bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis
Authors: Myserlis Evangelos Pavlos , Georgakis Marios K. , Parodi Livia , Mayerhofer Ernst , Rosand Jonathan , Banerjee Chirantan , Anderson Christopher D. 
Published: August 2024

AbstractObjectiveTo explore causal associations between BMI-independent body fat distribution profiles and cerebrovascular disease risk, and to investigate potential mediators underlying these associations.MethodsLeveraging data from genome wide association studies of BMI-independent gluteofemoral (GFAT), abdominal subcutaneous (ASAT), and visceral (VAT) adipose tissue volumes in UK Biobank, we selected variants associated with each trait, and performed univariable and multivariable mendelian randomization (MR) analyses on ischemic stroke and subtypes (large artery (LAS), cardioembolic (CES), small vessel (SVS)). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and an MRI-confirmed lacunar stroke as positive controls. For significant associations, we explored the mediatory role of four possible mediator categories in mediation MR analyses.ResultsHigher genetically proxied, BMI-independent GFAT volume was associated with decreased risk of ischemic stroke (FDR-p=0.0084), LAS (FDR-p=0.019), SVS (FDR-p<0.001), CAD (FDR-p<0.001), MRI-confirmed lacunar stroke (FDR-p=0.0053), and lower mean cIMT (FDR-p=0.0023), but not CES (FDR-p=0.749). Associations were largely consistent in pleiotropy- and sample structure-robust analyses. No association was observed between genetically proxied ASAT or VAT volumes and ischemic stroke/subtypes risk. In multivariable MR analyses, GFAT showed the most consistent independent association with ischemic stroke, LAS, and SVS. Common vascular risk factors were the predominant mediators in the GFAT-cerebrovascular disease axis, while adipose-tissue-specific adiponectin and leptin mediated a proportion of ischemic stroke and CAD risk.InterpretationGenetically proxied, BMI-independent higher GFAT volume is associated with reduced cerebrovascular disease risk. Although this is largely mediated by common vascular risk factor modification, targeting adipose-tissue specific pathways may provide additional cardiovascular benefit.
Leveraging Large Language Models in Gynecologic Oncology: A Systematic Review of Current Applications and Challenges
Authors: Mudrik Aya , Tsur Abraham , Nadkarni Girish N , Efros Orly , Glicksberg Benjamin S , Soffer Shelly , Klang Eyal 
Published: August 2024

ABSTRACTRationale and ObjectivesOver the past year, studies have been conducted to evaluate the performance of Large Language Models (LLMs), such as ChatGPT, in the fields of gynecologic oncology. This review aims to analyze the applications and risks associated with using LLMs in this specialized field.Materials and MethodsThis systematic review was performed in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, incorporating elements from the diagnostic test accuracy extension and the CHARMS checklist for reviews of prediction models. A systematic literature search was executed on July 17, 2024, across PubMed, Web of Science, and Scopus databases. We focused on identifying original research that integrates LLMs with gynecologic oncology. We assessed the risk of bias using the adapted QUADAS-2 criteria.ResultsOur search identified eight studies that met our criteria, focusing on healthcare education, clinical practice, and medical code generation. These studies revealed variability in ChatGPT’s performance across different applications. It excelled in genetic testing and counseling, achieving 97% accuracy rate. However, its performance in cervical cancer prevention was less robust, with an accuracy of 83%. While one study demonstrated ChatGPT’s high adherence to quality guidelines, another noted that established guidelines significantly outperformed ChatGPT’s outputs. Additionally, code generation using tools like Google Bard and RoBERTa have shown potential to improve accuracy in clinical predictions and quality assurance. For example, Natural Language Processing (NLP) assisted by RoBERTa (based on Google’s BERT model) has improved the prediction of residual disease in women with advanced epithelial ovarian cancer following cytoreductive surgery. Despite these advancements, challenges related to consistency, specificity, and personalization persist, underscoring the necessity for continuous enhancement of these technologies.ConclusionLLMs demonstrate inconsistent performance in gynecologic oncology. These findings emphasize the need for continuous evaluation of these models before they are implemented clinically.
Checklist to Support the Development and Implementation of AI in Clinical Settings
Authors: Owoyemi Ayomide , Osuchukwu Joanne , Salwei Megan , Boyd Andy 
Published: August 2024

AbstractThe integration of Artificial Intelligence (AI) in healthcare settings demands a nuanced approach that considers both technical performance and sociotechnical factors. Recognizing this, our study introduces the Clinical AI Sociotechnical Framework (CASoF), developed through literature synthesis, and refined via a Modified Delphi study involving global healthcare professionals. Our research identifies a critical gap in existing frameworks, which largely focus on either technical specifications or trial outcomes, neglecting the comprehensive sociotechnical dynamics essential for successful AI deployment in clinical environments. CASoF addresses this gap by providing a structured checklist that guides the planning, design, development, and implementation stages of AI systems in healthcare. The checklist emphasizes the importance of considering the value proposition, data integrity, human-AI interaction, technical architecture, organizational culture, and ongoing support and monitoring, ensuring that AI tools are not only technologically sound but also practically viable and socially adaptable within clinical settings. Our findings suggest that the successful integration of AI in healthcare depends on a balanced focus on both technological advancements and the socio-technical environment of clinical settings. CASoF represents a step forward in bridging this divide, offering a holistic approach to AI deployment that is mindful of the complexities of healthcare systems. The checklist aims to facilitate the development of AI tools that are effective, userfriendly, and seamlessly integrated into clinical workflows, ultimately enhancing patient care and healthcare outcomes.
A cell fractionation and quantitative proteomics pipeline to enable functional analyses of cotton fiber development
Authors: Lee Youngwoo , Rani Heena , Mallery Eileen L. , Szymanski Daniel B 
Published: August 2024

AbstractCotton fibers are aerial trichoblasts that employ a highly polarized diffuse growth mechanism to emerge from the developing ovule epidermis. After executing a complicated morphogenetic program, the cells reach lengths over 2 cm and serve as the foundation of a multi-billion-dollar textile industry. Important traits such as fiber diameter, length, and strength are defined by the growth patterns and cell wall properties of individual cells. At present, the ability to engineer fiber traits is limited by our lack of understanding regarding the primary controls governing the rate, duration, and patterns of cell growth. To gain insights into the compartmentalized functions of proteins in cotton fiber cells, we developed a label-free liquid chromatography mass spectrometry method for systems level analyses of fiber proteome. Purified fibers from a single locule were used to fractionate the fiber proteome into apoplast (APOT), membrane-associated (p200), and crude cytosolic (s200) fractions. Subsequently, proteins were identified, and their localizations and potential functions were analyzed using combinations of size exclusion chromatography, statistical and bioinformatic analyses. This method had good coverage of the p200 and apoplast fractions, the latter of which was dominated by proteins associated with particulate membrane-enclosed compartments. The apoplastic proteome was diverse, the proteins were not degraded, and some displayed distinct multimerization states compared to their cytosolic pool. This quantitative proteomic pipeline can be used to improve coverage and functional analyses of the cotton fiber proteome as a function of developmental time or differing genotypes.
Enhancement of response learning in male rats with intrastriatal infusions of a BDNF - TrkB agonist, 7,8-dihydroxyflavone
Authors: Gardner Robert S. , Ambalavanar Matthew T. , Gold Paul E. , Korol Donna L. 
Published: August 2024

AbstractEnhancement of learning and memory by cognitive and physical exercise may be mediated by brain-derived neurotrophic factor (BDNF) acting at tropomyosin receptor kinase B (TrkB). Upregulation of BDNF and systemic administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), enhance learning of several hippocampus-sensitive tasks in rodents. Although BDNF and 7,8-DHF enhance functions of other brain areas too, these effects have mainly targeted non-cognitive functions. One goal of the present study was to determine whether 7,8-DHF would act beyond the hippocampus to enhance cognitive functions sensitive to manipulations of the striatum. Here, we examined the effects of intrastriatal infusions of 7,8-DHF on learning a striatum-sensitive response maze and on phosphorylation of TrkB receptors in 3-month-old male Sprague Dawley rats. Most prior studies of BDNF and 7,8-DHF effects on learning and memory have administered the drugs for days to months before assessing effects on cognition. A second goal of the present study was to determine whether a single drug treatment near the time of training would effectively enhance learning. Moreover, 7,8-DHF is often tested for its ability to reverse impairments in learning and memory rather than to enhance these functions in the absence of impairments. Thus, a third goal of this experiment was to evaluate the efficacy of 7,8-DHF in enhancing learning in unimpaired rats. In untrained rats, intrastriatal infusions of 7,8-DHF resulted in phosphorylation of TrkB receptors, suggesting that 7,8-DHF acted as a TrkB agonist and BDNF mimic. The findings that a single, intra-striatal infusion of 7,8-DHF 20 min before training enhanced response learning in rats suggest that, in addition to its trophic effects, BDNF modulates learning and memory through receptor mediated cell signaling events.
Phlorotannin richAscophyllum nodosumseaweed extract inhibits influenza infection
Authors: Mega Daniele F. , Sharma Parul , Kipar Anja , Hetzel Udo , Bramwell Chloe , Merritt Alan , Wright Samuel , Plummer Chris , Urbanowicz Richard A. , Stewart James P. 
Published: August 2024

AbstractSeaweed derived compounds are a renewable resource utilised in the manufacturing and food industry. This study focuses on an Enriched seaweed extract (ESE) isolated fromAscophyllum nodosum.ESE was screened for antiviral activity by plaque reduction assays against influenza A viruses (IAV) H1N1 and H3N2 subtypes. Time of addition assays and FACS analysis were used to help determine the modes of action. The therapeutic potential of ESE was then explored using differentiated human bronchiole epithelial cells at the air liquid interphase and a murine model challenged with IAV. The data indicates ESE primarily interacts directly with virions, preventing virus cell binding. Interestingly, ESE also inhibits early and late stage of the influenza A lifecycle when treatment occurs after cell binding. This inhibitory effect appears to prevent internalisation of virus and release of progeny virus by targeting neuraminidase activity. Intranasal administration of ESE in mice infected with IAV reduced viral load in lung tissue. ESE may be a promising broad acting antiviral agent in the treatment of influenza infections.
Brain-Engrafted Monocyte-derived Macrophages from Blood and Skull-Bone Marrow Exhibit Distinct Identities from Microglia
Authors: Du Siling , Drieu Antoine , Cheng Yumeng , Storck Steffen E. , Rustenhoven Justin , Mamuladze Tornike , Bhattarai Bishan , Brioschi Simone , Nguyen Khai , Ou Feiya , Cao Jay , Rodrigues Patrick F. , Smirnov Igor , DeNardo David , Ginhoux Florent , Cella Marina , Colonna Marco , Kipnis Jonathan 
Published: August 2024

SUMMARYMicroglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and to persist throughout life without much contribution from definitive hematopoiesis. Here, using lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and characteristics of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation, and defined the core transcriptional signatures of brain-engrafted MDMs. Lineage tracing mouse models revealed that MDMs transiently express CD206 during brain engraftment as CD206+microglia precursors in the YS. We found that brain-engrafted MDMs exhibit transcriptional and epigenetic characteristics akin to meningeal macrophages, likely due to environmental imprinting within the meningeal space. Utilizing parabiosis and skull transplantation, we demonstrated that monocytes from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains. Our results reveal the heterogeneous origins and cellular dynamics of brain parenchymal macrophages at baseline and in models of microglia depletion.
The Neuroactive Potential of the Elderly Human Gut Microbiome is Associated with Mental Health Status
Authors: Calderón-Romero Paulina , Valderrama Benjamin , Bastiaanssen Thomaz , Lillo Patricia , Thumala Daniela , Clarke Gerard , Cryan John F , Slachevsky Andrea , González-Billault Christian , Court Felipe A. 
Published: August 2024

AbstractAgeing is usually associated with physiological decline, increased mental health issues, and cognitive deterioration, alongside specific changes in the gut microbiome. However, the relationship between the neuroactive potential of the gut microbiome and mental health and cognition among the elderly remains less explored. This study examines a cohort of 153 older Chilean adults with cognitive complaints, assessing anthropometric data, mental health via five distinct tests, and gut microbiome composition through 16SV4 sequencing. Our findings reveal associations between anthropometric factors and depression scores in mental tests of participants with their gut microbiome composition. Notably, depression was associated with changes in the abundance ofLachnospiraceae Eubacterium xylanophilum groupandFusobacteriaceae Fusobacterium. Additionally, bacterial pathways involved in metabolising neuroactive compounds such as tryptophan, short-chain fatty acids, p-cresol, glutamate, and nitric oxide were associated with participant age, sex, and cognitive performance. Moreover, participants’ sex was associated with the neuroactive potential of specific bacteria, suggesting a role of the gut microbiome in sex-related mental health differences in the elderly. Together, to the best of our knowledge, this study demonstrates for the first time the association between the neuroactive potential of the human gut microbiome and mental health status in older individuals with cognitive complaints.
The spatial spread and the persistence of gene drives are affected by demographic feedbacks, density dependence and Allee effects
Authors: Kläy Léna , Girardin Léo , Calvez Vincent , Débarre Florence 
Published: August 2024

AbstractHoming gene drive alleles bias their own transmission by converting wild-type alleles into drive alleles. If introduced in a natural population, they might fix within a relatively small number of generations, even if they are deleterious. No engineered homing gene drive organisms have been released in the wild so far, and modelling is essential to develop a clear understanding of the potential outcomes of such releases. We use deterministic models to investigate how different demographic features affect the spatial spread of a gene drive. Building on previous work, we first consider the effect of the intrinsic population growth rate on drive spread. We confirm that including demographic dynamics can change outcomes compared to a model ignoring changes in population sizes, because changes in population density can oppose the spatial spread of a drive. Secondly, we study the consequences of including an Allee effect, and find that it makes a population more prone to eradication following drive spread. Finally, we investigate the effects of the fitness component on which density dependence operates (fecundity or survival), and find that it affects the speed of drive invasion in space, and can accentuate the consequences of an Allee effect. These results confirm the importance of checking the robustness of model outcomes to changes in the underlying assumptions, especially if models are to be used for gene drive risk assessment.
A PthXo2B ortholog inXanthomonas oryzaepv oryzae strain IX-221 acts as a major virulence factor onindicarice without activating a Clade IIISWEETgene
Authors: Mishra Prashant , S Shakespear , Carpenter Sara C D , S Hamsa , S Vigi , N Anith K , Dash Prasanta K , Bogdanove Adam J , Rai Rhitu 
Published: August 2024

AbstractTo infect rice,Xanthomonas oryzaepv. oryzae (Xoo) deploys transcriptionactivator-likeeffectors (TALEs) that specifically bind and upregulate host “susceptibility” (S) genes. 34-amino acid (aa) repeats in TALEs interact one-to-one with DNA bases. Variation at positions 12 and 13 in each repeat, the repeat-variable diresidue (RVD), determine specificity. Some repeat variants shorter or longer than 34 aa can disengage to accommodate a single base deletion in the target sequence.OsSWEET11,13, and14are key S genes, targeted by different TALEs from diverseXoostrains.xa13is aSWEET11allele lacking the TALE binding site and thus conferring resistance.xa13is overcome by TALEs that activateSWEET13orSWEET14. We report here that anxa13-compatibleXoostrain, IX-221, from India, harbours an ortholog of theSWEET14-targeting TALE PthXo3 and two orthologs of theSWEET13-cognate PthXo2, each with one or two 36-aa repeats capable of disengaging. One of the PthXo2 orthologs, PthXo2BIX-221, has a repeat region identical to the previously characterized PthXo2BPXO61, except for a two amino acid difference near the end of the 19threpeat. Like PthXo2BPXO61, PthXo2BIX-221upregulatesSWEET13in japonica rice and noSWEETinindicarice, but unlike PthXo2BPXO61it nonetheless rendersindicarice susceptible, pointing to an alternativeSgene. Further, a designer TALE (dTALE) constructed using a standard, consensus sequence for each repeat and RVDs identical to those of PthXo2BIX-221failed to renderindicarice susceptible. Alignment of the PthXo2BIX-221repeats shows a departure from the consensus in each of two repeats carrying the RVD ‘NN’: the sequence ‘MAIAN’ in place of ‘VAIAS’ beginning at position 7. Together, the PthXo2BIX-221results thus suggest that non-RVD sequence variation affects TALE targeting profiles. More broadly, the presence of the three aberrant repeat-harbouring TALEs in IX-221 suggests that widespread deployment ofxa13in India resulted in strains super-equipped to overcome it, capable of activating multipleSWEETgenes and alleles as well as an apparent alternate S gene.
The “DDVF” motif used by viral and bacterial proteins to hijack RSK kinases evolved as a mimic of a short linear motif (SLiM) found in proteins related to the RAS-ERK MAP kinase pathway
Authors: Veinstein Martin , Stroobant Vincent , Michiels Thomas , Sorgeloos Frédéric 
Published: August 2024

AbstractProteins of pathogens such as cardioviruses, kaposi sarcoma-associated herpes virus, varicella zoster virus and bacteria of the genusYersiniawere previously shown to use a common “DDVF” (D/E-D/E-V-F) short linear motif (SLiM) to hijack cellular kinases of the RSK (p90 ribosomal S6 kinases) family. Remarkable conservation of the SLiM docking site in RSKs suggested a physiological role for this site. Using SLiM prediction tools and AlphaFold docking, we screened the human proteome for proteins that would interact with RSKs through a DDVF-like SLiM. Using co-immunoprecipitation experiments, we show that two candidates previously known as RSK partners, FGFR1 and SPRED2, as well as two candidates identified as novel RSK partners, GAB3 and CNKSR2 do interact with RSKs through a similar interface as the one used by pathogens, as was recently documented for SPRED2. Moreover, we show that FGFR1 employs a DSVF motif to bind RSKs and that phosphorylation of the serine in this motif increases RSK binding. FGFR1, SPRED2, GAB3 and CNKSR2 as well as other candidate RSK binders act upstream of RSK in the RAS-ERK MAP kinase pathway. Analysis of ERK activation in cells expressing a mutated form of RSK lacking the DDVF-docking site suggests that RSK might interact with the DDVF-like SLiM of several partners to provide a negative feed-back to the ERK MAPK pathway. Thus, through SLiM mimicry, pathogens not only retarget RSKs toward unconventional substrates but also likely compete with human proteins to alter the regulation of the RAS-ERK MAP kinase pathway.Author SummaryShort linear motif (SLiM) are 3 to 10 amino acid-long protein sequences that can mediate the interaction with other proteins. We previously observed that highly unrelated pathogens, including viruses and bacteria, convergently evolved to hijack cellular enzymes of their host, through a common SLiM. In this work, we tested the hypothesis that the SLiM found in proteins of pathogens evolved to mimic a SLiM found in human proteins that regulate the cellular enzymes through the same interface. Protein-protein interactions mediated by SLiMs are often, low-affinity, transient interactions that are difficult to detect by conventional biochemical methods but that can nowadays be predicted with increasing confidence by artificial intelligence-based methods such as AlphaFold. Using such predictions, we identified several candidate human proteins and we confirmed experimentally that these proteins interact with the cellular enzymes the same way as pathogens’ proteins do. Identified proteins belong to the well-known RAS-ERK MAPK pathway which regulates important functions of the cell, suggesting that pathogens evolved to hijack this MAPK pathway by SLiM mimicry. By doing so, they can both dysregulate cellular physiology and hijack cellular enzymes to their own benefit.