bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepRBP: A novel deep neural network for inferring splicing regulation
Authors: Sancho Joseba , Ferrer-Bonsoms Juan A. , Olaverri-Mendizabal Danel , Carazo Fernando , Valcárcel Luis V. , Ochoa Idoia 
Published: April 2024

AbstractMotivationAlternative splicing plays a pivotal role in various biological processes. In the context of cancer, aberrant splicing patterns can lead to disease progression and treatment resistance. Understanding the regulatory mechanisms underlying alternative splicing is crucial for elucidating disease mechanisms and identifying potential therapeutic targets.ResultsWe present DeepRBP, a deep learning (DL) based framework to identify potential RNA-binding proteins (RBP)-Gene regulation pairs for further in-vitro validation. DeepRBP is composed of a DL model that predicts transcript abundance given RBP and gene expression data coupled with an explainability module that computes informative RBP-Gene scores. We show that the proposed framework is able to identify known RBP-Gene regulations, demonstrating its applicability to identify new ones.Availability and ImplementationDeepRBP is implemented in PyTorch, and all the code and material used in this work is available athttps://github.com/ML4BM-Lab/DeepRBP.Contactiochoal@unav.esSupplementary informationSupplementary data are available atBioinformaticsonline.
Phaeocystisblooms caused carbon drawdown during the Antarctic Cold Reversal from sedimentary ancient DNA
Authors: Weiß Josefine Friederike , Herzschuh Ulrike , Müller Juliane , Liang Jie , Vorrath Maria-Elena , Perfumo Amedea , Stoof-Leichsenring Kathleen R. 
Published: April 2024

AbstractThe Southern Ocean plays a crucial role in the global carbon budget. Modeling studies propose that the atmospheric CO2plateau during the Antarctic Cold Reversal (ACR; 14,700 to 12,700 calibrated years before present (cal yr BP)) is related to increased marine productivity. However, proxy evidence relating environmental conditions as well as primary community composition and productivity to carbon drawdown is missing. Our ancient DNA shotgun metagenomic analysis of marine sediments revealedPhaeocystis antarctica(haptophyte) as a key element of the primary producer community. Independent proxy evidence (blooming-related bacteria, Ba/Fe ratio) from the same sediment record point to high productivity in response to enhanced sea-ice seasonality caused by ACR cooling. Post ACR, abruptPhaeocystiscommunity loss shows how sensitive this ecosystem is to warming, potentially representing a key tipping element that may be further enhanced by thePhaeocystis-related sulfur cycle–climate feedback. As an analogy for present warming, it highlights the importance of regions with high seasonal sea-ice variability andPhaeocystis-dominance, such as the Ross Sea, for stabilizing atmospheric CO2content. Additionally, our shotgun metagenomic data portray complex Holocene ecosystem establishment including key Antarctic taxa such as penguins, whales, and Antarctic fishes with implications for ongoing conservation efforts.
HtDCR-like1regulates the development of structurally coloured cuticle by modulating cuticle chemistry and mechanical properties inHibiscus trionum
Authors: Ferria Jordan , Saladin Siriel , Ponraj Udhaya , Wightman Raymond , Giorio Chiara , Airoldi Chiara A. , Glover Beverley J. 
Published: April 2024

SummaryStructural colours are a unique trait present in some animals, plants and even bacteria. InHibiscus trionumflowers, they arise from nano-scaled cuticular ridges and may improve pollinator foraging efficiency. These ridges result from the buckling of the cuticle which is thought to be controlled by multiple parameters including anisotropic cell growth, chemical differentiation of the cuticle and formation of two layers of different mechanical properties.Here we investigate further the molecular and physical mechanisms by which structural colours are achieved inHibiscus trionum. We produced two transgenic lines overexpressingHtDCR-like1, encoding a BAHD acyltransferase involved in cuticle synthesis. Transgenic lines showed impairment of the production of cuticle striations. Cuticle thickness, cuticle chemistry, cell elongation and cuticle stiffness were then investigated to identify the cause of failed buckling.We found thatHtDCR-like1overexpression leads to modification of cuticle chemistry, including a decrease in detectable C16H32O4(10,16-DHP) and a change to the measured Young’s moduli of the cuticle layers without alteration of the cell growth pattern.This work demonstrates the mechanisms by which gene regulation may control complex physical phenomena such as cuticle buckling via alteration of material properties of living tissues.
Comparing the effect of imputation reference panel composition in four distinct Latin American cohorts
Authors: French Jennifer N , Pua Victor Borda , Laboulaye Roland , Leal Thiago Peixoto , Olivas Mario Cornejo , Lima-Costa Maria Fernanda , Horta Bernardo L , Barreto Mauricio L , Tarazona-Santos Eduardo , Mata Ignacio , O’Connor Timothy D. 
Published: April 2024

AbstractGenome-wide association studies have been useful in identifying genetic risk factors for various phenotypes. These studies rely on imputation and many existing panels are largely composed of individuals of European ancestry, resulting in lower levels of imputation quality in underrepresented populations. We aim to analyze how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We compared imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four populations; however, there were differences between chromosomes 7 and X in some cohorts. Excluding Latin Americans from analysis resulted in worse imputation quality in every cohort, while differential effects were seen when excluding Europeans and Africans between and within cohorts and between chromosomes 7 and X. Finally, increasing IA-like admixture proportions in the reference panel increased imputation quality at different levels in different populations. The difference in results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations.
Atypical Pupil-Linked Arousal Induced by Low-Risk Probabilistic Choices, and Intolerance of Uncertainty in Adults with ASD
Authors: Pultsina Kristina I. , Stroganova Tatiana A. , Kozunova Galina L. , Prokofyev Andrey O. , Miasnikova Aleksandra S. , Rytikova Anna M. , Chernyshev Boris V. 
Published: April 2024

AbstractAdults with autism spectrum disorder (ASD) report stress when acting in a familiar probabilistic environment, but the underlying mechanisms are unclear. Their decision-making may be affected by the uncertainty aversion implicated in ASD, and associated with increased autonomic arousal. Previous studies have shown that in neurotypical (NT) people, decisions with predictably better outcomes are less stressful and elicit smaller pupil-linked arousal than those involving random “trial-and-error” searches or self-imposed risk of exploration. Here, in a sample of 46 high-functioning ASD and NT participants, we explored pupil-linked arousal and behavioral performance in a probabilistic reward learning task with a stable advantage of one choice option over the other. Using mixed-effects model analysis, we contrasted pupil dilation response (PDR) between a preferred frequently rewarded exploitative decision and its explorative alternatives. We observed that subjects with ASD learned the advantageous probabilistic choices at the same rate over time and preferred them to the same degree as NT participants both in terms of choice ratio and decision speed. Despite similar reward prediction abilities, outcome predictability modulated decision-related PDR in ASD in the opposite direction than in NT individuals. Moreover, relatively enhanced PDR elicited by exploitative low-risk decisions predicted a greater degree of self-reported intolerance of uncertainty in everyday life. Our results suggest that in a non-volatile probabilistic environment, objectively good predictive abilities in people with ASD are coupled with elevated physiological stress and subjective uncertainty regarding the decisions with the best possible but still uncertain outcome that contributes to their intolerance of uncertainty.
A Novel Simple ImmunoAssay for Quantification of Blood Anti-NMDAR1 Autoantibodies
Authors: Vaughn Melonie , Powell Susan , Risbrough Victoria , Zhou Xianjin 
Published: April 2024

AbstractHigh titers of anti-NMDAR1 autoantibodies in human brain cause anti-NMDAR1 encephalitis, a rare disease that displays a variety of psychiatric symptoms and neurological symptoms. Currently, immunohistochemical staining and cell-based assays are the standard methods for detection and semi-quantification of the anti-NMDAR1 autoantibodies. Low titers of blood circulating anti-NMDAR1 autoantibodies have been reported in a significant subset of the general human population. However, detection and quantification of these low titers of blood circulating anti-NMDAR1 autoantibodies are problematic because of high non-specific background from less diluted serum/plasma. Development of a new method to quantify these low titers of blood anti-NMDAR1 autoantibodies is necessary to understand their potential impacts on psychiatric symptoms and cognition. Based on our previous One-Step assay, we report the development of a novel simple immunoassay to quantify cross-species blood anti-NMDAR1 autoantibodies, and its validation with immunohistochemistry and cell-based assays in both humans and mice.
Reassessing global historical ℛ0estimates of canine rabies
Authors: Li Michael , Roswell Michael , Hampson Katie , Bolker Benjamin M. , Dushoff Jonathan 
Published: April 2024

AbstractRabies spread by domestic dogs continues to cause tens of thousands of human deaths every year in low- and middle-income countries. Nevertheless rabies is often neglected, perhaps because it has already been eliminated from high-income countries through dog vaccination. Estimates of canine rabies’s intrinsic reproductive number (ℛ0), a metric of disease spread, from a wide range of times and locations are relatively low (values<2), with narrow confidence intervals. Given rabies’s persistence, this consistently low and narrow range of estimates is surprising. We combined incidence data from historical outbreaks of canine rabies from around the world with in-depth contact-tracing data from Tanzania to investigate initial growth rates (r0), generation-interval distributions (G), and reproductive numbers (ℛ0). We improved on earlier estimates by choosing outbreak windows algorithmically; fittingr0using a more appropriate statistical method that accounts for decreases through time; and incorporating uncertainty from bothr0andGin our confidence intervals onℛ0. Ourℛ0estimates are larger than previous estimates, with wider confidence intervals. These revisedℛ0estimates suggest that a greater level of vaccination effort will be required to eliminate rabies than previously thought, but that the level of coverage required remains feasible. Our hybrid approach for estimatingℛ0and its uncertainty is applicable to other disease systems where researchers estimateℛ0by combining data-based estimates ofr0andG.
Effects of environmental change on population growth: monitoring time-varying carrying capacity in free-ranging spotted hyenas
Authors: Bailey Liam D. , Höner Oliver P. , Davidian Eve , Dheer Arjun , Radchuk Viktoriia , Walter Leonie F. , White Ella W. , Courtiol Alexandre 
Published: April 2024

AbstractIn conservation, a growing population is often taken as a sign of success. But trends in population size can be misleading. When individuals are long-lived, populations may keep growing—for a time—even as the environment begins to stabilize or deteriorate. Trends in carrying capacity (K) would better reflect the situation that a population finds itself in, yetKis commonly assumed to be static. We developed an individual-based modelling approach to estimate time-varying carrying capacity (Kt) in a population of free-ranging spotted hyenas.Ktnoticeably varied due to events such as disease outbreaks, but not in response to recent conservation interventions. Although the population tripled in size during the 26-year study period, we found no corresponding trend inKt. Rather, population recovery resulted from earlier environmental improvements. Our approach, which can be applied to populations of other species, allows for a faster and more accurate assessment of conservation needs.
Uncovering porphyrin accumulation in the tumor microenvironment
Authors: Adapa Swamy R. , Sami Abdus , Meshram Pravin , Ferreira Gloria C. , Jiang Rays H.Y. 
Published: April 2024

AbstractHeme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be exquisitely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termed ‘Porphyrin Overdrive’. Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TME’s stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no porphyrin accumulation, and CAFs deprived of tumor cease porphyrin overproduction, indicating that both cancer and tumor-stromal porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.
Vimentin regulates mitochondrial ROS production and inflammatory responses of neutrophils
Authors: Huynh Thao Ngoc , Toperzer Jody , Scherer Allison , Gumina Anne , Brunetti Tonya , Mansour Michael K. , Markovitz David M. , Russo Brian C. 
Published: April 2024

AbstractThe intermediate filament vimentin is present in immune cells and is implicated in proinflammatory immune responses. Whether and how it supports antimicrobial activities of neutrophils is not well established. Here, we developed an immortalized neutrophil model to examine the requirement of vimentin. We demonstrate that vimentin restricts the production of proinflammatory cytokines and reactive oxygen species (ROS), but enhances phagocytosis and swarming. We observe that vimentin is dispensable for neutrophil extracellular trap (NET) formation, degranulation, and inflammasome activation. Moreover, gene expression analysis demonstrated that the presence of vimentin was associated with changes in expression of multiple genes required for mitochondrial function and ROS overproduction. Treatment of wild-type cells with rotenone, an inhibitor for complex I of the electron transport chain, increases the ROS levels. Likewise, treatment with mitoTEMPO, a SOD mimetic, rescues the ROS production in cells lacking vimentin. Together, these data show vimentin regulates neutrophil antimicrobial functions and alters ROS levels through regulation of mitochondrial activity.
Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program
Authors: Powell Nicholas R. , Geck Renee C. , Lai Dongbing , Shugg Tyler , Skaar Todd C. , Dunham Maitreya 
Published: April 2024

ABSTRACTGlucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals withG6PDpolymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable throughG6PDgenetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence ofG6PDvariants is limited by over 800G6PDvariants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improveG6PDgenotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm thatG6PDcoding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation forG6PDvariants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, ofG6PDgenetic tests through a more complete clinical interpretation ofG6PDvariants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing ofG6PDwill be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.
Artificial Intelligence in Diabetes Care: Evaluating GPT-4’s Competency in Reviewing Diabetic Patient Management Plan in Comparison to Expert Review
Authors: Mondal Agnibho , Naskar Arindam 
Published: April 2024

AbstractBackgroundThe escalating global burden of diabetes necessitates innovative management strategies. Artificial intelligence, particularly large language models like GPT-4, presents a promising avenue for improving guideline adherence in diabetes care. Such technologies could revolutionize patient management by offering personalized, evidence-based treatment recommendations.MethodsA comparative, blinded design was employed, involving 50 hypothetical diabetes mellitus case summaries, emphasizing varied aspects of diabetes management. GPT-4 evaluated each summary for guideline adherence, classifying them as compliant or non-compliant, based on the ADA guidelines. A medical expert, blinded to GPT-4’s assessments, independently reviewed the summaries. Concordance between GPT-4 and the expert’s evaluations was statistically analyzed, including calculating Cohen’s kappa for agreement.ResultsGPT-4 labelled 30 summaries as compliant and 20 as non-compliant, while the expert identified 28 as compliant and 22 as non-compliant. Agreement was reached on 46 of the 50 cases, yielding a Cohen’s kappa of 0.84, indicating near-perfect agreement. GPT-4 demonstrated a 92% accuracy, with a sensitivity of 86.4% and a specificity of 96.4%. Discrepancies in four cases highlighted challenges in AI’s understanding of complex clinical judgments related to medication adjustments and treatment modifications.ConclusionGPT-4 exhibits promising potential to support health-care professionals in reviewing diabetes management plans for guideline adherence. Despite high concordance with expert assessments, instances of non-agreement underscore the need for AI refinement in complex clinical scenarios. Future research should aim at enhancing AI’s clinical reasoning capabilities and exploring its integration with other technologies for improved healthcare delivery.
Evaluating General Vision-Language Models for Clinical Medicine
Authors: Jiang Yixing , Omiye Jesutofunmi A. , Zakka Cyril , Moor Michael , Gui Haiwen , Alipour Shayan , Mousavi Seyed Shahabeddin , Chen Jonathan H. , Rajpurkar Pranav , Daneshjou Roxana 
Published: April 2024

AbstractRecently emerging large multimodal models (LMMs) utilize various types of data modalities, including text and visual inputs to generate outputs. The incorporation of LMMs into clinical medicine presents unique challenges, including accuracy, reliability, and clinical relevance. Here, we explore clinical applications of GPT-4V, an LMM that has been proposed for use in medicine, in gastroenterology, radiology, dermatology, and United States Medical Licensing Examination (USMLE) test questions. We used standardized robust datasets with thousands of endoscopy images, chest x-ray, and skin lesions to benchmark GPT-4V’s ability to predict diagnoses. To assess bias, we also explored GPT-4V’s ability to determine Fitzpatrick skin tones with dermatology images. We found that GPT-4V is limited in performance across all four domains, resulting in decreased performance compared to previously published baseline models. The macro-average precision, recall, and F1-score for gastroenterology were 11.2%, 9.1% and 6.8% respectively. For radiology, the best performing task of identifying cardiomegaly had precision, recall, and F1-score of 28%, 94%, and 43% respectively. In dermatology, GPT-4V had an overall top-1 and top-3 diagnostic accuracy of 6.2% and 21% respectively. There was a significant accuracy drop when predicting images of darker skin tones (p<0.001). GPT-4V accurately identified Fitzpatrick skin tones for 56.5% of images. For the multiple-choice-styled USMLE image-based test questions, GPT-4V had an accuracy of 59%. Our findings demonstrate that the current version of GPT-4V is limited in its diagnostic abilities across multiple image-based medical specialties. Future work should be done to explore LMM’s sensitivity to prompting as well as hybrid models that can combine LMM’s capabilities with other robust models.