bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-Time Prescribing of GLP-1 Receptor Agonists from 2018-2023: A Descriptive Analysis
Authors: Rodriguez Patricia J , Gratzl Samuel , Goodwin Cartwright Brianna M , Brar Rajdeep , Gluckman Ty J , Stucky Nicholas L 
Published: August 2023

AbstractAimsLimited recent data exist on prescribing patterns and patient characteristics for glucagon-like peptide 1 receptor agonists (GLP-1 RAs), an important drug class for patients with type 2 diabetes mellitus (T2D) and/or overweight or obesity. We describe trends in first-time prescribing of GLP-1 RAs.Materials and MethodsUsing aggregated US electronic health record data, we identified first-time prescriptions of GLP-1 RAs between January 2018 and June 2023 for adults receiving regular care. We describe prescribing volumes stratified by patient characteristics, specific drug, and FDA-labelled indication. The 5.5-year analysis period was divided into six-month periods.ResultsIn total, 274,562 patients were newly prescribed a GLP-1 RA, with a significant increase over time (January to June, 2018: 9,642 versus 2023: 66,569; p < 0.001). Overall, 181,860 (66.2%) patients had T2D and 229,715 (83.7%) had obesity or overweight. The proportion with T2D decreased over time (January through June, 2018: 84.1% versus 2023: 49%; p < 0.001), while the proportion with overweight or obesity increased (January through June, 2018: 75.9% versus 2023: 90.7%; p <.001). Of prescriptions with a known FDA-labelled indication (74.2%), 87% were labelled for T2D and 13% were labelled for overweight or obesity. Patients first prescribed a GLP-1 RA labelled for T2D were 59.1% female with a mean (SD) age of 58.6 (13) years, while those prescribed a GLP-1 RA labelled for overweight or obesity were 82.9% female, with a mean (SD) age of 48.2 (12.2) years.ConclusionsWe observed an increase in first-time prescribing of GLP-1 RAs overall, and a shift away from a predominately T2D population.
Developing and Evaluating Pediatric Phecodes (Peds-Phecodes) for High-Throughput Phenotyping Using Electronic Health Records
Authors: Grabowska Monika E. , Van Driest Sara L. , Robinson Jamie R. , Patrick Anna E. , Guardo Chris , Gangireddy Srushti , Ong Henry , Feng QiPing , Carroll Robert , Kannankeril Prince J. , Wei Wei-Qi 
Published: August 2023

ABSTRACTObjectivePediatric patients have different diseases and outcomes than adults; however, existing phecodes do not capture the distinctive pediatric spectrum of disease. We aim to develop specialized pediatric phecodes (Peds-Phecodes) to enable efficient, large-scale phenotypic analyses of pediatric patients.Materials and MethodsWe adopted a hybrid data- and knowledge-driven approach leveraging electronic health records (EHRs) and genetic data from Vanderbilt University Medical Center to modify the most recent version of phecodes to better capture pediatric phenotypes. First, we compared the prevalence of patient diagnoses in pediatric and adult populations to identify disease phenotypes differentially affecting children and adults. We then used clinical domain knowledge to remove phecodes representing phenotypes unlikely to affect pediatric patients and create new phecodes for phenotypes relevant to the pediatric population. We further compared phenome-wide association study (PheWAS) outcomes replicating known pediatric genotype-phenotype associations between Peds-Phecodes and phecodes.ResultsThe Peds-Phecodes aggregate 15,533 ICD-9-CM codes and 82,949 ICD-10-CM codes into 2,051 distinct phecodes. Peds-Phecodes replicated more known pediatric genotype-phenotype associations than phecodes (248 versus 192 out of 687 SNPs, p<0.001).DiscussionWe introduce Peds-Phecodes, a high-throughput EHR phenotyping tool tailored for use in pediatric populations. We successfully validated the Peds-Phecodes using genetic replication studies. Our findings also reveal the potential use of Peds-Phecodes in detecting novel genotype-phenotype associations for pediatric conditions. We expect that Peds-Phecodes will facilitate large-scale phenomic and genomic analyses in pediatric populations.ConclusionPeds-Phecodes capture higher-quality pediatric phenotypes and deliver superior PheWAS outcomes compared to phecodes.
Potent and broadly neutralizing antibodies against sarbecoviruses induced by sequential COVID-19 vaccination
Authors: Zhao Xiaoyu , Qiu Tianyi , Huang Xiner , Mao Qiyu , Wang Yajie , Qiao Rui , Mao Tiantian , Wang Yuan , Li Jiayan , Luo Cuiting , Yoon Chaemin , Wang Xun , Li Chen , Cui Yuchen , Zhao Chaoyue , Li Minghui , Chen Yanjia , Cai Guonan , Geng Wenye , Hu Zixin , Cao Jinglei , Zhang Wenhong , Cao Zhiwei , Chu Hin , Sun Lei , Wang Pengfei 
Published: August 2023

AbstractThe current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum neutralizing activity against diverse coronaviruses. Through single B cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, one potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1 and SARS-CoV viral challenge in golden Syrian hamsters, respectively. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.
Unravelling the influence of affective stimulation on functional neurological symptoms: A pilot experiment examining potential mechanisms
Authors: Pick Susannah , Merritt Millman L. S. , Ward Emily , Short Eleanor , Stanton Biba , Reinders A.A.T.S. , Winston Joel S. , Nicholson Timothy R. , Edwards Mark J. , Goldstein Laura H. , David Anthony S. , Chalder Trudie , Hotopf Matthew , Mehta Mitul A. 
Published: August 2023

AbstractBackgroundDifferences in affective processing have previously been shown in functional neurological disorder (FND); however, the mechanistic relevance is uncertain. We tested the hypotheses that highly arousing affective stimulation would result in elevated subjective functional neurological symptoms (FNS), and this would be associated with elevated autonomic reactivity. The possible influence of cognitive detachment was also explored.MethodsIndividuals diagnosed with FND (motor symptoms/seizures; n=14) and healthy controls (HCs; n=14) viewed Positive, Negative, and Neutral images in blocks, whilst passively observing the stimuli (“Watch”) or detaching themselves (“Distance”). The FND group rated their primary FNS, and all participants rated subjective physical (arousal, pain, fatigue) and psychological states (positive/negative affect, dissociation), immediately after each block. Skin conductance (SC) and heartrate (HR) were monitored continuously.ResultsFNS ratings were higher after Negative compared to Positive and Neutral blocks in the FND group (p=0.002, ηp2=0.386); however, this effect was diminished in the Distance condition relative to the Watch condition (p=0.018, ηp2=0.267). SC and/or HR correlated with FNS ratings in the Negative-Watch and Neutral-Distance conditions (r-values: 0.527-0.672, p-values: 0.035-0.006). The groups did not differ in subjective affect or perceived arousal (p-values: 0.541-0.919, ηp2: <0.001-0.015).ConclusionsEmotionally significant events may exert an influence on FNS which is related to autonomic activation rather than altered subjective affect or perceived arousal. This influence may be modulated by cognitive detachment. Further work is needed to determine the relevance and neural bases of these processes in specific FND phenotypes.
Detection and characterisation of copy number variants from exome sequencing in the DDD study
Authors: Danecek Petr , Gardner Eugene J. , Fitzgerald Tomas W. , Gallone Giuseppe , Kaplanis Joanna , Eberhardt Ruth Y. , Wright Caroline F. , Firth Helen V. , Hurles Matthew E. 
Published: August 2023

AbstractPurposeStructural variants such as multi-exon deletions and duplications are an important cause of disease, but are often overlooked in standard exome/genome sequencing analysis. We aimed to evaluate the detection of copy number variants (CNVs) from exome sequencing (ES) in comparison to genome-wide low-resolution and exon-resolution chromosomal microarrays (CMA), and to characterise the properties ofde novoCNVs in a large clinical cohort.MethodsWe performed CNV detection using ES of 13,462 parent-offspring trios in the Deciphering Developmental Disorders (DDD) study, and compared them to CNVs detected from exon-resolution array comparative genomic hybridization (aCGH) in 5,197 probands from the DDD study.ResultsIntegrating calls from multiple ES-based CNV algorithms using random forest machine learning generated a higher quality dataset than using individual algorithms. Both ES- and aCGH-based approaches had the same sensitivity of 89% and detected the same number of unique pathogenic CNVs not called by the other approach. Of DDD probands pre-screened with low resolution CMA, 2.6% had a pathogenic CNV detected by higher resolution assays.De novoCNVs were strongly enriched in known DD-associated genes and exhibited no bias in parental age or sex.ConclusionES-based CNV calling has higher sensitivity than low-resolution CMAs currently in clinical use, and comparable sensitivity to exon-resolution CMA. With sufficient investment in bioinformatic analysis, exomebased CNV detection could replace low-resolution CMA for detecting pathogenic CNVs.
Harnessing the Open Access Version of ChatGPT for Enhanced Clinical Opinions
Authors: Tenner Zachary M , Cottone Michael , Chavez Martin 
Published: August 2023

AbstractWith the advent of Large Language Models (LLMs) like ChatGPT, the integration of AI into clinical medicine is becoming increasingly feasible. This study aimed to evaluate the ability of the freely available ChatGPT-3.5 to generate complex differential diagnoses, comparing its output to case records of the Massachusetts General Hospital published in the New England Journal of Medicine (NEJM). Forty case records were presented to ChatGPT-3.5, with prompts to provide a differential diagnosis and then narrow it down to the most likely diagnosis. Results indicated that the final diagnosis was included in ChatGPT-3.5’s original differential list in 42.5% of the cases. After narrowing, ChatGPT correctly determined the final diagnosis in 27.5% of the cases, demonstrating a decrease in accuracy compared to previous studies using common chief complaints. These findings emphasize the need for further investigation into the capabilities and limitations of LLMs in clinical scenarios, while highlighting the potential role of AI as an augmented clinical opinion. With anticipated growth and enhancements to AI tools like ChatGPT, physicians and other healthcare workers will likely find increasing support in generating differential diagnoses. However, continued exploration and regulation are essential to ensure the safe and effective integration of AI into healthcare practice. Future studies may seek to compare newer versions of ChatGPT or investigate patient outcomes with physician integration of this AI technology. By understanding and expanding AI’s capabilities, particularly in differential diagnosis, the medical field may foster innovation and provide additional resources, especially in underserved areas.
Herptile gut microbiomes: a natural system to study multi-kingdom interactions between filamentous fungi and bacteria
Authors: Vargas-Gastélum Lluvia , Romer Alexander S. , Alexander N. Reed , Ghotbi Marjan , Moe Kylie C. , McPhail Kerry L. , Neuhaus George F. , Shadmani Leila , Spatafora Joseph W. , Stajich Jason E. , Tabima Javier F. , Walker Donald M. 
Published: August 2023

ABSTRACTReptiles and amphibians (herptiles) represent some of the more endangered and threatened species on the planet and numerous conservation strategies are being implemented with the goal of ensuring species recovery. Little is known, however, about the wild gut microbiome of herptiles and how it relates to the health of wild populations. Here we report results from both a broad survey of hosts and a more intensive sampling of hosts and geography of fungi and bacteria associated with herptile gut microbiomes. We demonstrate that bacterial communities sampled from frogs, lizards and salamanders are structured by the host higher level taxonomy and that the fungusBasidiobolusis a common and natural component of these wild gut microbiomes. Intensive sampling of multiple hosts across the ecoregions of Tennessee revealed that geography and host:geography interactions are strong predictors of distinctBasidiobolusOTUs present within a given host. Co-occurrence analyses ofBasidiobolusand bacterial community diversity supports a correlation and interaction betweenBasidiobolusand bacteria, suggesting thatBasidiobolusmay play a role in structuring the bacterial community. We further the hypothesis that this interaction is advanced by unique specialized metabolism originating from horizontal gene transfer from bacteria toBasidiobolus, and demonstrate thatBasidiobolusis capable of producing a diversity of specialized metabolites including small cyclic peptides.IMPORTANCEThis work significantly advances our understanding of interactions in herptile microbiomes; the role that fungi play as a structural and functional member of herptile gut microbiomes; and the chemical functions that structure host:microbiome phenotypes. We also provide an important observational system of how the gut microbiome represents a unique environment that selects for novel metabolic functions through horizontal gene transfer between fungi and bacteria. Such studies are needed to better understand the complexity of gut microbiomes in nature and will inform conservation strategies for threatened species of herpetofauna.
Sex-dependent, lateralized engagement of anterior insular cortex inputs to the dorsolateral striatum in binge alcohol drinking
Authors: Haggerty David L. , Atwood Brady K. 
Published: August 2023

AbstractHow does alcohol consumption alter synaptic transmission across time, and do these alcohol-induced neuroadaptations occur similarly in both male and female mice? Previous work shows that anterior insular cortex (AIC) projections to the dorsolateral striatum (DLS) are uniquely sensitive to alcohol-induced neuroadaptations in male, but not female mice, and play a role in governing binge alcohol consumption in male mice. Here, by using high-resolution behavior data paired within-vivofiber photometry, we show how similar levels of alcohol intake are achieved via different behavioral strategies across sex, and how inter-drinking session thirst states predict future alcohol intakes in females, but not males. Further, we show how presynaptic calcium activity recorded from AIC synaptic inputs in the DLS across 3 weeks of water consumption followed by 3 weeks of binge alcohol consumption change across, fluid, time, sex, and brain circuit lateralization. By time-locking presynaptic calcium activity from AIC inputs to the DLS to peri-initiation of drinking events we also show that AIC inputs into the left DLS robustly encode binge alcohol intake behaviors relative to water consumption and AIC inputs into the right DLS in males, but not females. These findings suggest a fluid-, sex- and lateralization-dependent role for the engagement of AIC inputs into the DLS that encode binge alcohol consumption behaviors and further contextualize alcohol-induced neuroadaptations at AIC inputs to the DLS.
The HSF-DREB-MYB transcriptional regulatory module regulates flavonol biosynthesis and flavonoid B-ring hydroxylation in banana (Musa acuminata)
Authors: Naik Jogindra , Rajput Ruchika , Singh Samar , Stracke Ralf , Pandey Ashutosh 
Published: August 2023

AbstractPlant flavonols act primarily as ultraviolet radiation absorbers, reactive oxygen species scavengers, and phytoalexins, and they contribute to biotic and abiotic stress tolerance in plants. Banana (Musa acuminata), an herbaceous monocot and important fruit crop, accumulates flavonol derivatives in different organs, including the edible fruit pulp. Although flavonol content varies greatly in different organs, the molecular mechanisms involving transcriptional regulation of flavonol synthesis in banana are not known. Here, we characterized three SG7-R2R3 MYB transcription factors (MaMYBFA1, MaMYBFA2, and MaMYBFA3) and their upstream regulators, heat shock transcription factor (MaHSF11) and dehydration responsive element binding factor (MaDREB1), to elucidate the molecular mechanism involved in transcriptional regulation of flavonol biosynthesis in banana. MaMYBFA positively regulateflavonol synthase2 (MaFLS2)and downregulatesMaFLS1. We show these transcription factors to be weak regulators of flavonol synthesis. Overexpression ofMaHSF11enhances flavonol contents, particularly that of myricetin, and promotes flavonol B-ring hydroxylation, which contributes to the diversity of flavonol derivatives. MaHSF11 directly interacts with theMaFLS1andflavonoid 3′, 5′-hydroxylase1 (MaF3′5′H1)promoters, bothin vitroandin vivo. MaHSF11 activates the expression ofMaDREB1directly, which in turn regulates the expression ofMaMYBFA3. Overall, our study elucidates a novel regulatory mechanism for flavonol synthesis in banana and suggests possible targets for genetic optimization to enhance nutritional value and stress responses in this globally important fruit crop.Significance statementOur study reveals that the three stress-responsive SG7 MYB factors, MaMYBFA1-3, are modest regulators of flavonol biosynthesis in banana. In contrast, the drought– and heat-responsive MaHSF11 plays a strong, positive role in this pathway, enhancing flavonol biosynthesis and flavonoid B-ring hydroxylation by upregulating key biosynthetic genes, such asMaFLS1andMaF3’5’H1, as well asMaDREB1, another regulator of flavonol biosynthesis in banana.
Ligand-induced segregation from large cell-surface phosphatases is a critical step in γδ TCR triggering
Authors: Li Fenglei , Roy Sobhan , Niculcea Jacob , Gould Keith , Adams Erin J. , van der Merwe P. Anton , Choudhuri Kaushik 
Published: August 2023

AbstractGamma/delta (γδ) T cells are unconventional adaptive lymphocytes that recognize structurally diverse ligandsviasomatically-recombined antigen receptors (γδ TCRs). The molecular mechanism by which ligand recognition initiates γδ TCR signaling, a process known as TCR triggering, remains elusive. Unlike αβ TCRs, γδ TCRs are not mechanosensitive, and do not require coreceptors or typical binding-induced conformational changes for triggering. Here, we show that γδ TCR triggering by nonclassical MHC class Ib antigens, a major class of ligands recognized by γδ T cells, requires steric segregation of the large cell-surface phosphatases CD45 and CD148 from engaged TCRs at synaptic close contact zones. Increasing access of these inhibitory phosphatases to sites of TCR engagement, by elongating MHC class Ib ligands or truncating CD45/148 ectodomains, abrogates TCR triggering and T cell activation. Our results identify a critical step in γδ TCR triggering and provide insight into the core triggering mechanism of endogenous and synthetic tyrosine-phosphorylated immunoreceptors.
PSPire: a machine learning predictor for high-performance screening of phase-separating proteins without intrinsically disordered regions
Authors: Hou Shuang , Hu Jiaojiao , Yu Zhaowei , Liu Cong , Zhang Yong 
Published: August 2023

AbstractThe burgeoning comprehension of protein phase separation (PS) has ushered in a wealth of bioinformatics tools for the prediction of phase-separating proteins (PSPs). These tools often skew towards PSPs with a high content of intrinsically disordered regions (IDRs), thus frequently undervaluing potential PSPs without IDRs. Nonetheless, PS is not only steered by IDRs but also by the structured modular domains and interactions that aren’t necessarily reflected in amino acid sequences. In this work, we introduce PSPire, a unique machine learning predictor designed to incorporate both residue-level and structure-level features for the precise prediction of PSPs. Compared to current PSP predictors, PSPire shows a notable improvement in identifying PSPs without IDRs, which underscores the crucial role of non-IDR, structure-based characteristics in multivalent interactions throughout the PS process. Additionally, our biological validation experiments substantiate the predictive capacity of PSPire, with 6 out of the 8 chosen candidate PSPs confirmed to form condensates within cells. This highlights the considerable potential of structure-based models in the accurate prediction and comprehensive understanding of protein PS.
Protection of β2GPI Deficient Mice from Thrombosis Reflects a Defect in PAR3-facilitated Platelet Activation
Authors: Kulkarni Paresh P , Alluri Ravi Kumar , Godwin Matthew , Forbes Gabriel L , Merkulova Alona , Vijay Aatira , Palihati Maierdan , Kundu Suman , Jun-Shim Young , Schmaier Alvin , Holinstat Michael , Cameron Scott J. , McCrae Keith R 
Published: August 2023

AbstractBackgroundAntibodies to β2-glycoprotein I (β2GPI) cause thrombosis in antiphospholipid syndrome, however the role of β2GPI itself in regulation of coagulation pathwaysin vivois not well understood.MethodsWe developed β2GPI-deficient mice(Apoh-/-)by deleting exon 2 and 3 ofApohusing CRISPR/Cas9 and compared the propensity of wild-type (WT) andApoh-/-mice to develop thrombosis using rose bengal and FeCl3-induced carotid thrombosis, laser-induced cremaster arteriolar injury, and inferior vena cava (IVC) stasis models. We also compared tail bleeding times and assessed platelet activation in WT andApoh-/-mice in the absence and presence of exogenous β2GPI.ResultsCompared to WT littermates,Apoh-/-mice demonstrated a prolonged time to occlusion of the carotid artery after exposure to rose bengal or FeCl3, and reduced platelet and fibrin accumulation in cremasteric arterioles after laser injury. Similarly, significantly smaller thrombi were retrieved from the IVC ofApoh-/-mice 48 hours after IVC occlusion. The activated partial thromboplastin time (aPTT) and prothrombin time, as well as aPTT reagent- and tissue factor-induced thrombin generation times using plasma fromApoh-/-and WT mice revealed no differences. However, we observed significant prolongation of tail bleeding inApoh-/-mice, and reduced P-selectin expression and binding of fibrinogen to the activated α2bβ3 integrin on platelets from these mice after stimulation with low thrombin concentrations; these changes were reversed by exogenous β2GPI. An antibody to PAR3 blocked thrombin-induced activation of WT, but notApoh-/-platelets, as well as the ability of β2GPI to restore the activation response ofApoh-/-platelets to thrombin. β2GPI deficiency did not affect platelet activation by a PAR4-activator peptide, or ADP.ConclusionsIn mice, β2GPI may mediate procoagulant activity by enhancing the ability of PAR3 to present thrombin to PAR4, promoting platelet activation at low thrombin concentrations.Key Pointsβ2GPI deficient mice are protected from experimental arterial, venous, and microvascular thrombosis.β2GPI deficient mice display prolonged tail bleeding times and reduced PAR3-facilitated platelet activation by low concentrations of thrombin.