bluuebunny/crossref_metadata_2025_split huggingface dataset:
The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling
Authors: Madan Babita , Wadia Shawn , Patnaik Siddhi , Harmston Nathan , Tan Emile , Huat Tan Iain Bee , Nes W. David , Petretto Enrico , Virshup David M. 
Published: December 2023

ABSTRACTWnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here we report for the first time that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulates the abundance of specific C4-methyl sterols lophenol and dihydro-TMAS. Highlighting its clinical relevance, FAXDC2 is repressed in Wnt/β-catenin high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulates in the cancerous tissues and not in adjacent normal tissues. FAXDC2 links Wnts to RTK/MAPK signaling. Wnt inhibition drives increased recycling of RTKs and activation of the MAPK pathway, and this requires FAXDC2. Blocking Wnt signaling in Wnt-high cancers causes both differentiation and senescence; and this is prevented by knockout of FAXDC2. Our data shows the integration of three ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.Abstract Figure
A compendium of Amplification-Related Gain Of Sensitivity (ARGOS) genes in human cancer
Authors: Rendo Veronica , Schubert Michael , Khuu Nicholas , Suarez Peredo Rodriguez Maria F , Huang Kaimeng , Swift Michelle , He Yizhou , Zerbib Johanna , Smith Ross , Raaijmakers Jonne , Bandopadhayay Pratiti , Guenther Lillian M. , Hwang Justin H. , Iniguez Amanda , Moody Susan , Seo Ji-Heui , Stover Elizabeth , Garraway Levi , Hahn William C. , Stegmaier Kimberly , Medema René H. , Chowdhury Dipanjan , Colomé-Tatché Maria , Ben-David Uri , Beroukhim Rameen , Foijer Floris 
Published: December 2023

AbstractChromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While the effect of sustained oncogene expression has been characterized, the impact of copy-number gains affecting collaterally-amplified “bystander” genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map of dosage compensations across human cancers by integrating expression and copy number profiles from over 8,000 TCGA tumors and CCLE cell lines. Further, we analyzed the effect of gene overexpression across 17 human cancer ORF screens to provide an overview of genes that prove toxic to cancer cells when overexpressed. Combining these two independent approaches we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes. These genes are located in commonly amplified regions of the genome, have lower expression levels than expected by their copy-number status, and are toxic to cancer cells when overexpressed. We experimentally validatedCDKN1AandRBM14as high-confidence pan-cancer ARGOS genes in lung and breast cancer cell line models. We additionally suggest that RBM14’s mechanism of toxicity involves altered DNA damage response and innate immune signaling processes following gene overexpression. Finally, we provide a comprehensive catalog of compensated, toxic, and ARGOS genes as a community resource.
Developing and optimizing machine learning algorithms for predicting in-hospital patient charges for Congestive Heart Failure Exacerbations, Chronic Obstructive Pulmonary Disease Exacerbations and Diabetic Ketoacidosis
Authors: Arnold Monique , Liou Lathan , Boland Mary Regina 
Published: December 2023

AbstractBackgroundHospitalizations for exacerbations of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and diabetic ketoacidosis (DKA) are costly in the United States.ObjectiveThe purpose of this study is to predict in-hospital charges for each condition using Machine Learning (ML) models.MethodsWe conducted a retrospective cohort study on national discharge records of hospitalized adult patients from January 1st, 2016, to December 31st, 2019. We used numerous ML techniques to predict in-hospital total cost.ResultsWe found that linear regression (LM), gradient boosting (GBM) and extreme gradient boosting (XGB) models had good predictive performance and were statistically equivalent, with training R-Squared values ranging from 0.49–0.95 for CHF; 0.56–0.95 for COPD; and 0.32–0.99 for DKA. We identified important key features driving costs, including patient age, length-of-stay, number of procedures. and elective/non-elective admission.ConclusionsML methods may be used to accurately predict costs and identify drivers of high cost for COPD exacerbations, CHF exacerbations and DKA. Overall, our findings may inform future studies that seek to decrease the underlying high patient costs for these conditions.
A Novel Question-Answering Framework for Automated Abstract Screening Using Large Language Models
Authors: Akinseloyin Opeoluwa , Jiang Xiaorui , Palade Vasile 
Published: December 2023

AbstractObjectiveThis paper aims to address the challenges in abstract screening within Systematic Reviews (SR) by leveraging the zero-shot capabilities of large language models (LLMs).MethodsWe employ LLM to prioritise candidate studies by aligning abstracts with the selection criteria outlined in an SR protocol. Abstract screening was transformed into a novel question-answering (QA) framework, treating each selection criterion as a question addressed by LLM. The framework involves breaking down the selection criteria into multiple questions, properly prompting LLM to answer each question, scoring and re-ranking each answer, and combining the responses to make nuanced inclusion or exclusion decisions.ResultsLarge-scale validation was performed on the benchmark of CLEF eHealth 2019 Task 2: Technology- Assisted Reviews in Empirical Medicine. Focusing on GPT-3.5 as a case study, the proposed QA framework consistently exhibited a clear advantage over traditional information retrieval approaches and bespoke BERT- family models that were fine-tuned for prioritising candidate studies (i.e., from the BERT to PubMedBERT) across 31 datasets of four categories of SRs, underscoring their high potential in facilitating abstract screening.ConclusionInvestigation justified the indispensable value of leveraging selection criteria to improve the performance of automated abstract screening. LLMs demonstrated proficiency in prioritising candidate studies for abstract screening using the proposed QA framework. Significant performance improvements were obtained by re-ranking answers using the semantic alignment between abstracts and selection criteria. This further highlighted the pertinence of utilizing selection criteria to enhance abstract screening.
Association Between Uric Acid and Hemorrhagic Transformation: A Systematic Review and Meta-Analysis
Authors: Qian Ying , Li Na , Li Yuanyuan , Tao Chenxi , Liu Zhenhong , Zhang Guoxia , Yang Fan , Zhang Hongrui , Gao Yonghong 
Published: December 2023

ABSTRACTBackgroundThe relationship between uric acid (UA) and hemorrhagic transformation (HT) remained controversial. The purpose of this study was to investigate the relationship between UA degrees and the risk of HT after acute ischemic stroke (AIS).Methods and methodsElectronic databases were sought for studies on UA and HT from inception to October 31, 2023. Two researchers independently reviewed the studies for inclusion. STATA Software 16.0 was used to compute the standardized mean difference (SMD) and 95% confidence interval (CI) of the pooled and post-outlier outcomes. The heterogeneity was evaluated using the I2statistic and the Galbraith plot, and sensitivity analysis was also performed. Begg’s funnel plot and Egger’s test were used to assess publication bias.Results12 trials were included in the meta-analysis, with a total of 4,708 individuals. Low UA degrees were linked to higher HT post-AIS patients following the pooled SMDs’ forest plot (SMD = -0.34, 95% CI = -0.60–0.08,P= 0.010). The high heterogeneity (I2= 89.0%,P<0.001) was found in the studies. Six papers were outside the Galbraith plot regression line and there was no heterogeneity when they were excluded (I2= 45.8%,P= 0.100). Meanwhile, the repeated SMDs (SMD = -0.487, 95% CI = -0.632–0.342,P= 0.000) still meant that the HT group had lower UA degrees. There was no publication bias in our meta-analysis following Begg’s funnel plot or Egger’s test.ConclusionsThe meta-analysis illustrated a substantial positive connection between UA degrees and HT, with lower UA separately linked with higher HT post-AIS. It provided a certain theoretical basis for the later related research.
Differential detection workflows for multi-sample single-cell RNA-seq data
Authors: Gilis Jeroen , Perin Laura , Malfait Milan , Van den Berge Koen , Assefa Alemu Takele , Verbist Bie , Risso Davide , Clement Lieven 
Published: December 2023

AbstractIn single-cell transcriptomics, differential gene expression (DE) analyses typically focus on testing differences in the average expression of genes between cell types or conditions of interest. Single-cell transcriptomics, however, also has the promise to prioritise genes for which the expression differ in other aspects of the distribution. Here we develop a workflow for assessing differential detection (DD), which tests for differences in the average fraction of samples or cells in which a gene is detected. After benchmarking eight different DD data analysis strategies, we provide a unified workflow for jointly assessing DE and DD. Using simulations and two case studies, we show that DE and DD analysis provide complementary information, both in terms of the individual genes they report and in the functional interpretation of those genes.
Prevalence of orthostatic intolerance in Long Covid clinic patients: A multicentre observational study
Authors: Lee Cassie , Greenwood Darren C , Master Harsha , Balasundaram Kumaran , Williams Paul , Scott Janet T. , Wood Conor , Cooper Rowena , Darbyshire Julie L. , Gonzalez Ana Espinosa , Davies Helen E. , Osborne Thomas , Corrado Joanna , Iftekhar Nafi , Rogers Natalie , Delaney Brendan , Greenhalgh Trish , Sivan Manoj 
Published: December 2023

AbstractPurposeOrthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with symptoms and comorbidities.MethodsParticipants were recruited from 8 UK long covid clinics, and healthy volunteers from general population. All undertook standardised National Aeronautics and Space Administration Lean Test (NLT). Participants’ history of typical OI symptoms (e.g. dizziness, palpitations) prior to and during the NLT were recorded.Results277 long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or PoTS, 10% had asymptomatic OH. 130 (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. 41 (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive to one reading, resulted in 11% of long covid participants meeting criteria for PoTS, but not in healthy volunteers.ConclusionMore than half of long covid patients experienced OI symptoms during NLT and more than one in ten patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.Trial registration numbersNCT05057260, ISRCTN15022307
The Montreal Cognitive Assessment: Normative Data from a Large, Population-Based Sample of Healthy Adults in China
Authors: Wei Qiang , Du Baogen , Liu Yuanyuan , Cao Shanshan , Yin Shanshan , Zhang Ying , Bai Tongjian , Wu Xingqi , Tian Yanghua , Hu Panpan , Wang Kai 
Published: December 2023

AbstractBackgroundThe Montreal Cognitive Assessment (MoCA) is a valuable tool for detecting cognitive impairment, but its accuracy is significantly influenced by demographic and socio-cultural factors. Consequently, the development of appropriate normative values becomes particularly crucial in ensuring its reliable use and interpretation.ObjectiveGenerate MoCA normative values based on demographics for healthy chinese adults.MethodsThe assessment conducted in this study utilizes the MoCA scale, specifically employing the Mandarin-8.1 version (Chinese Mandarin version). Based on the geographical distribution of administrative regions in mainland china, this study recruited a total of 3,097 healthy individuals aged over 20 years. Drawing on insights from prior normative studies, we performed multiple linear regression analysis, incorporating age, gender, and education level as predictor variables, to examine their associations with the total score and sub-cognitive domains of MoCA. Subsequently, we established normative values and cut-off values stratified by age and education level.ResultsThe participants in this study (n=3,097) exhibit a balanced gender distribution, with an average age of 54.46 years (SD 14.38) and an average education period of 9.49 years (SD 4.61). The study population demonstrates an average MoCA score of 23.25 points (SD 4.82). The findings from the multiple linear regression analysis indicate that the total score of MoCA is influenced by age and education level, collectively accounting for 46.8% of the total variance. Higher age and lower education level are correlated with lower MoCA total scores.ConclusionThis study offers normative MoCA values specific to the Chinese population. Furthermore, the research findings indicate that a score of 26 may not represent the most optimal cut-off value. When assessing MoCA scores, it is imperative to comprehensively account for the participants’ age and educational background.
Empowering GWAS Discovery through Enhanced Genotype Imputation
Authors: De Marino Adriano , Mahmoud Abdallah Amr , Bohn Sandra , Lerga-Jaso Jon , Novković Biljana , Manson Charlie , Loguercio Salvatore , Terpolovsky Andrew , Matushyn Mykyta , Torkamani Ali , Yazdi Puya G. 
Published: December 2023

AbstractGenotype imputation, crucial in genomics research, often faces accuracy limitations, notably for rarer variants. Leveraging data from the 1000 Genomes Project, TOPMed and UK Biobank, we demonstrate that Selphi, our novel imputation method, significantly outperforms Beagle5.4, Minimac4 and IMPUTE5 across various metrics (12.5%-26.5% as measured by error count) and allele frequencies (13.0%-27.1% for low-frequency variants).This improvement in accuracy boosts variant discovery in GWAS and improves polygenic risk scores.
HIV risk score and prediction model in the United States: A Scoping Review Protocol
Authors: Patel Maitri , Vaddiparti Krishna , Christina Parisi , Woody Aislin , Cook Robert , Prosperi Mattia , Pyche Courtney , Cook Christa , Liu Yiyang 
Published: December 2023

AbstractHuman immunodeficiency virus (HIV) remains a significant public health concern in the United States, affecting approximately 1.2 million individuals, with a substantial portion unaware of their infection status. Identifying individuals at elevated risk of HIV infection through predictive models holds promise for enhancing public health efforts. A preliminary search from PubMed revealed a handful of studies focused on developing HIV risk prediction models or risk scores, each employing varying methodologies such as logistic regression and machine learning. These studies targeted a diverse population including men who have sex with men, emergency department visitors, and the general population, drawing data from surveys, surveillance, and electronic health records. Despite these individual efforts, there is a notable absence of comprehensive review papers summarizing the outcomes of these studies. Addressing this gap, this scoping review systematically identifies and synthesizes results from existing predictive models for HIV risk. The primary objective is to determine the variables used in HIV risk scoring and prediction models, contributing to a more comprehensive understanding of HIV risk assessment. This protocol describes the thorough procedure for conducting a scoping review. It outlines the inclusion and exclusion criteria for relevant studies and offers the search methods that will be used in PubMed, EMBASE, and CINAHL. Detailed paper screening, data extraction, and risk of bias assessment process were described.
White matter hyperintensity genetic risk factorTRIM47regulates autophagy in brain endothelial cells
Authors: Yeung Sunny Hoi-Sang , Lee Ralph Hon-Sun , Cheng Gerald Wai-Yeung , Ma Iris Wai-Ting , Kofler Julia , Kent Candice , Ma Fulin , Herrup Karl , Fornage Myriam , Arai Ken , Tse Kai-Hei 
Published: December 2023

ABSTRACTWhite matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. GWAS identified TRIM47 at 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found selectively expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially-induced autophagy while downregulated in hypertension-like conditions. Usingin silicosimulation, immunocytochemistry and super-resolution microscopy, we identified the highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencingTrim47significantly increased autophagy with ULK1 phosphorylation induction, transcription and vacuole formation. Together, we confirm that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.SUMMARY STATEMENTTRIM47, top genetic risk factor for white matter hyperintensity formation, is a negative regulator of autophagy in brain endothelial cells and implicates a novel cellular mechanism for age-related cerebrovascular changes.
Neural codes for visual numerosity independent of other quantities are present both in the dorsal and in the ventral stream of the human brain
Authors: Karami Alireza , Castaldi Elisa , Eger Evelyn , Piazza Manuela 
Published: December 2023

AbstractRepresenting the number of items in sets (numerosity) is a core and evolutionary ancient ability. In a recent fMRI study Castaldi et al. (eLife 2019) showed that visual numerosity is represented independently from other visual features starting from early visual areas and progressively amplified along the dorsal stream hierarchy up to parietal areas. However, because in this study we recorded the brain activity from a restricted brain volume, and performed the analyses only in a series of retinotopically organized regions of interest along the dorsal stream, we still miss an exhaustive picture of the full network of regions encoding pure numerosity across the whole brain. In this research advance, we extend the findings of Castaldi et al. in two significant ways. First, we recorded the whole brain which allowed us to characterize the neural responses to numerosity beyond the dorsal stream using a searchlight analysis in addition to an ROIs approach. Second, in addition to the classical model-based analytical approach, such as RSA, we compared the neural representational geometries across the different regions using multi-dimensional scaling, an hypothesis-free approach capable of unveiling latent neural dimensions that might otherwise go unnoticed. Our results confirm that numerosity is represented over and above other visual features in early visual areas and progressively enhanced in associative areas of the dorsal stream but also, notably, of the ventral stream. We also found that numerosity representations in association areas differ substantially from those of early visual areas, and that in associative regions of both streams numerosity is represented on a similar manifold akin to a curved number line, a structure suggestive of their similar involvement in numerosity-based decision making. Taken together, these results call for an important revision of the existing neurocognitive models of number cognition.Impact statementVisual numerosity is represented in associative areas of dorsal and ventral streams on a neural manifold that also reflects decision variables, suggesting a common role in numerosity decision-making.
Regulator of Chromosome Condensation (RCC1) a novel therapeutic target in pancreatic ductal adenocarcinoma drives tumor progression via the c-Myc-RCC1-Ran axis
Authors: Bannoura Sahar F. , Aboukameel Amro , Khan Husain Yar , Uddin Md. Hafiz , Jang Hyejeong , Beal Eliza , Thangasamy Amalraj , Kim Seongho , Wagner Kay Uwe , Mohammad Ramzi , Al-Hallak Mohammed Najeeb , Pasche Boris C. , Azmi Asfar S. 
Published: December 2023

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Here we for the first time evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC subsistence and drug resistance. RCC1 expression was found to be elevated in PDAC tissues in comparison with normal pancreatic tissues and was linked to poor prognosis. RCC1 silencing in a panel of PDAC cells by RNA interference and CRISPR-Cas9 resulted in reduced cellular proliferation in 2D and 3D cultures. RCC1 KD reduced migratory and clonogenic ability, enhanced apoptosis, and altered cell cycle distribution in human PDAC cells as well as cells isolated from the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx1-Cre (KPC) mouse tumors. Subcutaneous cell-derived xenografts show significantly attenuated growth of RCC1 KO tumors. Mechanistically, RCC1 knockdown resulted in disruption of subcellular Ran distribution indicating that stable nuclear Ran localization is critical for PDAC proliferation. Nuclear and cytosolic proteomic analysis revealed altered subcellular proteome in RCC1 KD KPC-tumor-derived cells. Altered cytoplasmic protein pathways include several metabolic pathways and PI3K-Akt signaling pathway. Pathways enriched in altered nuclear proteins include cell cycle, mitosis, and RNA regulation. RNA sequencing of RCC1 KO cells showed widespread transcriptional alterations. Upstream of RCC1, c-Myc activates the RCC1-Ran axis, and RCC1 KO enhances the sensitivity of PDAC cells to c-Myc inhibitors. Finally, RCC1 knockdown resulted in the sensitization of PDAC cells to Gemcitabine. Our results indicate that RCC1 is a potential therapeutic target in PDAC that warrants further clinical investigations.