bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phylogenetic-based methods for fine-scale classification of PRRSV-2 ORF5 sequences: a comparison of their robustness and reproducibility
Authors: VanderWaal Kimberly , Pamornchainvakul Nakarin , Kikuti Mariana , Linhares Daniel , Trevisan Giovani , Zhang Jianqiang , Anderson Tavis K. , Zeller Michael , Rossow Stephanie , Holtkamp Derald J. , Makau Dennis N. , Corzo Cesar A. , Paploski Igor A.D. 
Published: May 2024

AbstractDisease management and epidemiological investigations of porcine reproductive and respiratory syndrome virus-type 2 (PRRSV-2) often rely on grouping together highly related sequences. In the USA, the last five years have seen a major paradigm shift within the swine industry when classifying PRRSV-2, beginning to move away from RFLP (restriction fragment length polymorphisms)-typing and adopting the use of phylogenetic lineage-based classification. However, lineages and sub-lineages are large and genetically diverse, and the rapid mutation rate of PRRSV coupled with the global prevalence of the disease has made it challenging to identify new and emerging variants. Thus, within the lineage system, a dynamic fine-scale classification scheme is needed to provide better resolution on the relatedness of PRRSV-2 viruses to inform disease management and monitoring efforts and facilitate research and communication surrounding circulating PRRSV viruses. Here, we compare potential fine-scale systems for classifying PRRSV-2 variants (i.e., genetic clusters of closely related ORF5 sequences at finer scales than sub-lineage) using a database of 28,730 sequences from 2010 to 2021, representing >55% of the U.S. pig population. In total, we compared 140 approaches that differed in their tree-building method, criteria, and thresholds for defining variants within phylogenetic trees usingTreeCluster.Three approaches produced epidemiologically meaningful variants (i.e., ≥5 sequences per cluster), and resulted in reproducible and robust outputs even when the input data or input phylogenies were changed. In the three best performing approaches, the average genetic distance amongst sequences belonging to the same variant was 2.1 – 2.5%, and the genetic divergence between variants was 2.5-2.7%. Machine learning classification algorithms were also trained to assign new sequences to an existing variant with >95% accuracy, which shows that newly generated sequences could be assigned without repeating the phylogenetic and clustering analyses. Finally, we identified 73 sequence-clusters (dated <1 year apart with close phylogenetic relatedness) associated with circulation events on single farms. The percent of farm sequence-clusters with an ID change was 6.5-8.7% for our best approaches. In contrast, ∼43% of farm sequence-clusters had variation in their RFLP-type, further demonstrating how our proposed fine-scale classification system addresses shortcomings of RFLP-typing. Through identifying robust and reproducible classification approaches for PRRSV-2, this work lays the foundation for a fine-scale system that would more reliably group related field viruses and provide better improved clarity for decision-making surrounding disease management.
A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice
Authors: Gottlieb Sam , van der Vaart Andrew , Hassan Annalise , Bledsoe Douglas , Morgan Alanna , O’Rourke Brennen , Rogers Walker D. , Wolstenholme Jennifer T. , Miles Michael F. 
Published: May 2024

ABSTRACTOver 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3β) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3β inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3β inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on β-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3β in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.
IL-4 Licenses B Cell Activation Through Cholesterol Synthesis
Authors: Steach Holly R. , York Autumn G. , Skadow Mathias H. , Chen Shuting , Zhao Jun , Williams Kevin J. , Zhou Quan , Hsieh Weu-Yuan , Brewer J. Richard , Qu Rihao , Shyer Justin A. , Harman Christian , Sefik Esen , Mowell Walter K. , Bailis Will , Cui Can , Kluger Yuval , Bensinger Steven J. , Craft Joe , Flavell Richard A. 
Published: May 2024

ABSTRACTLymphocyte activation involves a transition from quiescence and associated catabolic metabolism to a metabolic state with noted similarities to cancer cells such as heavy reliance on aerobic glycolysis for energy demands and increased nutrient requirements for biomass accumulation and cell division1–3. Following antigen receptor ligation, lymphocytes require spatiotemporally distinct “second signals”. These include costimulatory receptor or cytokine signaling, which engage discrete programs that often involve remodeling of organelles and increased nutrient uptake or synthesis to meet changing biochemical demands4–6. One such signaling molecule, IL-4, is a highly pleiotropic cytokine that was first identified as a B cell co-mitogen over 30 years ago7. However, how IL-4 signaling mechanistically supports B cell proliferation is incompletely understood. Here, using single cell RNA sequencing we find that the cholesterol biosynthetic program is transcriptionally upregulated following IL-4 signaling during the early B cell response to influenza virus infection, and is required for B cell activationin vivo. By limiting lipid availabilityin vitro, we determine cholesterol to be essential for B cells to expand their endoplasmic reticulum, progress through cell cycle, and proliferate. In sum, we demonstrate that the well-known ability of IL-4 to act as a B cell growth factor is through a previously unknown rewiring of specific lipid anabolic programs, relieving sensitivity of cells to environmental nutrient availability.
Intensifying marine heatwaves and limited protection threaten global kelp forests
Authors: Arafeh-Dalmau Nur , Villaseñor-Derbez Juan Carlos , Schoeman David S. , Mora-Soto Alejandra , Bell Tom W. , Butler Claire L. , Costa Maycira , Dunga Loyiso V. , Houskeeper Henry F. , Lagger Cristian , Pantano Carolina , Laínez del Pozo Daniela , Sink Kerry J. , Micheli Fiorenza , Cavanaugh Kyle C. 
Published: May 2024

AbstractKelp forests are one of the earth’s most productive ecosystems and are at the greatest risk from climate change, yet little is known regarding their future threats and current conservation status. By combining a global remote sensing dataset of floating kelp forests with climate data and projections, we find that exposure to projected marine heatwaves will increase ∼8 times compared to contemporary (2001-2020) exposure for intermediate climate scenarios. While exposure will intensify for all forests, climate refugia emerge for some southern hemisphere kelp forests, which have lower exposure to contemporary and projected marine heatwaves. Under these escalating threats, less than 3% of global kelp forests are currently within highly restrictive marine protected areas, the most effective conservation measure for providing climate resilience. Our findings emphasize the urgent need to increase the global protection of kelp forests and set bolder climate adaptation goals.
CREATION OF SAFE DOSE ZONES USING ISODOSE MAPS IN VIDEO FLUOROSCOPIC SWALLOWING STUDIES FOR PEDIATRIC PATIENTS
Authors: María Ignacia Gac P. , Sofía Moncada H. , Mathias Redenz R. , Marco Jiménez H. , Ricardo Castillo V. 
Published: May 2024

AbstractBackgroundDuring video fluoroscopic procedures in pediatric patients, a considerable number of individuals, including occupationally exposed professionals (OEP) and patient companions, must be present, exposing themselves to radiation.ObjectiveTo determine safety areas for OEP to receive the lowest absorbed dose during the examination, as shown in isodose maps.MethodTechnical parameters used in the examination were obtained by reviewing exams conducted during the years 2021 and 2022. Subsequently, a procedure was conducted to simulate these data using an anthropomorphic phantom and taking measurements at different points and levels of the examination room to create a map with dose zones in three dimensions. A Geiger Müller ionization chamber was used to measure the doses.ResultsIt was found that the points closest to the patient at pelvic level of the professional had the highest doses.ConclusionOEP who must remain close to the patient have an essential obligation to comply with the use of radiological protection elements, and the relocation of elements in the room could be considered.
The Health for Life in Singapore (HELIOS) Study: delivering Precision Medicine research for Asian populations
Authors: Wang Xiaoyan , Mina Theresia , Sadhu Nilanjana , Jain Pritesh R , Ng Hong Kiat , Low Dorrain Yanwen , Tay Darwin , Tong Terry Yoke Yin , Choo Wee-Lin , Kerk Swat Kim , Low Guo Liang ,   The HELIOS Study team, Lam Benjamin Chih Chiang , Dalan Rinkoo , Wanseicheong Gervais , Yew Yik Weng , Leow Ee-J , Brage Soren , Michelotti Gregory A , Wong Kari E , Sheridan Patricia A , Low Pin Yan , Yeo Zhen Xuan , Bertin Nicolas , Bellis Claire , Hebrard Maxime , Goy Pierre-Alexis , Tsilidis Kostas , Sanikini Harinakshi , Guan Xue Li , Lim Tock Han , Lee Lionel , Best James D , Tan Patrick , Elliott Paul , Lee Eng Sing , Lee Jimmy , Ngeow Joanne , Riboli Elio , Lam Max , Loh Marie , Chambers John C 
Published: May 2024

AbstractAsian people are under-represented in population-based, clinical, and genomic research.1,2To address this gap, we have initiated the HELIOS longitudinal cohort study, comprising comprehensive behavioural, phenotypic, and genomic measurements from 10,004 Asian men and women of Chinese, Indian or Malay background. Phenotyping has been carried out using validated approaches, that are internationally interoperable. Health record linkage enriches both baseline phenotyping and evaluation of prospective outcomes. The integrated multi-omics data include whole-genome and RNA sequencing, quantification of DNA methylation, and metabolomic profiling. Our data reveal extensive lifestyle, physiological, genomic, and molecular diversity between the distinct Asian ethnic groups, and the biological interconnectivity between functional layers. This includes characterisation of divergent patterns of genome regulation between Asian individuals, that correlate with differences in educational attainment, dietary quality, and adiposity, and which overlap transcription factors and DNA methylation sites linked to the development of diabetes and other chronic diseases. Our unique HELIOS Asian Precision Medicine cohort study represents a state-of-the art platform to enable biomedical researchers to understand the aetiology and pathogenesis of diverse disease outcomes in Asia, and to generate insights that have the potential to improve health outcomes for Asian populations globally.
TILTomorrow today: dynamic factors predicting changes in intracranial pressure treatment intensity after traumatic brain injury
Authors: Bhattacharyay Shubhayu , van Leeuwen Florian D , Beqiri Erta , Åkerlund Cecilia , Wilson Lindsay , Steyerberg Ewout W , Nelson David W , Maas Andrew I R , Menon David K , Ercole Ari ,   the CENTER-TBI investigators and participants
Published: May 2024

AbstractPractices for controlling intracranial pressure (ICP) in traumatic brain injury (TBI) patients admitted to the intensive care unit (ICU) vary considerably between centres. To help understand the rational basis for such variance in care, this study aims to identify the patient-level predictors of changes in ICP management. We extracted all heterogeneous data (2,008 pre-ICU and ICU variables) collected from a prospective cohort (n=844, 51 ICUs) of ICP-monitored TBI patients in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. We developed the TILTomorrow modelling strategy, which leverages recurrent neural networks to map a token-embedded time series representation of all variables (including missing values) to an ordinal, dynamic prediction of the following day’s five-category therapy intensity level (TIL(Basic)) score. With 20 repeats of 5-fold cross-validation, we trained TILTomorrow on different variable sets and applied the TimeSHAP (temporal extension of SHapley Additive exPlanations) algorithm to estimate variable contributions towards predictions of next-day changes in TIL(Basic). Based on Somers’Dxy, the full range of variables explained 68% (95% CI: 65–72%) of the ordinal variation in next-day changes in TIL(Basic)on day one and up to 51% (95% CI: 45–56%) thereafter, when changes in TIL(Basic)became less frequent. Up to 81% (95% CI: 78–85%) of this explanation could be derived from non-treatment variables (i.e., markers of pathophysiology and injury severity), but the prior trajectory of ICU management significantly improved prediction of future de-escalations in ICP-targeted treatment. Whilst there was no significant difference in the predictive discriminability (i.e., area under receiver operating characteristic curve [AUC]) between next-day escalations (0.80 [95% CI: 0.77–0.84]) and de-escalations (0.79 [95% CI: 0.76– 0.82]) in TIL(Basic)after day two, we found specific predictor effects to be more robust with de-escalations. The most important predictors of day-to-day changes in ICP management included preceding treatments, age, space-occupying lesions, ICP, metabolic derangements, and neurological function. Serial protein biomarkers were also important and may serve a useful role in the clinical armamentarium for assessing therapeutic needs. Approximately half of the ordinal variation in day-to-day changes in TIL(Basic)after day two remained unexplained, underscoring the significant contribution of unmeasured factors or clinicians’ personal preferences in ICP treatment. At the same time, specific dynamic markers of pathophysiology associated strongly with changes in treatment intensity and, upon mechanistic investigation, may improve the timing and personalised targeting of future care.
The triple combination of Remdesivir (GS-441524), Molnupiravir and Ribavirin is highly efficient in inhibiting coronavirus replication in human nasal airway epithelial cell cultures and in a hamster infection model
Authors: Do Thuc Nguyen Dan , Abdelnabi Rana , Boda Bernadett , Constant Samuel , Neyts Johan , Jochmans Dirk 
Published: May 2024

ABSTRACTThe use of fixed dose-combinations of antivirals with different mechanisms of action has proven a key in the successful treatment of infections with HIV and HCV. For the treatment of infections with SARS-CoV-2 and possible future epi-/pandemic coronaviruses, it will be important to explore the efficacy of combinations of different drugs, in particular to avoid resistance development, such as in patients with immunodeficiencies. As a first effort, we studied the antiviral potency of combinations of antivirals. To that end, we made use of primary human airway epithelial cell (HAEC) cultures grown at the air-liquid interface that were infected with the beta coronavirus OC43. We found that the triple combination of GS-441524 (parent nucleoside of remdesivir), molnupiravir, and ribavirin resulted in a more pronounced antiviral efficacy than what could be expected from a purely additive antiviral effect. The potency of this triple combination was next tested in SARS-CoV-2 infected hamsters. To that end, for each of the drugs, intentionally suboptimal or even ineffective doses were selected. Yet, in the lungs of all hamsters that received triple prophylactic therapy with suboptimal/inactive doses of GS-441524, molnupiravir, and ribavirin, no infectious virus was detectable. Our finding indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available.
An acylated N-terminus and a conserved loop regulate the activity of the ABHD17 de-acylase
Authors: Holme Sydney , Sapia Jennifer , Davey Michael , Vanni Stefano , Conibear Elizabeth 
Published: May 2024

AbstractThe dynamic addition and removal of long chain fatty acids modulates protein function and localization. The alpha/beta hydrolase domain-containing (ABHD) 17 enzymes remove acyl chains from membrane localized proteins such as the oncoprotein NRas, but how the ABHD17 proteins are regulated is unknown. Here, we used cell-based studies and molecular dynamics simulations to show that ABHD17 activity is controlled by two mobile elements – an S-acylated N-terminal helix and a loop – that flank the substrate-binding pocket. S-acylation at multiple sites buries the helix in the membrane, which allows hydrophobic residues in the loop to interact with the bilayer. This stabilizes the conformation of both helix and loop, alters the conformation of the binding pocket and optimally positions the enzyme for substrate engagement. S-acylation may be a general feature of acyl-protein thioesterases. By providing a mechanistic understanding of how the lipid modification of a lipid-removing enzyme promotes its enzymatic activity, this work contributes to our understanding of cellular S-acylation cycles.
Experiences of breastfeeding peer support: views from current, past and trainee breastfeeding peer support volunteers in Wales, UK
Authors: Jones H , Davies R , Williams F , Evans R , Bath R , Embling R , Brophy S 
Published: May 2024

AbstractBackgroundBreastfeeding peer support involves mothers with personal experience of breastfeeding providing support, information, and encouragement to other breastfeeding mothers. The Unicef UK Baby Friendly Initiative standards require that additional support for new mothers, such as peer support, is provided and that services work together to ensure that mothers can get additional help as needed. As work begins on a national framework for feeding support, we wanted to explore the current activity of breastfeeding supporters in Wales, UK. We aimed to explore the experiences of current, past and trainee breastfeeding peer support volunteers to understand what they need from a refreshed All Wales Breastfeeding Action Plan and how they could benefit.MethodsCurrent, past and trainee breastfeeding peer support volunteers were invited by Public Health Wales to complete an online survey about their experiences of providing breastfeeding peer support including both open and closed questions. Codebook thematic analysis was used to generate key themes arising from qualitative data.Results81 volunteers completed the online survey between 21/12/23 and 22/1/24. Their experiences were described as ’rewarding’ (50% (44/81)) and ‘empowering’ (12%, 10/81), but also ’frustrating’ (19%, 15/81) and ’challenging’ (8%, 7/81). Peer supporters supported basic positioning and latching, challenges with milk supply, frequency of feeds, weaning, and poor weight gain. Three key themes were developed from the open-ended question ‘why did you decide to undertake peer support training?’ (1) Paying it forward (2) Limited peer support in local areas and (3) The need for more support. Funding was noted as a barrier to continuing to provide breastfeeding peer support.ConclusionsBreastfeeding peer support was associated with benefits for the peer supporters themselves and recognised as beneficial for the mothers they helped. Investment in training future breastfeeding peer supporters is essential to ensure the continued success of these important initiatives.
Precision fMRI reveals that the language network exhibits adult-like left-hemispheric lateralization by 4 years of age
Authors: Ozernov-Palchik Ola , O’Brien Amanda M. , Lee Elizabeth Jiachen , Richardson Hilary , Romeo Rachel , Lipkin Benjamin , Small Hannah , Capella Jimmy , Nieto-Castañón Alfonso , Saxe Rebecca , Gabrieli John D. E. , Fedorenko Evelina 
Published: May 2024

AbstractLeft hemisphere damage in adulthood often leads to linguistic deficits, but many cases of early damage leave linguistic processing preserved, and a functional language system can develop in the right hemisphere. To explain this early apparent equipotentiality of the two hemispheres for language, some have proposed that the language system is bilateral during early development and only becomes left-lateralized with age. We examined language lateralization using functional magnetic resonance imaging with two large pediatric cohorts (total n=273 children ages 4-16; n=107 adults). Strong, adult-level left-hemispheric lateralization (in activation volume and response magnitude) was evident by age 4. Thus, although the right hemisphere can take over language function in some cases of early brain damage, and although some features of the language system do show protracted development (magnitude of language response and strength of inter-regional correlations in the language network), the left-hemisphere bias for language is robustly present by 4 years of age. These results call for alternative accounts of early equipotentiality of the two hemispheres for language.Significance StatementLanguage is the most canonical function that shows a strong hemispheric asymmetry in adult brains. However, whether the language system is already lateralized to the left hemisphere early in development has long been debated, given that early left-hemisphere damage often leaves language processing unimpaired. We examined the developmental trajectory of language lateralization in two large-scale pediatric datasets using robust individual-subject fMRI approaches. We found that the language system exhibits adult-like left-hemispheric lateralization by age 4, although other aspects of the neural infrastructure for language show a clear change between age 4 and late childhood. These findings challengethe claim that the language system is bilateral during early development and call for alternative accounts of early hemispheric equipotentiality for language.