , Khan Fatima S. , Wells Gabrielle A. , Villanueva Hugo , Qin Yong , Bhattacharya Rishav , Patel Sapna , Grimm Elizabeth A. 
Published: October 2022

AbstractUveal melanoma (UM) originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of insulin-like growth factor −1 and its receptor (IGF-1/IGF-1R) signaling in UM. We found that the insulin receptor substrate −1 (IRS-1) is overexpressed in UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2 in blocking this pathway in UM. NT157 treatment in UM cells resulted in reduced cell survival and migration, and increased apoptosis. This treatment also significantly inhibited UM tumor growthin vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating thein vitroeffect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell survival, migrationin vitroand tumor growthin vivovia inhibiting IGF-1 signaling in UM.
Highlight Results, Don’t Hide Them: Enhance interpretation, reduce biases and improve reproducibility
Authors: Taylor Paul A. , Reynolds Richard C. , Calhoun Vince , Gonzalez-Castillo Javier , Handwerker Daniel A. , Bandettini Peter A. , Mejia Amanda F. , Chen Gang 
Published: October 2022

AbstractMost neuroimaging studies display results that represent only a tiny fraction of the collected data. While it is conventional to present “only the significant results” to the reader, here we suggest that this practice has several negative consequences for both reproducibility and understanding. This practice hides away most of the results of the dataset and leads to problems of selection bias and irreproducibility, both of which have been recognized as major issues in neuroimaging studies recently. Opaque, all-or-nothing thresholding, even if well-intentioned, places undue influence on arbitrary filter values, hinders clear communication of scientific results, wastes data, is antithetical to good scientific practice, and leads to conceptual inconsistencies. It is also inconsistent with the properties of the acquired data and the underlying biology being studied. Instead of presenting only a few statistically significant locations and hiding away the remaining results, we propose that studies should “highlight” the former while also showing as much as possible of the rest. This is distinct from but complementary to utilizing data sharing repositories: the initial presentation of results has an enormous impact on the interpretation of a study. We present practical examples for voxelwise, regionwise and cross-study analyses using publicly available data that was analyzed previously by 70 teams (NARPS; Botvinik-Nezer, et al., 2020), showing that it is possible to balance the goals of displaying a full set of results with providing the reader reasonably concise and “digestible” findings. In particular, the highlighting approach sheds useful light on the kind of variability present among the NARPS teams’ results, which is primarily a varied strength of agreement rather than disagreement. Using a meta-analysis built on the informative “highlighting” approach shows this relative agreement, while one using the standard “hiding” approach does not. We describe how this simple but powerful change in practice---focusing on highlighting results, rather than hiding all but the strongest ones---can help address many large concerns within the field, or at least to provide more complete information about them. We include a list of practical suggestions for results reporting to improve reproducibility, cross-study comparisons and meta-analyses.HighlightsMost studies do not present all results of their analysis, hiding subthreshold ones.Hiding results negatively affects the interpretation and understanding of the study.Neuroimagers should present all results of their study, highlighting key ones.Using the public NARPS data, we show several benefits of the “highlighting” approach.The highlighting approach improves individual studies and meta-analyses.