bluuebunny/crossref_metadata_2025_split huggingface dataset:
PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment
Authors: Darrous Liza , Hemani Gibran , Smith George Davey , Kutalik Zoltán 
Published: April 2023

AbstractMendelian Randomisation (MR) is a statistical method that estimates causal effects between risk factors and common complex diseases using genetic instruments. Heritable confounders, pleiotropy and heterogeneous causal effects violate MR assumptions and can lead to biases. To tackle these, we propose an approach employing a PheWAS-based clustering of the MR instruments (PWC-MR). We apply this method to revisit the surprisingly large apparent causal effect of body mass index (BMI) on educational attainment (EDU):α= -0.19 [-0.22, -0.16].As a first step of PWC-MR, we clustered 324 BMI-associated genetic instruments based on their association profile across 407 traits in the UK Biobank, which yielded six distinct groups. The subsequent cluster-specific MR revealed heterogeneous causal effect estimates on EDU. A cluster strongly enriched for traits related to socio-economic position yielded the largest BMI-on-EDU causal effect estimate (α= -0.49 [-0.56, -0.42]) whereas a cluster enriched for primary impact on body-mass had the smallest estimate (α= -0.09 [-0.13, - 0.05]). Several follow-up analyses confirmed these findings: (i) within-sibling MR results (α= -0.05 [-0.09, -0.01]); (ii) MR for childhood BMI on EDU (α= -0.03 [-0.06, -0.002]); (iii) step-wise multivariable MR (MVMR) (α= -0.06 [-0.09, -0.04]) where time spent watching television and past tobacco smoking (two proxies for potential confounders) were jointly modelled.Through a detailed examination of the BMI-EDU causal relationship we demonstrated the utility of our PWC-MR approach in revealing distinct pleiotropic pathways and confounder mechanisms.
omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
Authors: Alvarado Chelsea X. , Makarious Mary B. , Weller Cory A. , Vitale Dan , Koretsky Mathew J. , Bandres-Ciga Sara , Iwaki Hirotaka , Levine Kristin , Singleton Andrew , Faghri Faraz , Nalls Mike A. , Leonard Hampton L. 
Published: April 2023

SummaryTreatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer’s Disease, highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use Summary-data-based Mendelian Randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer’s disease, 3 amyotrophic lateral sclerosis, 5 Lewy body dementia, 46 Parkinson’s disease, and 9 Progressive supranuclear palsy target genes passing multiple test corrections (pSMR_multi< 2.95×10−6and pHEIDI> 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics - classifying 41noveltargets, 3knowntargets, and 115difficulttargets (of these 69.8% are expressed in the disease relevant cell type from single nucleus experiments). Ournovelclass of genes provides a springboard for new opportunities in drug discovery, development and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as Riluzole in AD. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community [https://nih-card-ndd-smr-home-syboky.streamlit.app/].
Predictive links between petal color and pigment quantities in naturalPenstemonhybrids
Authors: Stevens Joshua T.E. , Wheeler Lucas C. , Williams Noah H. , Norton Alice M. , Wessinger Carolyn A. 
Published: April 2023

AbstractFlowers have evolved remarkable diversity in petal color, in large part due to pollinator-mediated selection. This diversity arises from specialized metabolic pathways that generate conspicuous pigments. Despite the clear link between flower color and floral pigment production, studies determining predictive relationships between pigmentation and petal color are currently lacking. In this study, we analyze a dataset consisting of hundreds of naturalPenstemonhybrids that exhibit variation in flower color, including blue, purple, pink, and red. For each individual hybrid, we measured anthocyanin pigment content and petal spectral reflectance. We found that floral pigment quantities are correlated with hue, chroma, and brightness as calculated from petal spectral reflectance data: hue is related to the relative amounts of delphinidin vs. pelargonidin pigmentation, whereas brightness and chroma are correlated with the total anthocyanin pigmentation. We used a partial least squares regression approach to identify predictive relationships between pigment production and petal reflectance. We find that pigment quantity data provide robust predictions of petal reflectance, confirming a pervasive assumption that differences in pigmentation should predictably influence flower color. Moreover, we find that reflectance data enables accurate inferences of pigment quantities, where the full reflectance spectra provide much more accurate inference of pigment quantities than spectral attributes (brightness, chroma, and hue). Our predictive framework provides readily interpretable model coefficients relating spectral attributes of petal reflectance to underlying pigment quantities. These relationships represent key links between genetic changes affecting anthocyanin production and ecological functions of petal coloration.
Objects sharpen visual scene representations: evidence from MEG decoding
Authors: Brandman Talia , Peelen Marius V. 
Published: April 2023

AbstractReal-world scenes consist of objects, defined by local information, and scene background, defined by global information. While objects and scenes are processed in separate pathways in visual cortex, their processing interacts. Specifically, previous studies have shown that scene context makes blurry objects look sharper, an effect that can be observed as a sharpening of object representations in visual cortex from around 300 ms after stimulus onset. Here, we use MEG to show that objects can also sharpen scene representations, with the same temporal profile. Photographs of indoor (closed) and outdoor (open) scenes were blurred such that they were difficult to categorize on their own but easily disambiguated by the inclusion of an object. Classifiers were trained to distinguish MEG response patterns to intact indoor and outdoor scenes, presented in an independent run, and tested on degraded scenes in the main experiment. Results revealed better decoding of scenes with objects than scenes alone and objects alone from 300 ms after stimulus onset. This effect was strongest over left posterior sensors. These findings show that the influence of objects on scene representations occurs at similar latencies as the influence of scenes on object representations, in line with a common predictive processing mechanism.
Establishment and Evaluation of Rat Models of Cervical Spondylopathy with Yin Deficiency Syndrome
Authors: Yang Wenlong , Liu Muqing , Sun Qinran , Liu Lei , Wu Wenqing , Gao Peng , Liu Fangming , Liu Zhizhen 
Published: April 2023

AbstractObjectiveCervical spondylosis (CS) with Yin deficiency syndrome is an important classification of traditional Chinese medicine (TCM) symptoms of CS. However, there is no animal model for studying this TCM syndrome. This study aimes to establish and evaluate rat models of cervical spondylopathy with Yin deficiency syndrome.MethodThirty-six Sprague–Dawley male rats were randomly divided into the blank control (control), CS and CS with Yin deficiency syndrome (YCS) groups (n = 12 rats/group). CS was induced using cervical static–dynamic imbalance to mimic disk degeneration (except in the control group). After 30 days of the CS rat model, rats in the YCS group were subjected to sustained sleep deprivation for 168h. After different induction times, the rats in each group were observed for behavior and weight. Pain behavior was assessed by a withdrawal response to von Frey filament application, and heart rate and blood pressure were measured using a rat noninvasive sphygmomanometer. Intervertebral disc pathology sections were observed using hematoxylin and eosin staining and an electron microscope. Western blotting was used to evaluate the protein level of collagen-II, Bcl-2, Bax and Bcl-2/Bax expression in the cervical intervertebral disc. Determination of related laboratory serum indexes, cyclic adenosine monophosphate, and cyclic guanosine phosphate were conducted using enzyme-linked immunosorbent assay.ResultsThe laboratory indexes in the YCS group were significantly different from those in the control and CS groups (P < 0.05), and indicators of 72-, 120-, and 178-h sleep deprivation showed varying degrees of difference from those of the CS group.ConclusionAfter establishing a model of CS, continuous sleep deprivation for 72 h was used to create a rat model of CS with Yin deficiency syndrome. The established rat models of CS with Yin deficiency syndrome met the clinical and Chinese medicine characteristics, and thus, they can be expected to become an ideal model for studying CS with Yin deficiency syndrome in the future.
A Weighted Two-stage Sequence Alignment Framework to Identify DNA Motifs from ChIP-exo Data
Authors: Li Yang , Wang Yizhong , Wang Cankun , Fennell Anne , Ma Anjun , Jiang Jing , Liu Zhaoqian , Ma Qin , Liu Bingqiang 
Published: April 2023

ABSTRACTIdentifying precise transcription factor binding sites (TFBS) or regulatory DNA motifs plays a fundamental role in researching transcriptional regulatory mechanisms in cells and in helping construct regulatory networks. Current algorithms developed for motif searching focus on the analysis of ChIP-enriched peaks but are not able to integrate the ChIP signal in nucleotide resolution. We present a weighted two-stage alignment tool (TESA). Our framework implements an analysis workflow from experimental datasets to TFBS prediction results. It employs a binomial distribution model and graph searching model with ChIP-exonuclease (ChIP-exo) reads depth and sequence data. TESA can effectively measure the possibility for each position to be an actual TFBS in a given promoter sequence and predict statistically significant TFBS sequence segments. The algorithm substantially improves prediction accuracy and extends the scope of applicability of existing approaches. We apply the framework to a collection of 20 ChIP-exo datasets of E. coli from proChIPdb and evaluate the prediction performance through comparison with three existing programs. The performance evaluation against the compared programs indicates that TESA is more accurate for identifying regulatory motifs in prokaryotic genomes.
Obstructive Sleep Apnea Improves with Non-invasive Hypoglossal Nerve Stimulation using Temporal Interference
Authors: Missey Florian , Ejneby Malin Silverå , Ngom Ibrahima , Donahue Mary J. , Trajlinek Jan , Acerbo Emma , Botzanowski Boris , Cassarà Antonino M. , Neufeld Esra , Glowacki Eric D. , Shangold Lee , Hanes William M. , Williamson Adam 
Published: April 2023

ABSTRACTBackgroundPeripheral nerve stimulation is used in both clinical and fundamental research for therapy and exploration. At present, non-invasive peripheral nerve stimulation still lacks the penetration depth to reach deep nerve targets and the stimulation focality to offer selectivity. It is therefore rarely employed as the primary selected nerve stimulation method. We have previously demonstrated that a new stimulation technique, temporal interference stimulation, can overcome depth and focality issues.MethodsHere, we implement a novel form of temporal interference, bilateral temporal interference stimulation, for bilateral hypoglossal nerve stimulation in rodents and humans. Pairs of electrodes are placed alongside both hypoglossal nerves to stimulate them synchronously and thus decrease the stimulation amplitude required to activate hypoglossal-nerve controlled tongue movement.ResultsComparing bilateral temporal interference stimulation with unilateral temporal interference stimulation, we show that it can elicit the same behavioral and electrophysiological responses at a reduced stimulation amplitude. Traditional transcutaneous stimulation evokes no response with equivalent amplitudes of stimulation.ConclusionsDuring first in-man studies, temporal interference stimulation was found to be well-tolerated, and to clinically reduce apnea-hypopnea events in a subgroup of female patients with obstructive sleep apnea. These results suggest a high clinical potential for the use of temporal interference in the treatment of obstructive sleep apnea and other diseases as a safe, effective, and patient-friendly approach.Trial registrationThe protocol was conducted with the agreement of the International Conference on Harmonisation Good Clinical Practice (ICH GCP), applicable United States Code of Federal Regulations (CFR) and followed the approved BRANY IRB File # 22-02-636-1279.
Male rats emit aversive 44-kHz ultrasonic vocalizations during prolonged Pavlovian fear conditioning
Authors: Olszyński Krzysztof H. , Polowy Rafał , Wardak Agnieszka D. , Łaska Izabela A. , Grymanowska Aneta W. , Puławski Wojciech , Gawryś Olga , Koliński Michał , Filipkowski Robert K. 
Published: April 2023

AbstractRats are believed to communicate their emotional state by emitting two distinct types of ultrasonic vocalizations. The first is long “22-kHz” vocalizations (>300 ms, <32 kHz) with constant frequency, signaling aversive states and the second, is short “50-kHz” calls (<150 ms, >32 kHz), often frequency-modulated, in appetitive situations. Here we describe aversive vocalizations emitted at a higher pitch by male Wistar and spontaneously hypertensive rats (SHR) in an intensified aversive state – prolonged fear conditioning. These calls, which we named “44-kHz” vocalizations, are long (>150 ms), generally at a constant frequency (usually within 35-50 kHz range) and have an overall spectrographic image similar to 22-kHz calls. Some 44-kHz vocalizations are comprised of both 22-kHz-like and 44-kHz-like elements. Furthermore, two separate clustering methods confirmed that these 44-kHz calls can be separated from other vocalizations. We observed 44-kHz calls to be associated with freezing behavior during fear conditioning training, during which they constituted up to 19.4% of all calls and most of them appeared next to each other forming uniform groups of vocalizations (bouts). We also show that some of rats’ responses to the playback of 44-kHz calls were more akin to that of aversive calls, e.g., heart rate changes, whereas other responses were at an intermediate level between aversive and appetitive calls. Our results suggest that rats have a wider vocal repertoire than previously believed, and current definitions of major call types may require reevaluation. We hope that future investigations of 44-kHz calls in rat models of human diseases will contribute to expanding our understanding and therapeutic strategies related to human psychiatric conditions.
Single-cell RNA-sequencing identifies a novel subset of CD9+reparative macrophages modulated by CCN2 derived from Nlrx1 deficient cardiomyocytes in the infarcted heart
Authors: Li Jun , He Guangxiang , Wang Linyi , Wang Haijuan , Ma Ruixue , Sun Wenjie , Hu Jintao , Liang Jun , Li Renqi , Wu Xingan , Yang Yanling , Chen Jun , Liu Rongrong , Pei Jianming 
Published: April 2023

AbstractRationaleNlrx1, a pattern recognition receptor belonging to the NLR family, is highly expressed in the heart and is significantly increased after myocardial infarction in vivo, however, the role of Nlrx1 in post-infarction inflammation and healing is poorly understood. Although the effects of infiltrating macrophages on survival of cardiomyocytes and healing of injured hearts have been intensely studied, whether or not and how surviving cardiomyocytes might influence the phenotype and function of macrophages in the infarcted hearts was largely unexplored.ObjectiveTo investigate the role of Nlrx1 in post-infarction inflammation and healing and to dissect the underlying mechanism.Methods and resultsSingle cell RNA-sequencing of 23,805 cells isolated from infarcted hearts revealed 7 clusters of infarct macrophages including CCR2+, Isg+, Mki67+proliferative, and LYVE1+cardiac resident macrophages, and identified a novel subset of CD9+Il1rn+macrophages, which were characterized by high expression ofCd9, Il1rn, GpnmbandSpp1,and downregulation of proinflammatory cytokines and chemokines. CD9+Il1rn+macrophages were largely found in infarcted hearts of Nlrx1KO mice, and were transcriptionally unique with reparative phenotype. Loss of Nlrx1 attenuated ventricular dysfunction and adverse remodeling, and decreased post-infarction mortality. Flow cytometry analysis showed markedly increased number of CD9+macrophages and higher mean fluorescence intensity of CD9 in Nlrx1KO mice. RNA-seq analysis revealed that CD9+macrophages of Nlrx1KO infarcted hearts exhibited a reparative and anti-inflammatory phenotype as featured by upregulation of wound healing-associated genes includingCD9, Spp1andFn1, and downregulation of proinflammatory genes. Conditioned medium from Nlrx1 deficient cardiomyocytes upon hypoxia stimulation skewed macrophage polarization towards a reparative and inflammation-suppressed phenotype. Gain-and loss-of function of Nlrx1 combined with RNA-seq analysis identified CCN2, whose expression and secretion were significantly increased in Nlrx1 deficient cardiomyocytes upon hypoxia, as a cardiomyocytes-derived mediator responsible, at least partly, for reprograming macrophage towards a reparative phenotype. In vivo, CCN2 expression was markedly elevated in Nlrx1KO infarcted hearts. Moreover, exogenous CCN2 partially mediated macrophage transition towards a reparative phenotype.ConclusionsCD9+IL1rn+macrophages modulated by Nlrx1 deficient cardiomyocytes-derived CCN2, is a novel subset of reparative macrophages contributing to infarct healing. Inhibition of myocardial Nlrx1 and/or activation of CCN2 to boost CD9+IL1rn+reparative macrophages may represent new therapeutics for infarct healing following ischemic injury.
Effect of hexanal treatment on fruit qualities and antioxidant activities on ‘Umran’ Indian jujube fruit during cold storage
Authors: Sharma Anil , Bons Harsimrat K. , Jawandha S K , Chung Sun Woo 
Published: April 2023

Abstract‘Umran’ Indian jujube is a widely grown cultivar due to its marketable quality and productivity, resulting in excellent market value. Despite its high quality, the product’s short shelf life poses a challenge for transportation, even within the domestic market. Hexanal with three concentrations (0.15%, 0.20%, and 0.25%) was applied to the fruit of ‘Umran’ Indian jujube at both pit hardening and color break stages. Harvested fruits were stored for 28 days in a cold chamber of 7.5±1°C and 90-95% RH. The changes in fruit qualities were assessed with physicochemical characteristics, bioactive compounds, and enzymatic antioxidant activities every seven days. Fruits treated with hexanal of 0.20% reduced fruit weight loss and spoilage and maintained fruit firmness, soluble solids content, carotenoid content, and antioxidant activity. The activities of cell wall degrading enzymes investigated were suppressed. Of the antioxidant activities, superoxide dismutase and peroxidase were positively activated. Therefore, these results indicated that pre-harvest application of hexanal 0.20% improved physiochemical characteristics, maintained bioactive compounds, antioxidant enzyme activities, and extended the shelf life of Indian jujube fruits up to 21 days during cold storage.
Relationship Between Donor Derived Cell-Free DNA and Tissue-Based Rejection-Related Transcripts In Heart Transplantation
Authors: Lee Dae Hyun , Usmani Ahsan , Wu Robby , Wicks Tammi , Burke Ryan , Ravichandran Vani , Wolf-Doty Theresa , Dumitru Ioana , Oliveira Guilherme H. , Berman Peter , Mackie Benjamin 
Published: April 2023

AbstractIntroductionEndomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs which may provide further insight into the pathophysiology of allograft rejection and injury.MethodsThis is a retrospective observational study of 186 endomyocardial biopsy (EMB) evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood prior to EMB (up to 1 month). Diagnostic agreement between traditional microscopy, MMDx, and dd-cfDNA (threshold of 0.20%) were compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated.ResultsMMDx characterized allograft tissue as no rejection (NR) (64.5%), antibody-mediated rejection (ABMR) (25.8%), T-cell-mediated rejection (TCMR) (4.8%), and mixed ABMR/ TCMR (4.8%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (74.7% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters correlated with dd-cfDNA scores, includingDSAST, GRIT, HT1, QCMAT and S4. For individual transcripts, tissueROBO4was significantly correlated with dd-cfDNA in both non-rejection and rejection as assessed by MMDx.ConclusionCollectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA andROBO4(a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of AMR, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to ACR.