bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reference-informed prediction of alternative splicing and splicing-altering mutations from sequences
Authors: Xu Chencheng , Bao Suying , Chen Hao , Jiang Tao , Zhang Chaolin 
Published: March 2024

AbstractAlternative splicing plays a crucial role in protein diversity and gene expression regulation in higher eukaryotes and mutations causing dysregulated splicing underlie a range of genetic diseases. Computational prediction of alternative splicing from genomic sequences not only provides insight into gene-regulatory mechanisms but also helps identify disease-causing mutations and drug targets. However, the current methods for the quantitative prediction of splice site usage still have limited accuracy. Here, we present DeltaSplice, a deep neural network model optimized to learn the impact of mutations on quantitative changes in alternative splicing from the comparative analysis of homologous genes. The model architecture enables DeltaSplice to perform “reference-informed prediction” by incorporating the known splice site usage of a reference gene sequence to improve its prediction on splicing-altering mutations. We benchmarked DeltaSplice and several other state-of-the-art methods on various prediction tasks, including evolutionary sequence divergence on lineage-specific splicing and splicing-altering mutations in human populations and neurodevelopmental disorders, and demonstrated that DeltaSplice outperformed consistently. DeltaSplice predicted ∼15% of splicing quantitative trait loci (sQTLs) in the human brain as causal splicing-altering variants. It also predicted splicing-alteringde novomutations outside the splice sites in a subset of patients affected by autism and other neurodevelopmental disorders, including 19 genes with recurrent splicing-altering mutations. Among the new candidate disease risk genes,MFN1is involved in mitochondria fusion, which is frequently disrupted in autism patients. Our work expanded the capacity ofin silicosplicing models with potential applications in genetic diagnosis and the development of splicing-based precision medicine.
Development and evaluation of a kidney health questionnaire and estimates of chronic kidney disease prevalence in the Cooperative Health Research In South Tyrol (CHRIS) study
Authors: Giulia Barbieri , Lucia Cazzoletti , Roberto Melotti , Essi Hantikainen , Rebecca Lundin , Laura Barin , Martin Gögele , Peter Riegler , Manuel Ferraro Pietro , Paul Pramstaller Peter , Giovanni Gambaro , Elisabetta Zanolin Maria , Cristian Pattaro 
Published: March 2024

AbstractIntroductionKidney diseases are a public health burden but, except for chronic kidney disease (CKD), they are poorly investigated in the general population. In light of inadequate survey tools for use in population studies, we developed a novel questionnaire to retrospectively assess the main kidney diseases, integrating it within the Cooperative Health Research In South Tyrol (CHRIS) study conducted between 2011 and 2018 in the Alpine district of Val Venosta/Vinschgau (Italy).MethodsThe questionnaire covers general kidney diseases, reduced kidney function, and renal surgeries. It was applied to the cross-sectional assessment of self-reported kidney health among 11,684 adults, along with measures of fasting estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). By factor analysis we contextualized the questionnaire content with respect to biochemical measurements. CKD was defined according to KDIGO guidelines, self-reported diagnosis, and their combination. Prevalence estimates were calibrated to the general target population via relative sampling weights.ResultsIn this population sample (median age=45 years; median eGFR=98.4 mL/min/1.73 m2; median UACR=5.7 mg/g), 8.3% of participants reported at least one kidney disease. Population-representative prevalence of glomerulonephritis, pyelonephritis, and congenital kidney diseases was 1.0%, 3.0%, and 0.2%, respectively, with corresponding odds ratio for females versus males of 1.4 (95% confidence interval: 1.0, 2.0), 8.7 (6.2, 12.3), and 0.7 (0.3, 1.6), respectively. CKD prevalence was 8.6% when based on KDIGO criteria and 0.7% when self-reported, indicating that 95.3% of affected individuals were unaware of having CKD, with a similar figure of 92.9% in those reporting diabetes or hypertension. Overall, 15.8% of the population was affected by a kidney disease of any kind.ConclusionIn this Alpine population, CKD prevalence aligned with Western European estimates. Kidney health questionnaire implementation in population studies is feasible and valuable to assess CKD awareness, which we found to be dramatically low.
Evaluating soluble Axl as a biomarker for glioblastoma: a pilot study
Authors: Raymond Daniel , Fukui Melanie B. , Zwernik Samuel , Kassam Amin , Rovin Richard A. , Akhtar Parvez 
Published: March 2024

AbstractWith current imaging, discriminating tumor progression from treatment effect following immunotherapy or oncolytic virotherapy of glioblastoma (GBM) is challenging. A blood based diagnostic biomarker would therefore be helpful. Axl is a receptor tyrosine kinase that is highly expressed by many cancers including GBM. Axl expression is regulated through enzymatic cleavage of its extracellular domain. The resulting fragment can be detected in serum as soluble Axl (sAxl). sAxl levels can distinguish patients with melanoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma from healthy controls. This is a pilot study to determine if sAxl is a candidate biomarker for GBM. The sAxl levels in the serum of 40 healthy volunteers and 20 GBM patients were determined using an enzyme-linked immunosorbent assay (ELISA). Pre- and post-operative sAxl levels were obtained. Volumetric MRI evaluation provided GBM tumor volume metrics. There was no significant difference in the sAxl levels of the volunteers (30.16±1.88 ng/ml) and GBM patients (30.74±1.96 ng/ml) p=0.27. The postoperative sAxl levels were significantly higher than preoperative levels (32.32±2.26 ng/ml vs 30.74±1.96 ng/ml, p=0.03). We found no correlation between tumor volume and sAxl levels. Axl expression was low or absent in 6 of 11 (55%) patient derived GBM cell lines. Given the wide range of Axl expression by GBM tumors, sAxl may not be a reliable indicator of GBM. However, given the small sample size in this study, a larger study may be considered.
Machine Learning Prediction of Autism Spectrum Disorder Through Linking Mothers’ and Children’s Electronic Health Record Data
Authors: Li Yongqiu , Huang Yu , Yang Shuang , Shychuk Elahe M. , Shenkman Elizabeth A. , Bian Jiang , Angell Amber M. , Guo Yi 
Published: March 2024

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children. Early detection of ASD, particularly in girls who are often diagnosed late, can aid long-term development for children. We aimed to develop machine learning models for predicting ASD diagnosis in children, both boys and girls, using child-mother linked electronic health records (EHRs) data from a large clinical research network. Model features were children and mothers’ risk factors in EHRs, including maternal health factors. We tested XGBoost and logistic regression with Random Oversampling (ROS) and Random Undersampling (RUS) to address imbalanced data. Logistic regression with RUS considering a three-year observation window for children’s risk factors achieved the best performance for predicting ASD among the overall study population (AUROC = 0.798), boys (AUROC = 0.786), and girls (AUROC = 0.791). We calculated SHAP values to quantify the impacts of important clinical and sociodemographic risk factors.
Changes in quantity and timing of foliar and reproductive phenology of tropical dry-forest trees under a warming and drying climate
Authors: Lai Hao Ran , Hill Timothy , Stivanello Silvio , Chapman Hazel M 
Published: March 2024

AbstractPlant phenology drives population dynamics and forest productivity; it is also impacted by shifting environmental cues under climate change such as more prevalent drought. It is imperative to better understand how species and community phenology respond to climate change in leaf turnover and reproduction, both of which are required to integrate phenology into full life-cycle assessments.However, relatively few studies to-date examined the quantity and timing of phenology simultaneously. We demonstrate that the simultaneous assessment of phenological quantity and timing across multiple organs reveals more nuanced and holistic insights into the consequences of climate change.Extending a regression approach based on Fourier series, we decomposed the long-term (2004–2020) monthly leaf shedding, leaf flush, flowering and fruiting of 617 trees across 94 taxa at a Nigerian seasonally dry tropical forest into three periodic components—mean intensity, amplitude and phase—which respectively represents the total quantity, pulse concentration and peak timing of phenology. We then related each periodic component to warming minimum temperature and drying wet-season rainfall.We found that climate explained more variation in phenological amplitudes (14–66%) compared to mean intensity and timing (6–49%). In drier years, more species (18%) shed leaves earlier (changing timing) or in more concentrated pulses (changing amplitude), while only a few (2%) shed leaves in greater total amounts (changing mean intensity). This combined with the decreased mean intensity of leaf flush imply a lower primary productivity as trees deployed fewer leaves for a shorter period. Some species (30%) produced fewer fruits despite no change or even increase in flowering; in a few species this could be explained by a shortened flowering period that limited pollination. At the community level, reproduction became more synchronous, potentially creating periods of scarcity for consumers.Synthesis:Our findings highlight several contrasting yet complementary phenology– climate insights, indicating that assessments of forests’ climate resilience necessitate multiple aspects of phenology rather than a single performance indicator. The decline of leaf and fruit productions, as well as the temporal mismatches in leaf turnover and reproduction, will have cascading impacts on trophic interactions and nutrient cycling.
Dietary regulation of silent synapses in the dorsolateral striatum
Authors: Meyers Allison M. , Gnazzo Federico G. , Barrera Eddy D. , Nabatian Tikva , Chan Larry , Beeler Jeff A. 
Published: March 2024

ABSTRACTObesity and drugs of abuse share overlapping neural circuits and behaviors. Silent synapses are transient synapses that are important for remodeling brain circuits. They are prevalent during early development but largely disappear by adulthood. Drugs of abuse increase silent synapses during adulthood and may facilitate reorganizing brain circuits around drug-related experience, facilitating addiction and contributing to relapse during treatment and abstinence. Whether obesity causes alterations in the expression of silent synapses in a manner similar to drugs of abuse has not been examined. Using a dietary-induced obesity paradigm, mice that chronically consumed high fat diet (HFD) exhibited increased silent synapses in both direct and indirect pathway medium spiny neurons in the dorsolateral striatum. Both the time of onset of increased silent synapses and their normalization upon discontinuation of HFD occurs on an extended time scale compared to drugs of abuse. These data demonstrate that chronic consumption of HFD, like drugs of abuse, can alter mechanisms of circuit plasticity likely facilitating neural reorganization analogous to drugs of abuse.
Optimisation of SARS-CoV-2 culture from clinical samples for clinical trial applications
Authors: Wooding Dominic , Buist Kate , Romero-Ramirez Alessandra , Savage Helen , Watkins Rachel , Bengey Daisy , Greenland-Bews Caitlin , Thompson Caitlin R , Kontogianni Nadia , Body Richard , Hayward Gail , Byrne Rachel L , Gould Susan , Group CONDOR Steering , Myerscough Christopher , Atkinson Barry , Shaw Victoria , Greenhalf Bill , Adams Emily , Cubas-Atienzar Ana , Khoo Saye , Fletcher Tom , Edwards Thomas 
Published: March 2024

AbstractClinical trials of SARS-CoV-2 therapeutics often include virological secondary endpoints to compare viral clearance and viral load reduction between treatment and placebo arms. This is typically achieved using RT-qPCR, which cannot differentiate replicant competent virus from non-viable virus or free RNA, limiting its utility as an endpoint. Culture based methods for SARS-CoV-2 exist; however, these are often insensitive and poorly standardised for use as clinical trial endpoints.We report optimisation of a culture-based approach evaluating three cell lines, three detection methods, and key culture parameters. We show that Vero-ACE2-TMPRSS2 (VAT) cells in combination with RT-qPCR of culture supernatants from the first passage provides the greatest overall detection of Delta viral replication (22/32, 68.8%), being able to identify viable virus in 83.3% (20/24) of clinical samples with initial Ct values <30. Likewise, we demonstrate that RT-qPCR using culture supernatants from the first passage of Vero hSLAM cells provides the highest overall detection of Omicron viral replication (9/31, 29%), detecting live virus in 39.1% (9/23) of clinical samples with initial Ct values < 25. This assessment demonstrates that combining RT-qPCR with virological end point analysis has utility in clinical trials of therapeutics for SARS-CoV-2; however, techniques may require optimising based on dominant circulating strain.
Exploring the Diagnostic Potential of miRNA Signatures in the Fabry Disease Serum: A Comparative Study of Automated and Manual Sample Isolations
Authors: Fang Josephine Y. , Ayyadurai Saravanan , Pybus Alyssa F. , Sugimoto Hiroshi , Qian Mark G. 
Published: March 2024

AbstractFabry disease, an X-linked lysosomal storage disorder caused by galactosidase alpha (GLA) gene mutations, exhibits diverse clinical manifestations, and poses significant diagnostic challenges. Early diagnosis and treatment are crucial for improved patient outcomes, pressing the need for reliable biomarkers. In this study, we aimed to identify miRNA candidates as potential biomarkers for Fabry disease using the KingFisher™ automated isolation method and NanoString nCounter® miRNA detection assay.Clinical serum samples were collected from both healthy subjects and Fabry disease patients. RNA extraction from the samples was performed using the KingFisher™ automated isolation method with the MagMAX mirVana™ kit or manually using the Qiagen miRNeasy kit. The subsequent NanoString nCounter® miRNA detection assay showed consistent performance and no correlation between RNA input concentration and raw count, ensuring reliable and reproducible results. Interestingly, the detection range and highly differential miRNA between the control and disease groups were found to be distinct depending on the isolation method employed. Nevertheless, enrichment analysis of miRNA-targeting genes consistently revealed significant associations with angiogenesis pathways in both isolation methods. Additionally, our investigation into the impact of enzyme replacement therapy on miRNA expression indicated that some differential miRNAs may be sensitive to treatment.Our study provides valuable insights to identify miRNA biomarkers for Fabry disease. While different isolation methods yielded various detection ranges and highly differential miRNAs, the consistent association with angiogenesis pathways suggests their significance in disease progression. These findings lay the groundwork for further investigations and validation studies, ultimately leading to the development of non-invasive and reliable biomarkers to aid in early diagnosis and treatment monitoring for Fabry disease.
Values and preferences in COVID-19 public health guidelines: A systematic review
Authors: Kirsh Sarah , Ling Michael , Jassal Tanvir , Pitre Tyler , Pigott Thomas , Zeraatkar Dena 
Published: March 2024

AbstractBackgroundInternationally accepted standards for trustworthy guidelines include the necessity to ground recommendations in values and preferences. Considering values and preferences respects the rights of citizens to participate in health decision-making and ensures that guidelines align with the needs and priorities of the communities they are intended to serve. Early anecdotal reports suggest that COVID-19 public health guidelines did not consider values and preferences.ObjectiveTo capture and characterize whether and how COVID-19 public health guidelines considered values and preferences.MethodsWe performed a systematic review of COVID-19 public health guidelines. We searched the eCOVID19 RecMap platform—a comprehensive international catalog of COVID-19 guidelines—up to July 2023. We included guidelines that made recommendations addressing vaccination, masking, isolation, lockdowns, travel restrictions, contact tracing, infection surveillance, and school closures. Reviewers worked independently and in duplicate to review guidelines for consideration of values and preferences.ResultsOur search yielded 129 eligible guidelines, of which 43 (33.3%) were published by national organizations, 73 (56.6%) by international organizations, and 14 (10.9%) by professional societies and associations. Twenty-six (20.2%) guidelines considered values and preferences. Among guidelines that considered values and preferences, most did so to assess the acceptability of recommendations (23; 88.5%) and by referencing published research (24; 92.3%). Guidelines only occasionally engaged laypersons as part of the guideline development group (6; 23.1%). None of the guidelines performed systematic reviews of the literature addressing values and preferences.ConclusionMost COVID-19 public health guidelines did not consider values and preferences. When values and preferences were considered, it was suboptimal. Disregard for values and preferences in guidelines might have partly contributed to divisive and unpopular COVID-19 policies. Given the possibility of future health emergencies, we recommend guideline developers identify efficient methods for considering values and preferences in crisis situations.
In vivo inhibition of miR-125b modulates monocyte trafficking through the CCR7 receptor and attenuates atherosclerosis
Authors: Mallén Adrian , Varela Cristian , Rotllan Noemí , Paloschi Valentina , Mäegdefessel Lars , Escolà Joan Carles , Aran Josep Maria , Navarro Estanis , Hueso Miguel 
Published: March 2024

ABSTRACTBackgroundAtherosclerosis (ATH) is a chronic systemic inflammatory disease affecting the vessel wall, wherein regulating non-coding RNAs play a crucial role. We previously demonstrated that miR-125b is upregulated in ATH and is a main regulator of cholesterol metabolism in macrophages. Herein we hypothesized that inhibiting miR-125b may attenuate ATH.Methods and resultsIn the ApoE-/-mice model fed with a high fat diet for 14 weeks, we inhibited miR-125b using an antagomiR over a 4-week period. We observed a significant reduction in plaque size, accompanied by diminished infiltration of F4/80 macrophages and attenuation of NF-κB+activation within plaques. We explored the mechanism using a Vas-on-Chip adhesion assay using Human Aortic Endothelial Cells (HAoEC) stimulated with TNFα. We observed an impairment in the trafficking of miR-125b transfected THP-1 monocytes, accompanied by the downregulation of the CD11b/CD18 integrin and the CCR7 receptor. Furthermore, we demonstrated a direct regulation of the CCR7 receptor by miR-125b using a reporter plasmid construct (p_CCR7.WT) containing the 3’UTR region of CCR7 gene fused with a luciferase coding sequence. In addition, miR-125b transfected monocytes inhibited CCR7 cell migration induced by the CCL21 ligand but did not affect migration induced by others ligands such as MCP1. Finally, we confirmed the downregulation of CCR7 in coronary plaques in both ApoE-/-mice and patients with coronary artery disease.ConclusionsInhibiting miR-125b offers a novel therapeutic approach for ameliorating ATH that results in a reduction of macrophage content and plaque lesion size. This improvement occurs through the enhancement of monocyte trafficking via CCR7 that facilitates the exit of foam cells from the plaque.CLINICAL PERSPECTIVEWhat is New?- We found evidences of a new therapeutic approach for atherosclerosis, in which miR-125b inhibition reduces macrophage content and plaque size.- We described the molecular mechanism underlying miR-125b, which involves regulating of monocyte trafficking to plaques and the downregulation of the chemokine receptor CCR7. CCR7 plays a crucial role in facilitating the egress of macrophages and foam cells from plaques, and its downregulation contribute to progression of ATH.- The results have been validated in a cohort of patients with coronary artery disease, where CCR7 expression was reduced in plaques.What are the clinical implications?- We highlight the pivotal role of monocyte trafficking in the inflammatory mechanism of atherosclerosis. Managing miR-125b/CCR7 signaling may improve the resolution of ATH promoting the exit of foam cells from plaque.- Inhibition of miR-125b in plaque macrophages represents a novel and promising therapeutic approach for cardiovascular disease.
Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors
Authors: Williams Kyle B. , Larsson Alex T. , Keller Bryant J. , Chaney Katherine E. , Williams Rory L. , Bhunia Minu M. , Draper Garrett M. , Jubenville Tyler A. , Hudson Wendy A , Moertel Christopher L. , Ratner Nancy , Largaespada David A. 
Published: March 2024

AbstractNeurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor geneNF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild typeNF1allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs ofNF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially killNF1-deficient cells, through which we identified 23 compounds capable of killingNF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were testedin vivousing both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.