bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alterations in Lipid Profiles in Children with Perinatally Acquired HIV Infection living in Ghana
Authors: Ayanful-Torgby Ruth , Shabanova Veronika , Essuman Akosua A. , Boafo Emmanuel , Amoah Linda E. , Paintsil Elijah 
Published: January 2025

AbstractChildren and adolescents who acquired HIV perinatally and are on lifelong antiretroviral therapy (ART) are at increased risk of lipid abnormalities, premature atherosclerosis, and early onset cardiovascular diseases (CVD). Majority of these children reside in sub-Saharan Africa, where monitoring of lipid profiles is not routine. In this study, we assessed the age dependent prevalence of dyslipidemia among children and adolescents who acquired HIV in Ghana.In this cross-sectional study we examined lipid profiles of 397 children aged 6 to 18 years. Dyslipidemia was defined by elevated total cholesterol (TC) (≥200 mg/dL) or triglyceride (TG) levels (>150 mg/dL) or low-density lipoprotein cholesterol (LDL-C) (>130 mg/dL) or reduced high-density lipoprotein cholesterol (HDL-C) (<35 mg/dL). Dyslipidemia prevalence, by at least one criterion and for each criterion separately, was compared between age groups 6 - 12 (pre-teen) and 13 - 18 (teenage) years, as well as by sex.The overall prevalence of dyslipidemia was 42.32%, and by individual criterion was 9.07% using LDL-C, 11.84% using TC, 15.87% using TG, and 24.00% using HDL-C. Additionaly, 5.04% (n=20) of the participants showed abnormalities across three parameters. Teenagers had a higher overall prevalence of dyslipidemia (46.75% vs. 39.04%, p=0.12). Criterion-based dyslipidemia prevalence varied across age groups, with TC-based (14.04% vs. 8.88%, p=0.12) being higher in the pre-teen group, while elevated TG-based (20.12% vs. 12.72%, p=0.05) and low levels of HDL- based (28.99% vs. 20.60%, p=0.05) were more prevalent in the teenagers. The mean levels of TC (p=0.04) and LDL-C (p=0.03) were significantly higher in the pre-teen age groups. Females had nearly twice as high as that of males with prevalence of abnormal LDL-C levels (11.39% vs. 6.67%, p=0.13).This study showed a high prevalence of dyslipidemia among children who acquired HIV perinatally and are on ART, with age-related variations in lipid profiles. These findings emphasize the importance of implementing routine monitoring for lipid disorders within this population.
GALILEO Generatively Expands Chemical Space and Achieves One-Shot Identification of a Library of Novel, Specific, Next Generation Broad-Spectrum Antiviral Compounds at High Hit Rates
Authors: Umansky Tyler , Woods Virgil , Russell Sean M. , Garvey David S. , Smith Davey M. , Haders Daniel 
Published: January 2025

AbstractThe COVID-19 pandemic (2019-2023) demonstrated the need for safe and effective, stockpiled broad-spectrum antiviral drugs to suppress unexpected viral outbreaks. The inability of the pharmaceutical industry to create such a therapeutic in the 6 years since the onset of COVID-19 demonstrates antiviral drug development must undergo a paradigm shift for this to occur. AI-based target and medicinal chemistry discovery platforms such as GALILEO and its geometric graph convolutional network tool ChemPrint, which we recently published, hold promise in accelerating and reimagining the drug development process. GALILEO identified the Thumb-1 site (an allosteric subdomain of the viral RNA polymerase) to be structurally conserved across numerous viral species and MDL-001 (an orally available therapeutic with a favorable pharmacokinetics and safety profile in humans) to be a potent inhibitor thereof. Published preclinical proof-of-concept studies demonstrated MDL-001 as a first-in-class broad-spectrum antiviral drug. This study leverages GALILEO’s generative and multimodal discovery tools to create trillions of new chemical entities (NCEs) from MDL-001’s pharmacophoric scaffold and select a library of highly specific and optimized compounds for next-generation broad-spectrum antiviral development. Specifically, ChemPrint’s one-shot predictions identified 12 NCEs with predicted affinity to Thumb-1 and significantly reduced, or no, affinity to MDL-001’s original target.In vitrobioassays demonstrated a 100% hit rate, with all 12 NCEs having antiviral activity against Hepatitis C Virus (HCV) and/or human Coronavirus 229E.In vitrostudies also demonstrated reduced activity of 800-fold to greater than 15,000-fold relative to MDL-001’s originally designed mechanism of action (MoA). In Tanimoto similarity plots, the 12 NCEs lacked chemical relatedness to known antiviral drugs, including MDL-001 (average Tanimoto coefficient: 0.38) and Beclabuvir, (average Tanimoto coefficient: 0.13) a HCV Thumb-1 ligand that lacks broad-spectrum activity. This study showcases GALILEO’s ability to generate vast NCE libraries and ChemPrint’s extrapolative capabilities to discover large, potent NCE libraries of compounds, specific to a complex target that are novel to known chemistry at high hit-rates.
Domain Knowledge Augmented Contrastive Learning on Dynamic Hypergraphs for Improved Health Risk Prediction
Authors: Choudhuri Akash , Vu Hieu , Jha Kishlay , Adhikari Bijaya 
Published: January 2025

AbstractAccurate health risk prediction is crucial for making informed clinical decisions and assessing the appropriate allocation of medical resources. While recent deep learning based approaches have shown great promise in risk prediction, they primarily focus on modeling the sequential information in Electronic Health Records (EHRs) and fail to leverage the rich mobility interactions among health entities. As a result, the existing approaches yield unsatisfactory performance in downstream risk prediction tasks, especially tasks such asClostridioides difficileInfection (CDI) incidence prediction that are primarily spread through mobility interactions. To address this issue, we propose a new approach that leverages Hypergraphs to explicitly model mobility interactions to improve predictive performance in health risk prediction tasks. Unlike regular graphs that are limited to modeling pairwise relationships, hypergraphs can effectively characterize the complex high-order semantic relationships between health entities. Moreover, we introduce a new contrastive learning strategy that exploits the domain knowledge to generate semantically meaningful positive (homologous) and negative (heterologous) pairs needed for contrastive learning. This unique contrastive pair augmentation strategy boosts the power of contrastive learning by generating feature representations that are both robust and well-aligned with the domain knowledge. Experiments on two real-world datasets demonstrate the advantage of our approach in both short-term and long-term risk prediction tasks, such asClostridioides difficileinfection incidence prediction and MICU transfer prediction. Our framework obtains gains in performance up to 29.49 % for PHOP, 30.64 % for MIMIC-IV for MICU transfer prediction, 13.17 % for PHOP, and 4.45 % for MIMIC-IV for CDI Incidence Prediction.
Impact of Digital Contact Tracing on Pandemic Control Analysed with Behaviour-driven Agent-based Modelling
Authors: Lopera González Luis Ignacio , Köber Göran , Kirchner Göran , Benzler Justus , Amft Oliver 
Published: January 2025

AbstractWe disentangle the efficacy of individual non-pharmaceutical interventions (NPIs), including digital contact tracing (DCT), with a novel behaviour-driven agent-based model (ABM) to inform ongoing pandemic preparedness efforts. Our model’s Zeitgeber architecture delineates contextual characteristics, including daytime, daily routines, locations, and activities. Our method determines each agent’s current location and behaviour in a realistic environment under the restrictions of NPIs. We model viral load transfer between agents from contact duration, distance, and the infected agent’s infectiousness level. We examine the effects of DCT adoption, adherence, and compliance, both individually and combined with other NPIs, on key pandemic indicators, thus providing novel insight into infection dynamics. DCT combined with other NPIs reduces the total infections up to 52% for realistic behaviour, whereas DCT alone yielded a 43% reduction. Surprisingly however, some NPI combinations do not improve pandemic parameters. Our approach offers fine-grained analysis capabilities on the effectiveness of NPI combinations that cannot be obtained in human studies due to confounding effects. Thus our approach can inform future pandemic control efforts and prioritisation in pandemic preparedness.
Genetic polymorphism and risk of anti-tuberculosis drug-induced liver injury (AT-DILI): a systematic review and meta-analysis
Authors: Tarazjani Amirreza Dehghan , Jouabadi Sima Mohammadi , Jouabadi Soroush Mohammadi , Naderi Elnaz , Sturkenboom Miriam , Ahmadizar Fariba 
Published: January 2025

AbstractAnti-tuberculosis (TB) drugs like isoniazid and rifampin can cause hepatotoxicity leading to treatment termination. Although Genome-wide association studies (GWAS) have identified variants linked to the risk of developing anti-tuberculosis drug-induced liver injury (AT-DILI), findings remain inconsistent. This study aimed to systematically summarise previous observational studies and assess the association between genetic polymorphisms and AT-DILI risk in adults.We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Libraries until January 10, 2023. The Newcastle-Ottawa Scale checklist was used to assess the methodological quality of the included studies. Pooled odds ratios (OR) with 95% confidence intervals (CIs) were employed using a random-effect model with the I2statistic to estimate the heterogeneity of results.Our study included 10 studies (n=3,322) of Asian ancestry. We identified genetic variants in drug-metabolizing enzymes, including NAT2, CYP2E1, and PXR, linked to AT-DILI risk. CYP2E1 C1/C1 and slow acetylators of NAT2*6A/6A, NAT26A/7B, NAT27B/7B, and NAT25B/7B genotypes were associated with increased risk, while rapid acetylators of NAT24/4 and NAT24/7B were linked to decreased risk. No significant association was found between CYP2E1B C1/C2, NAT2(*4/*6A, *4/*5B, *5B/*5B) and PXR with AT-DILI risk.This study revealed that NAT2 slow acetylator genotypes or CYP2E1 C1/C1 are causally linked to AT-DILI risk. The findings suggest that genetic variants in drug-metabolizing enzymes regulated by NAT2 and CYP2E1 are involved in developing drug-induced liver injury in users of anti-TB drugs.
Psychiatric symptom improvement from adjunctive statin prescribing in severe mental illness: three target trial emulation studies
Authors: Launders Naomi , Richards-Belle Alvin , Man Kenneth KC , Wong Ian CK , Osborn David PJ , Hayes Joseph F 
Published: January 2025

AbstractBackgroundRandomized controlled trials (RCTs) of statins as adjunct therapy for severe mental illness (SMI) have produced mixed results. Specific statin-antipsychotic combinations might improve psychiatric symptoms through: 1) blood-brain barrier (BBB) penetrant statins being anti-inflammatory/neuroprotective, and/or 2) statins that inhibit p-glycoprotein enhancing the effects of antipsychotics with high p-glycoprotein affinity.AimTo investigate these mechanisms via three target trial emulation studies.MethodsWe identified patients with SMI (schizophrenia, bipolar disorder, ‘other’ psychoses) prescribed antipsychotics/mood stabilisers and statins from 2000-2019 in English electronic health records. We defined three hypothetical RCTs and their observational analogues: 1) simvastatin (crosses BBB) vs. atorvastatin/pravastatin/rosuvastatin (non-penetrant); 2A) simvastatin/atorvastatin (p-glycoprotein inhibitors) vs. pravastatin in patients prescribed risperidone/olanzapine/aripiprazole (high p-glycoprotein affinity); 2B) risperidone/olanzapine/aripiprazole vs. quetiapine (low p-glycoprotein affinity) in patients prescribed simvastatin/atorvastatin. Primary outcome: 12-month psychiatric admissions. Secondary outcomes: self-harm, physical health, and accident/injury admissions.ResultsIn 72,096 patients prescribed statins and antipsychotics/mood stabilisers, we found no reduction in psychiatric admissions at 12 months in patients prescribed: 1) BBB-penetrant vs. non-penetrant statins (HR:1.07; 95%CI:0.88-1.31); 2A) antipsychotics with p-glycoprotein affinity and p-glycoprotein inhibiting statins vs. statins without inhibition (HR:0.77; 95%CI:0.28-2.15); 2B) p-glycoprotein inhibiting statins with antipsychotics having p-glycoprotein affinity vs. antipsychotics without affinity (HR:0.93; 95%CI:0.79-1.09). In 2B we observed reduced self-harm (HR:0.60; 95%CI:0.38-0.97) in per-protocol analysis and reduced psychiatric admissions in the ‘other’ psychoses subgroup (HR:0.53; 95%CI:0.34-0.85).ConclusionsBBB permeability is unlikely to be the mechanism by which statins improve SMI symptoms. Further research is needed to understand statin-antipsychotic interactions, and whether interaction with p-glycoprotein is a plausible mechanism.
A Novel Heme-Degrading Enzyme that Regulates Heme and Iron Homeostasis and Promotes Virulence inEnterococcus faecalis
Authors: Brunson Debra N. , Manzer Hader , Smith Alexander B. , Zackular Joseph P. , Kitten Todd , Lemos José A. 
Published: January 2025

ABSTRACTEnterococcus faecalis, a gut commensal, is a leading cause of opportunistic infections. Its virulence is linked to its ability to thrive in hostile environments, which includes host-imposed metal starvation. We recently showed thatE. faecalisevades iron starvation using five dedicated transporters that collectively scavenge iron from host tissues and other iron-deprived conditions. Interestingly, heme, the most abundant source of iron in the human body, supported growth of a strain lacking all five iron transporters (Δ5Fe). To release iron from heme, many bacterial pathogens utilize heme oxygenase enzymes to degrade the porphyrin that coordinates the iron ion of heme. AlthoughE. faecalislacks these enzymes, bioinformatics revealed a potential ortholog of the anaerobic heme-degrading enzyme anaerobilin synthase, found inEscherichia coliand a few other Gram-negative bacteria. Here, we demonstrated that deletion of OG1RF_RS05575 inE. faecalis(ΔRS05575) or in the Δ5Fe background (Δ5FeΔRS05575) led to intracellular heme accumulation and hypersensitivity under anaerobic conditions, suggestingRS05575encodes an anaerobilin synthase, the first of its kind described in Gram- positive bacteria. Additionally, deletion ofRS05575, either alone or in the Δ5Fe background, impairedE. faecaliscolonization in the mouse gastrointestinal tract and virulence in mouse peritonitis and rabbit infective endocarditis models. These results reveal that RS05575 is responsible for anaerobic degradation of heme and identify this relatively new enzyme class as a novel factor in bacterial pathogenesis. Findings from this study are likely to have broad implications, as homologues ofRS05575are found in other Gram-positive facultative anaerobes.IMPORTANCEHeme is an important nutrient for bacterial pathogens, mainly for its ability to serve as an iron source during infection. While bacteria are known to release iron from heme using enzymes called heme oxygenases, a new family of anaerobic heme-degrading enzymes has been described recently in Gram-negative bacteria. Here, we report the first description of anaerobic heme degradation by a Gram-positive bacterium, the opportunistic pathogenEnterococcus faecalis, and link activity of this enzyme to their ability to colonize and infect the host. We also show that homologues of this enzyme are found in many Gram-positive facultative anaerobes, implying that the ability to degrade heme under anaerobic conditions may be an overlooked fitness and virulence factor of bacterial pathogens.
Acute temporal, regional, and cell-type specific NKCC1 disruption following severe TBI in the developing gyrencephalic brain
Authors: Hochstetler Alexandra , Courtney Ya’el , Oloko Peace , Baskin Benjamin , Ding-Su Andrew , Stinson Tawny , McGuone Declan , Haynes Robin , Lehtinen Maria K. , Costine-Bartell Beth 
Published: January 2025

AbstractTraumatic brain injury (TBI) in children is a leading cause of morbidity and mortality, with no effective treatment and limited clinical management. We developed a multifactorial traumatic brain injury model in piglets which mirrors the evolving pathophysiology of severe pediatric TBI, showing age-dependent hypoxic-ischemic cerebral cortical injury and matrix metalloproteinase-driven vasogenic edema, with infant piglets experiencing less tissue damage than toddler piglets. Extracellular matrix breakdown can precipitate neuronal dysfunction, disrupting chloride homeostasis and the reversal potential for GABA. We hypothesized that ongoing tissue damage might be related to markers of “immature GABA”, evaluated by changes to the expression and phosphorylation of sodium-potassium-2-chloride cotransporter 1 (NKCC1), potassium-chloride cotransporter 2 (KCC2), and a regulatory kinase, (STE20/SPS1-related proline-alanine-rich protein kinase) SPAK. We mapped these markers in developing swine and infant human brain, identifying a postnatal pNKCC1 decrease in human infant hippocampus, and a perinatal cortical and hippocampal GABA switch in pigs, with no change in the thalamus. In infant piglets with severe TBI, upregulation of neuronal pNKCC1 correlated with hypoxic-ischemic injury and seizure duration. We also observed dysregulation of NKCC1, KCC2, and SPAK in cortex and hippocampus in infant and toddler piglets with severe TBI, with thalamus unchanged. We noted ectopic, non-apical localization of pNKCC1 signal in choroid plexus epithelium across ages in piglets and humans with severe TBI, indicating acute dysregulation of the CSF chloride milieu. These findings position swine as a useful model for pediatric TBI research and suggest that SPAK or NKCC1 inhibition in infants may be therapeutic.Significance statementSevere TBI in early childhood, the majority of which is due to abuse, remains an understudied area of neurotrauma. Our piglet model effectively replicates the pathophysiology of severe pediatric TBI, capturing age-dependent injury patterns and mechanisms of spreading hypoxic-ischemic injury throughout the cortical ribbon. We identified upregulation of neuronal-pNKCC1 in infant piglets, but not toddler piglets with severe TBI, and found this correlates with injury severity, seizure duration, and subarachnoid hemorrhage. Our findings indicate that treatments targeted to inhibit neuronal NKCC1 might alleviate evolving brain injury in infants with severe TBI. This model provides a valuable platform for studying mechanisms of TBI and testing new interventions, potentially advancing therapeutic strategies for pediatric brain injury where stopping traumatic seizures is difficult.
The complex interplay between microalgae and the microbiome in production raceways
Authors: Traver-Azuara Judith , Giner Caterina R. , García-Comas Carmen , Sánchez-Zurano Ana , Ciardi Martina , Acién Gabriel , Bondarenko Sofiya , Obiol Aleix , Massana Ramon , Sala Maria Montserrat , Logares Ramiro , Cermeño Pedro 
Published: January 2025

AbstractAlgae-associated microbiomes are underexplored, limiting our understanding of their influence on the productivity of large-scale microalgae reactors. To address this, we monitored microbial dynamics in two microalgae biomass production raceways over two 8-month intervals inoculated withDesmodesmus armatus. One reactor was fed with wastewater, while the other received clean water and fertilizers. Metabarcoding of the 18S and 16S rRNA genes revealed a high microbial diversity across two time series, showing thousands of eukaryotic and prokaryotic species growing alongside the microalgae. Chlorophyta and Fungi were the dominant eukaryotic groups, while Alphaproteobacteria, Gammaproteobacteria, Actinobacteria, and Bacteroidia dominated the prokaryotic communities. We found contrasting ASVs (Amplicon Sequence Variant) patterns between healthy (D. armatusabundance >70%) and unhealthy (D. armatusabundance <20%) microbiomes, across reactors and time series. Network analysis identified up to 10 potential ecological interactions amongD. armatusand its microbiome, predominantly positive. Our results suggest a link between microbiome composition andD. armatusabundance. Specifically, ASVs associated with a healthy microbiome were positively correlated withD. armatus, while ASVs characteristic of an unhealthy microbiome were negatively correlated. Potentially pathogenic bacteria includedMycobacteriumandFlavobacterium, whereas potentially beneficial taxa includedGeminocystis, Thiocapsa, AhniellaandBosea. Several fungal ASVs showed context-specific associations, whereas specificP. tribonemae,A. parallelum,A. desmodesmi,Aphelidiomycotasp., Rozellomycota sp. and,Rhizophidiumsp. ASVs were identified as potentially harmful. This study reveals the striking diversity and complexity of microalgae-associated microbiomes within raceways, providing valuable insights for optimizing industrial production processes, particularly for wastewater treatment and sustainable green biomass generation.Abstract FigureGraphical Abstract.General overview of the metabarcoding methodology. Step 1: Sample collection, 2: DNA extraction of the samples, 3: PCR and DNA sequencing of the 18S and 16S rRNA genes, 4: Processing and quality filtering of the DNA sequencing data, 5: Taxonomic, community, and network analyses and, 6: Interpretation and discussion of the results.