bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grain Utilization by the Gut Microbiome as a Human Health Phenotype to Identify Multiple Effect Loci in Genome-Wide Association Studies ofSorghum bicolor
Authors: Korth Nate , Yang Qinnan , Van Haute Mallory J. , Tross Michael C. , Peng Bo , Shrestha Nikee , Zwiener Mackenzie , Mural Ravi V. , Schnable James C. , Benson Andrew K. 
Published: September 2023

AbstractA growing epidemic of complex lifestyle diseases such as obesity and metabolic diseases are explained in part by dysbiosis of the human gut microbiome. The gut microbiome, comprising trillions of microorganisms, contributes to functions ranging from digestion to the immune system. Diet plays a critical role in determining the species composition and functionality of the gut microbiome. Substantial functional metabolic diversity exists within the cultivated grain crops which directly or indirectly provide more than half of all calories consumed by humans around the globe, however much of this diversity is poorly characterized and the effects of such diversity on the human gut microbiome is not well studied. We employed a quantitative genetics approach to identify genetic variants in sorghum that alter the composition and function of human gut microbes. Using an automated high-throughput phenotyping method based onin vitromicrobiome fermentation of grain from a diverse population ofSorghum bicolorcultivars, we demonstrate sorghum genetics can explain effects of grain variation on fermentation patterns of bacterial taxa across multiple human microbiomes. In a genome-wide analysis using a sorghum association panel, we identified fifteen multiple-effect loci (MEL) where different alleles in the sorghum genome produced changes in seed that affect the abundance of multiple bacterial taxa across two human microbiomes in automated in vitro fermentations. In a number of cases parallel genome-wide association studies conducted for biochemical and agronomic traits identified seed traits potentially causal for the link between sorghum genetics and human microbiome outcomes. This work demonstrates that genetic factors affecting sorghum seed can drive significant effects on human gut microbes, particularly bacterial taxa considered beneficial. Understanding these relationships will enable targeted crop breeding strategies to improve human health through gut microbiome modulation.
Accurate somatic variant calling performance using Avidity Sequencing with Burning Rock’s OncoScreenTMPlus panel
Authors: Zhang Guangliang , Liu Yangyang , Luo Yilun , Han Yusheng , Zhang Zhihong 
Published: September 2023

AbstractBackgroundNext-generation sequencing (NGS) comprehensive genomic profiling panels provide targeted genome-wide detection of the somatic variant landscape of various cancer types. Recently, an innovative sequencing technology, Avidity Sequencing from Element Biosciences, has emerged to provide economical option for mid-throughput sequencing, with high quality (Q40).AimsThe aim of this study was to evaluate the performance characteristics of AVITI sequencing by avidity on detection of somatic variants from reference samples, and to compare the variant detection concordance between AVITI and NovaSeq sequencing platforms by evaluating the variant callings of 518 cancer-related genes using Burning Rock’s OncoScreenTMPlus panel.MethodsContrived commercial reference control samples (harboring known variants) and clinical Formalin-Fixed Paraffin-Embedded tissue (FFPE) samples were examined to evaluate the variant detection performance of two sequencing platforms, with respects to Single Nucleotide Variant (SNV), Insertion-Deletion (Indel), Structure Variant (SV/Fusion), Copy Number Variation (CNV), Microsatellite Instability (MSI), and Tumor Mutation Burden (TMB). Variant specific QC metrics were developed to evaluate sequencing-level and variant calling level accuracy. All samples were processed utilizing the OncoScreenTMPlus assay, including library preparation and bioinformatics post sequencing data analysis.ResultsThe OncoScreenTMPlus assay is compatible with the AVITI system. Samples prepared with the OncoScreenTMPlus panel and sequenced on the AVITI system has successfully detected cancer related variants including SNV/Indels, SV/Fusion, CNVs, MSIs, and TMB, which were highly concordant with reference controls. In addition, the AVITI system produced a higher overall quality score, index assignment rate, mean target coverage, and lower optical duplication rate AVITI than NovaSeq system.ConclusionThe new sequencing technology Avidity from AVITI system can be applied seamlessly to current high-performance targeted oncology assays to reliably identify somatic variants in a flexible and cost-effective manner.
Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in rodent and swine photoreceptors
Authors: Cheng Shun-Yun , Caiazzi Jillian , Biscans Annabelle , Alterman Julia F. , Echeverria Dimas , McHugh Nicholas , Hassler Matthew , Jolly Samson , Giguere Delaney , Cipi Joris , Khvorova Anastasia , Punzo Claudio 
Published: September 2023

AbstractInherited retinal dystrophies caused by dominant mutations in photoreceptor-expressed genes, are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery. Thus, an unmet need exists to identify siRNA chemistry that targets photoreceptor-expressed genes. Here we evaluated 12 different fully chemically modified siRNA configurations, where the valency and conjugate structure were systematically altered. The impact on retinal distribution following intravitreal delivery was examined. We found that the increase in valency (tetravalent siRNA) supports the best photoreceptor accumulation. A single intravitreal administration induces multi-months efficacy in rodent and porcine retinas while showing a good safety profile. The data suggest that this configuration can treat retinal diseases caused by photoreceptor-expressed genes with 1-2 intravitreal injections per year.
GammaGateR: semi-automated marker gating for single-cell multiplexed imaging
Authors: Xiong Jiangmei , Kaur Harsimran , Heiser Cody N , McKinley Eliot T , Roland Joseph T , Coffey Robert J , Shrubsole Martha J , Wrobel Julia , Ma Siyuan , Lau Ken S , Vandekar Simon 
Published: September 2023

AbstractMotivationMultiplexed immunofluorescence (mIF) is an emerging assay for multichannel protein imaging that can decipher cell-level spatial features in tissues. However, existing automated cell phenotyping methods, such as clustering, face challenges in achieving consistency across experiments and often require subjective evaluation. As a result, mIF analyses often revert to marker gating based on manual thresholding of raw imaging data.ResultsTo address the need for an evaluable semi-automated algorithm, we developed GammaGateR, an R package for interactive marker gating designed specifically for segmented cell-level data from mIF images. Based on a novel closed-form gamma mixture model, GammaGateR provides estimates of marker-positive cell proportions and soft clustering of marker-positive cells. The model incorporates user-specified constraints that provide a consistent but slide-specific model fit. We compared GammaGateR against the newest unsupervised approach for annotating mIF data, employing two colon datasets and one ovarian cancer dataset for the evaluation. We showed that GammaGateR produces highly similar results to a silver standard established through manual annotation. Furthermore, we demonstrated its effectiveness in identifying biological signals, achieved by mapping known spatial interactions between CD68 and MUC5AC cells in the colon and by accurately predicting survival in ovarian cancer patients using the phenotype probabilities as input for machine learning methods. GammaGateR is a highly efficient tool that can improve the replicability of marker gating results, while reducing the time of manual segmentation.Availability and ImplementationThe R package is available athttps://github.com/JiangmeiRubyXiong/GammaGateR.ContactPlease address correspondence tojiangmei.xiong@vanderbilt.eduandsimon.vandekar@vumc.org.Key PointsGammaGateR is the first semi-automated marker gating tool for mIF image, and it will help to diminish the inconsistency with manual marker gating.With novel cfGMM, GammaGateR can fit flexibly across slides with different distributions and incorporate biology priors.GammaGateR is proven to reveal credible prognostic information, and it can quantify known findings in tumor cell populations.
Combination of memantine and alpha7 nicotinic acetylcholine receptor ligands exerts superior efficacy over monotreatments to improve cognitive performance of aged rats
Authors: Bruszt Nóra , Bali Zsolt Kristóf , Nagy Lili Veronika , Bodó Kornélia , Engelmann Péter , Ledneczki István , Némethy Zsolt , Lendvai Balázs , Hernádi István 
Published: September 2023

AbstractCombination treatments based on pharmacological interactions at α7 nAChRs are promising therapeutic approaches for neurocognitive disorders (NCDs). Memantine, an already approved medication in some NCDs, may not only act as an antagonist of the glutamatergic NMDA receptors (NMDAR) but also serve as an antagonist of the cholinergic α7 nAChRs. Here we set out to utilize a combination treatment regime with an α7 nAChR-selective agonist (PHA-543613) and a novel proprietary α7 nAChR ligand with marked positive allosteric modulator (PAM) activity (CompoundX). The cognitive efficacy of combination treatments was tested in a naturally aged rat model. Naturally aged rats showed marked cognitive decline in the novel object recognition (NOR) test, and they displayed pathological changes at the molecular level in terms of various inflammatory markers. In addition, aged rats also exhibited cholinergic changes such as mRNA upregulation of α7 nAChRs. Memantine-PHA-543613 and memantine-CompoundX combination treatments successfully alleviated the age-related decline of recognition memory of rats by exceeding the null-effects of the corresponding subtherapeutic levels of monotreatments. Results indicate a positive interaction between memantine and α7-nAChR agonists and PAMs, which reflects a prominent role of α7 nAChRs in the cognitive enhancement of combination treatments especially in age-related cognitive decline. Moreover, the putative direct action of memantine on α7 nAChRs may also contribute to the observed synergistic interaction between memantine and other selective α7 nAChR compounds.
Patterns and drivers of pollen co-transport networks vary across pollinator groups
Authors: Carneiro Liedson Tavares , Williams Jessica Nicole , Barker Daniel A , Anderson Joseph W , Martel Carlos , Arceo-Gomez Gerardo 
Published: September 2023

SummaryPollen transport is an understudied process with consequences for plant reproductive success and floral evolution. Recently, pollinator bodies have been described as pollen competition arenas, with implications for plant community assembly. However, the identity, strength, and diversity of pollen competitive interactions and how they vary across pollinator groups is unknown. Evaluating patterns and drivers of the pollen competition landscape across different pollinator groups is central to further our understanding of plant coexistence mechanisms. Here, we integrate information on insect pollen loads with network analyses to uncover novel pollen co-transport networks and how these vary across pollinators. We evaluate differences in pollen load size, diversity and their phenological and phylogenetic attributes among insect groups and how these relate to body size and sex. Pollen co-transport networks revealed differences in the number and identity of competitors that pollen species encounter across pollinator groups. These networks were highly modular, with groups of pollen species interacting more often on pollinator bodies. Pollen load size and richness were shaped by bee size and sex. Sex also influenced the pollen phylogenetical diversity. Pollinators can impose vastly different competitive landscapes during pollen transport, with so far unknown consequences for plant reproductive success, floral evolution and community assembly.
Preconfigured cortico-thalamic neural dynamics constrain movement-associated thalamic activity
Authors: González-Pereyra Perla , Martínez-Montalvo Mario G. , Ortega-Romero Diana I. , Pérez-Díaz Claudia I. , Merchant Hugo , Tellez Luis A. , Rueda-Orozco Pavel E. 
Published: September 2023

AbstractNeural preconfigured activity patterns (nPAPs) have been proposed as building blocks for cognitive and sensory processing. However, their existence and function in motor networks have not been explicitly studied. Here, we explore the possibility that nPAPs are present in the motor thalamus (VL/VM) and their potential contribution to motor-related activity. To this end, we developed a preparation where VL/VM multiunitary activity could be robustly recorded in mouse behavior evoked by primary motor cortex (M1) optogenetic stimulation and forelimb movements. VL/VM-evoked activity was organized as rigid stereotypical activity patterns at the single and population levels. These activity patterns were unable to dynamically adapt to different temporal architectures of M1 stimulation. Moreover, they were experience-independent and present in virtually all animals, confirming their preconfigured nature. Finally, subpopulations expressing specific M1-evoked patterns also displayed specific movement-related patterns. Our data demonstrate that the behaviorally related identity of specific neural subpopulations is tightly linked to nPAPs.
Individual Differences Elucidate the Perceptual Benefits Associated with Robust Temporal Fine-Structure Processing
Authors: Borjigin Agudemu , Bharadwaj Hari M. 
Published: September 2023

The auditory system is unique among sensory systems in its ability to phase lock to and precisely follow very fast cycle-by-cycle fluctuations in the phase of sound-driven cochlear vibrations. Yet, the perceptual role of this temporal fine structure (TFS) code is debated. This fundamental gap is attributable to our inability to experimentally manipulate TFS cues without altering other perceptually relevant cues. Here, we circumnavigated this limitation by leveraging individual differences across 200 participants to systematically compare variations in TFS sensitivity to performance in a range of speech perception tasks. TFS sensitivity was assessed through detection of interaural time/phase differences, while speech perception was evaluated by word identification under noise interference. Results suggest that greater TFS sensitivity is not associated with greater masking release from fundamental-frequency or spatial cues, but appears to contribute to resilience against the effects of reverberation. We also found that greater TFS sensitivity is associated with faster response times, indicating reduced listening effort. These findings highlight the perceptual significance of TFS coding for everyday hearing.Significance StatementNeural phase-locking to fast temporal fluctuations in sounds–temporal fine structure (TFS) in particular– is a unique mechanism by which acoustic information is encoded by the auditory system. However, despite decades of intensive research, the perceptual relevance of this metabolically expensive mechanism, especially in challenging listening settings, is debated. Here, we leveraged an individual-difference approach to circumnavigate the limitations plaguing conventional approaches and found that robust TFS sensitivity is associated with greater resilience against the effects of reverberation and is associated with reduced listening effort for speech understanding in noise.
Molecular Photoswitches Regulating the Activity of the Human Serotonin Transporter
Authors: Singer Nadja K. , González Leticia , Monari Antonio 
Published: September 2023

AbstractSerotonin is an essential mediator regulating diverse neural processes, and its deregulation is related to debilitating neurological diseases. In particular, the human serotonin transporter (hSERT) is fundamental in completing the synaptic neural cycle by allowing the reuptake of serotonin. Its inhibition is particularly attractive, especially as a pharmacological target against depressive syndrome. Here, we analyze, by using long-range molecular dynamic simulations, the behavior of a molecular photoswitch whosecis- andtrans-isomers inhibit the hSERT differently. In particular, we evidence the structural and molecular basis behind the higher inhibiting capacity of thecis-isomer, which blocks more efficiently the hSERT conformational cycle leading to serotonin uptake.TOC Graphic
Deactivation of ligand-receptor interactions enhancing lymphocyte infiltration drives melanoma resistance to Immune Checkpoint Blockade
Authors: Sahni Sahil , Wang Binbin , Wu Di , Dhruba Saugato Rahman , Nagy Matthew , Patkar Sushant , Ferreira Ingrid , Wang Kun , Ruppin Eytan 
Published: September 2023

AbstractImmune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (ImmunotherapyResistance cell-cellInteractionScanner), a machine learning model aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to mediate ICB resistance in the tumor microenvironment (TME). We developed and applied IRIS to identify resistance-mediating cell-type-specific ligand-receptor interactions by analyzing deconvolved transcriptomics data of the five largest melanoma ICB therapy cohorts. This analysis identifies a set of specific ligand-receptor pairs that are deactivated as tumors develop resistance, which we refer to asresistance deactivated interactions (RDI).Quite strikingly, the activity of these RDIs in pre-treatment samples offers a markedly stronger predictive signal for ICB therapy response compared to those that are activated as tumors develop resistance. Their predictive accuracy surpasses the state-of-the-art published transcriptomics biomarker signatures across an array of melanoma ICB datasets. Many of these RDIs are involved in chemokine signaling. Indeed, we further validate on an independent large melanoma patient cohort that their activity is associated with CD8+ T cell infiltration and enriched in hot/brisk tumors. Taken together, this study presents a new strongly predictive ICB response biomarker signature, showing that following ICB treatment resistant tumors turn inhibit lymphocyte infiltration by deactivating specific key ligand-receptor interactions.
Increased LPS-Induced Fever and Sickness Behavior in Adult Male and Female Rats Perinatally Exposed to Morphine
Authors: Harder Hannah J. , Gomez Morgan G. , Searles Christopher T. , Vogt Meghan E. , Murphy Anne Z. 
Published: September 2023

AbstractAs a result of the current opioid crisis, the rate of children born exposed to opioids has skyrocketed. Later in life, these children have an increased risk for hospitalization and infection, raising concerns about potential immunocompromise, as is common with chronic opioid use. Opioids can act directly on immune cells or indirectly via the central nervous system to decrease immune system activity, leading to increased susceptibility, morbidity, and mortality to infection. However, it is currently unknown how perinatal opioid exposure (POE) alters immune function. Using a clinically relevant and translatable model of POE, we have investigated how baseline immune function and the reaction to an immune stimulator, lipopolysaccharide, is influenced byin uteroopioid exposure in adult male and female rats. We report here that POE potentiates the febrile and neuroinflammatory response to lipopolysaccharide, likely as a consequence of suppressed immune function at baseline (including reduced antibody production). This suggests that POE increases susceptibility to infection by manipulating immune system development, consistent with the clinical literature. Investigation of the mechanisms whereby POE increases susceptibility to pathogens is critical for the development of potential interventions for immunosuppressed children exposed to opioidsin utero.HighlightsPerinatal exposure to morphine leads to increased fever and sickness post-LPSPerinatal exposure to morphine alters peripheral immunityPerinatal exposure to morphine increases microglial activation
Transgenic tools targeting striatal and pallidal subpopulations revealed evolutionary conservation and specialization of the cortico-basal ganglia circuit in zebrafish
Authors: Tanimoto Yuki , Kakinuma Hisaya , Aoki Ryo , Shiraki Toshiyuki , Higashijima Shin-ichi , Okamoto Hitoshi 
Published: September 2023

SummaryThe cortico-basal ganglia circuit mediates decision-making. Here, we generated transgenic tools for adult zebrafish targeting specific subpopulations of the components of this circuit and utilized them to identify evolutionary homologs of the mammalian direct- and indirect-pathway striatal neurons which respectively project to the homologs of the internal and external segment of the globus pallidus (dEN and Vl) as in mammals. Unlike in mammals, the Vl mainly projected to the dEN directly, not by way of the subthalamic nucleus. Further single-cell RNA sequencing analysis revealed two pallidal output pathways: a major shortcut pathway directly connecting the dEN with the pallium and the evolutionarily conserved closed loop by way of the thalamus. Our resources and circuit map provide the common basis for the functional study of the basal ganglia in a small and optically tractable zebrafish brain for the comprehensive mechanistic understanding of the cortico-basal ganglia circuit.
NuFold: A Novel Tertiary RNA Structure Prediction Method Using Deep Learning with Flexible Nucleobase Center Representation
Authors: Kagaya Yuki , Zhang Zicong , Ibtehaz Nabil , Wang Xiao , Nakamura Tsukasa , Huang David , Kihara Daisuke 
Published: September 2023

AbstractRNA is not only playing a core role in the central dogma as mRNA between DNA and protein, but also many non-coding RNAs have been discovered to have unique and diverse biological functions. As genome sequences become increasingly available and our knowledge of RNA sequences grows, the study of RNA’s structure and function has become more demanding. However, experimental determination of three-dimensional RNA structures is both costly and time-consuming, resulting in a substantial disparity between RNA sequence data and structural insights. In response to this challenge, we propose a novel computational approach that harnesses state-of-the-art deep learning architecture NuFold to accurately predict RNA tertiary structures. This approach aims to offer a cost-effective and efficient means of bridging the gap between RNA sequence information and structural comprehension. NuFold implements a nucleobase center representation, which allows it to reproduce all possible nucleotide conformations accurately.