bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gradient Oriented Active Learning for Candidate Drug Design
Authors: Medabalimi Venkatesh 
Published: July 2024

AbstractOne of the primary challenges of drug design is that the complexity of Biology often comes to the fore only when proposed candidates are eventually tested in reality. This necessitates making the discovery process more efficient by making itactively seek what it wants to know of reality. We propose Gradient Oriented Active Learning (GOAL), a technique for optimizing sequence design through active exploration of sequence space that interleaves performing experiments and learning models that propose experiments for the next iteration through gradient based descent in the sequence space. We demonstrate the promise of this method using the challenge of mRNA design as our guiding example. Using computational methods as a surrogate for experimental data, we provide evidence that for certain objectives, if one were restricted by the bandwidth or the number of experiments they can perform in parallel, increasing the number of iterations can still facilitate optimization using very few experiments in total. We show that availability of high-throughput experiments can considerably bring down the number of iterations required. We further investigate the intricacies of performing multi-objective optimization using GOAL.
Performance of three diagnostic tests for tuberculosis among Human Immunodeficiency Virus (HIV) patients presenting to a health facility in an informal urban settlement in Nairobi, Kenya
Authors: Ochola Eunita A. , Mweu Marshal M. 
Published: July 2024

AbstractThe absence of an accurate reference test complicates the evaluation of tuberculosis (TB) diagnostic tests among people living with Human Immunodeficiency Virus (PLWHIV). The objective of this study was to estimate (using Bayesian latent class models [BLCM]) the sensitivity (Se), specificity (Sp) and negative and positive predictive values (NPV and PPV) of sputum smear microscopy (SSM), Xpert Ultra and lipoarabinomannan antigen (LAM) tests for TB among PLWHIV in Nairobi, Kenya.This cross-sectional study enrolled a total of 190 patients aged ≥ 18 years with presumptive TB seeking treatment at the Kibra Community Health Center Comprehensive Care Centre (CCC) clinic between September 2022 and March 2023. The diagnostic data obtained from the three tests were analysed using a BLCM framework to derive accuracy estimates of the three diagnostic tests.The Xpert Ultra assay registered a higher Se (85.0; 95% PCI [41.4 – 99.4]) compared to LAM (26.8; 95% PCI [4.7 – 67.6]) and SSM (56.7 [16.4 – 97.4]). However, SSM had the highest Sp (99.6; 95% PCI [97.7 – 100.0]). The Xpert Ultra assay yielded the highest overall combination of Se and Sp at 80.8% (95% PCI [37.0 – 96.5]). On predictive values, SSM recorded the highest PPV at 84.5% (95% PCI [38.4 – 99.4]). Nonetheless, all the tests exhibited noticeably high NPVs (>96%).An optimal testing approach in this low-prevalence TB setting could entail an initial screening with the more sensitive Xpert Ultra test, with any resultant positives retested with the more specific SSM test - a two-test serial testing strategy.
Investigating the effects of transcutaneous Vagus Nerve Stimulation on motor cortex excitability and inhibition through paired-pulse Transcranial Magnetic Stimulation
Authors: Sara Boscarol , Letizia Turchi , Viola Oldrati , Cosimo Urgesi , Alessandra Finisguerra 
Published: July 2024

AbstractTranscutaneous Vagus Nerve stimulation (tVNS) has been proposed as a prospective treatment for clinical conditions with altered GABAergic transmission. While possible effects of tVNS on behavioral performance in inhibitory control tasks have been previously reported, neurophysiological evidence showing its effects on GABA-mediated inhibition in the motor cortex is limited. Concurrently, the possible influence of participant’s gender and state conditions remains unexplored. Here, we applied, single- and paired-pulse TMS to the right or the left primary motor in two different groups of participants. We measured corticospinal excitability (CSE), short and long intracortical inhibition (SICI and LICI), cortical silent period (cSP) and intracortical facilitation (ICF) indexes. The measures were taken, in separated sessions of a within-subject design, at baseline prior to tVNS and after delivering active and sham tVNS in the Cymba conchae of the left ear. To exploit state dependent effects and assess the role of tVNS in motor learning, tVNS was applied, during the execution of a computerized visuomotor task. In the left TMS group, we observed better visuomotor performance during active than sham tVNS, regardless of participant’s gender. Interestingly, in both groups, we found a specific increase of SICI, which is mediated by GABAa activity, after active compared to sham-tVNS and baseline evaluations, which was specifically limited to female participants. No effects on CSE, ICF or GABAb-mediated intracortical inhibition indexes were observed. The results show specific effects of tVNS on motor learning and GABAa-mediated motor inhibition, providing supportive evidence for the application of tVNS as an alternative and coadjuvant treatment for disorders featured by altered inhibition mechanisms.
TCMNP: a data processing and visualization database and R package for traditional Chinese medicine network pharmacology
Authors: Liu Jinkun , Feng Jing , Wu Bin , Ying Min 
Published: July 2024

AbstractBackgroundNetwork pharmacology is pivotal for the study of the mechanism of action of traditional Chinese medicine (TCM). However, there are currently some challenges in data processing and visualization for traditional Chinese medicine network pharmacology (TCMNP). We develop the R-environment-based software database and package TCMNP.MethodsTCMNP is designed for the analysis and visualization of compositions in TCM compounds, herbs, ingredients, corresponding targets and pathway enrichment. Data analysis and visualization in R using “dplyr”, “clusterProfiler”, “ggplot2”, and “circlize” packages, as well as functions of our own making.ResultsTCMNP is designed for the analysis and visualization of compositions in TCM compounds, herbs, ingredients, corresponding targets and pathway. The TCMNP database contains 571 kinds of TCM herbs, 17,118 ingredients, 10,013 diseases, and 15,956 targets. TCMNP simplifies the data analysis process and realizes a complete set of process operations from Chinese herbal compound composition, component and target automatic screening, enrichment analysis visualization, protein interaction and TF and target gene screening. Its built-in functions of various types provide a tidy interface for the visualization of TCM network pharmacology. TCMNP database is freely available athttps://tcmlab.top/tcmr. TCMNP package is freely available athttps://github.com/tcmlab/TCMNP.ConclusionThe TCMNP database and package provide a comprehensive overview of the interconnections between components of a TCM compound and its potential effects on disease treatment. TCMNP database is available for free athttps://tcmlab.top/tcmr/. TCMNP package is available for free athttps://github.com/tcmlab/TCMNP. We anticipate that TCMNP will help to explore the mechanism of TCM to treat diseases.
Neuron loss in the brain starts in childhood, increases exponentially with age and is halted by GM-CSF treatment in Alzheimer’s disease
Authors: Sillau Stefan H. , Coughlan Christina , Ahmed Md. Mahiuddin , Nair Kavita , Araya Paula , Galbraith Matthew D. , Bettcher Brianne M. , Espinosa Joaquin M. , Chial Heidi J. , Epperson Neill , Boyd Timothy D. , Potter Huntington 
Published: July 2024

SummaryAging increases the risk of neurodegeneration, cognitive decline, and Alzheimer’s disease (AD). Currently no means exist to measure neuronal cell death during life or to prevent it. Here we show that cross-sectional measures of human plasma proteins released from dying/damaged neurons (ubiquitin C-terminal hydrolase-L1/UCH-L1 and neurofilament light/NfL) become exponentially higher from age 2-85; UCH-L1 rises faster in females. Glial fibrillary acidic protein (GFAP) concentrations, indicating astrogliosis/inflammation, increase exponentially after age 40. Treatment with human granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) halted neuronal cell death, as evidenced by reduced plasma UCH-L1 concentrations, in AD participants to levels equivalent to those of five-year-old healthy controls. The ability of GM-CSF treatment to reduce neuronal apoptosis was confirmed in a rat model of AD. These findings suggest that the exponential increase in neurodegeneration with age, accelerated by neuroinflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment.
Molecular Landscape of Modality-Specific Exercise Adaptation in Human Skeletal Muscle through Large-Scale Multi-OMICs Integration
Authors: Jacques Macsue , Landen Shanie , Sharples Adam P , Garnham Andrew , Schittenhelm Ralf , Stele Joel , Heikkinen Aino , Sillanpää Elina , Ollikainen Miina , Broatch James , Zarekookandeh Navabeh , Hanson Ola , Ekström Ola , Asplund Olof , Lamon Séverine , Alexander Sarah E. , Smith Cassandra , Bauer Carlie , Woessner Mary N. , Levinger Itamar , Teschendorff Andrew E , Gillberg Linn , Blom Ida , Wulff Helge Jørn , Harvey Nicholas R , Haupt Larisa M , Griffiths Lyn R , Deshmukh Atul S. , Pietiläinen Kirsi H , Piirilä Päivi , Seaborne Robert AE , Jones-Freeman Bernadette , Eynon Nir 
Published: July 2024

SummaryWe conducted a large-scale, statistically powered, meta-analysis of exercise adaptations in human skeletal muscles, integrating epigenetic, transcriptomic, transcription factors, and proteomic data across 12 independent cohorts comprising over 1000 participants and 2340 human muscle samples. Our study identified distinctive signatures associated with maximal oxygen consumption (VO2max), and identified five genes robustly intersecting multi-OMIC layers. Notably, transcription factors predominantly functioned as activators across these layers, regulating expression of target genes irrespective of whether DNA methylation levels were low or high, indicating a synergistic effect between TFs and the methylome. Analysis of distinct exercise modalities (aerobic and resistance exercise) revealed unique gene pathways, contrasting with patterns observed in inactivity (muscle disuse) studies. These findings offer a comprehensive understanding of exercise and modality-specific adaptations, shedding light on muscle health and the molecular mechanisms associated with cardiorespiratory fitness, aging, and disease prevention.
Mutational and evolutionary dynamics of non-structural and spike proteins from variants of concern (VOC) of SARS-CoV-2 in India
Authors: Chaudhuri Ankur , Das Subhrangshu , Chakrabarti Saikat 
Published: July 2024

AbstractMonitoring the genetic diversity and emerging mutations of SARS-CoV-2 still remains to be crucial in India. This study extensively analyzes the lineage dynamics, mutation screening, structural analysis, and phylodynamics of SARS-CoV-2 variants of concern (VOC) in India from October 2020 to September 2023. Predominant variants identified include alpha, beta, delta, and omicron, with delta and omicron making up 76.05% of sequenced genomes. The B.1.617.2 lineage of delta was the major contributor to COVID-19 cases before the rapid rise of omicron. Mutation screening of non-structural proteins (NSPs) and spike revealed distinct profiles for each VOC. Co-mutation patterns/networks of the most frequently observed mutations specific for each VOC were also identified and subsequently structural and energetic alteration of the co-mutants were analyzed using rigorous molecular dynamics simulations. Furthermore, comparative analysis of phylogenetic trees based on genomic and mutational data revealed that nsp1, nsp3, nsp4, nsp13, and nsp14 exhibit strongest association with the increased mutation load across the genome of SARS-CoV-2 in Indian population. Our comparative phylogenetic study also revealed that mutability patterns of nsp14 and spike have highest similarity supporting critical role of nsp14 for SARS-CoV-2 infectivity and persistence. This research provides a comprehensive overview of SARS-CoV-2 evolution in India.
Retinal pigment epithelial cells reduce vascular leak and proliferation in retinal neovessels
Authors: Tzaridis Simone , Aguilar Edith , Dorrell Michael I , Friedlander Martin , Eade Kevin T 
Published: July 2024

AbstractRetinal pigment epithelial (RPE)-cells possess numerous functions and may respond to stress and damage of the neuroretina. In different neurodegenerative diseases, including age-related macular degeneration (AMD), retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), RPE-cells have been shown to proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Though pigmentary changes are associated with disease progression, it is not known if their presence is protective or detrimental. In this study, we evaluated the impact of pigment plaques on vascular changes and disease progression in patients with macular telangiectasia type 2 (MacTel), an example of a progressive neurodegenerative retinal disease. We then studied underlying pathomechanisms using a mouse model mirroring these changes, the very-low-density lipoprotein receptor mutant (Vldlr–/–) mouse.In a retrospective, longitudinal study, we analyzed multimodal retinal images of patients with MacTel and showed that pigment plaques were associated with a decrease in vascular leakage and stabilized neovascular growth. Using genetic approaches, we analyzed changes in expression levels of relevant genes in the RPE and retinas of Vldlr-/- mice during RPE-proliferation and migration. Our data indicated that RPE-cells transitioned from an epithelial to a mesenchymal state (“epithelial-mesenchymal transition”, EMT), proliferated and accumulated along neovessels. Using dextran angiography and immunofluorescence, we demonstrated that the perivascular accumulation of RPE-cells reduced vascular leakage. Pharmacologic inhibition of EMT led to a decrease in pigment coverage and exacerbation of neovascular growth and exudation.Our findings indicate that the proliferation, migration and perivascular accumulation of RPE-cells may stabilize vascular proliferation and exudation, thereby exerting a protective effect on the diseased retina. We conclude that interfering with this “natural repair mechanism” may have detrimental effects on the course of the disease and should thus be avoided.
Post-Mortemvalidation ofin vivo18kDa Translocator Protein (TSPO) PET as a microglial biomarker
Authors: Wijesinghe Sasvi S. , Rowe James B. , Mason Hannah D. , Allinson Kieren S. J. , Thomas Reuben , Vontobel Davi , Fryer Tim D. , Hong Young T. , Bacioglu Mehtap , Spillantini Maria Grazia , Van den Ameele Jelle , O’Brien John T. , Kaalund Sanne , Malpetti Maura , Quaegebeur Annelies 
Published: July 2024

AbstractNeuroinflammation is a feature of many neurodegenerative diseases, and can be quantifiedin vivoby PET imaging with radioligands for the translocator protein (TSPO, e.g. [11C]-PK11195). TSPO radioligand binding correlates with clinical severity and predicts clinical progression. However, the cellular substrate of altered TSPO binding is controversial and requires neuropathological validation.We used progressive supranuclear palsy (PSP) as a demonstrator condition, to test the hypothesis that [11C]-PK11195 PET reflects microglial changes. We included people with PSP-Richardson’s syndrome who had undergone [11C]-PK11195 PET in life. Inpost-mortembrain tissue from the same participants we characterised cell-type specific TSPO expression with double-immunofluorescence labelling and quantified microgliosis in eight cortical and eleven subcortical regions with CD68 immunohistochemistry.Double-immunofluorescence labelling for TSPO and cell markers showed TSPO expression in microglia, astrocytes, and endothelial cells. Microglial TSPO expression was higher in donors with PSP compared to controls, which was not the case for astrocytic TSPO expression. There was a significant positive correlation between regional [11C]-PK11195 binding potentialante-mortemand the density ofpost-mortemCD68+ phagocytic microglia, as well as microglial TSPO expression.We conclude that [11C]-PK11195 bindingin vivois driven by microglia and can be interpreted as a biomarker of microglia-mediated neuroinflammation in tauopathies.
Enhanced Gut Microbiome Capacity for Amino Acid Metabolism is associated with Peanut Oral Immunotherapy Failure
Authors: Özçam Mustafa , Lin Din L. , Gupta Chhedi L. , Li Allison , Wheatley Lisa M. , Baloh Carolyn H. , Sanda Srinath , Jones Stacie M. , Lynch Susan V. 
Published: July 2024

AbstractPeanut Oral Immunotherapy (POIT) holds promise for remission of peanut allergy, though treatment is protracted and successful in only a subset of patients. Because the gut microbiome is linked to food allergy, we sought to identify fecal microbial predictors of POIT efficacy and to develop mechanistic insights into treatment response. Longitudinal functional analysis of the fecal microbiome of children (n=79) undergoing POIT in a first double-blind, placebo-controlled clinical trial, identified five microbial-derived bile acids enriched in fecal samples prior to POIT initiation that predicted treatment efficacy (AUC 0.71). Failure to induce disease remission was associated with a distinct fecal microbiome with enhanced capacity for bile acid deconjugation, amino acid metabolism, and increased peanut peptide degradationin vitro. Thus, microbiome mechanisms of POIT failure appear to include depletion of immunomodulatory secondary bile and amino acids and the antigenic peanut peptides necessary to promote peanut allergy desensitization and remission.
Genetic surveillance reveals low, sustained malaria transmission with clonal replacement in Sao Tome and Principe
Authors: Chen Ying-An , Ng Peng-Yin , Garcia Daniel , Elliot Aaron , Palmer Brian , Assunção Carvalho Ronalg Mendes Costa d’ , Tseng Lien-Fen , Lee Cheng-Sheng , Tsai Kun-Hsien , Greenhouse Bryan , Chang Hsiao-Han 
Published: July 2024

AbstractDespite efforts to eliminate malaria in Sao Tome and Principe (STP), cases have recently increased. Understanding residual transmission structure is crucial for developing effective elimination strategies. This study collected surveillance data and generated amplicon sequencing data from 980 samples between 2010 and 2016 to examine the genetic structure of the parasite population. The mean multiplicity of infection (MOI) was 1.3, with 11% polyclonal infections, indicating low transmission intensity. Temporal trends of these genetic metrics did not align with incidence rates, suggesting that changes in genetic metrics may not straightforwardly reflect changes in transmission intensity, particularly in low transmission settings where genetic drift and importation have a substantial impact. While 88% of samples were genetically linked, continuous turnover in genetic clusters and changes in drug-resistance haplotypes were observed. Principal component analysis revealed some STP samples were genetically similar to those from Central and West Africa, indicating possible importation. These findings highlight the need to prioritize several interventions such as targeted interventions against transmission hotspots, reactive case detection, and strategies to reduce the introduction of new parasites into this island nation as it approaches elimination. This study also serves as a case study for implementing genetic surveillance in a low transmission setting.
The Relationship between Noise Pollution and Depression and Implications for Healthy Ageing: A Spatial Analysis using Routinely Collected Primary Care Data
Authors: Tsimpida Dialechti , Tsakiridi Anastasia 
Published: July 2024

AbstractEnvironmental noise is a significant public health concern, ranking among the top environmental risks to citizens’ health and quality of life. Despite various studies exploring the effects of atmospheric pollution on mental health, spatial investigations into the effects of noise pollution have been notably absent. This study addresses this gap by investigating the association between noise pollution (from road and rail networks) and depression for the first time in England and first explores localised patterns based on area deprivation. Depression prevalence, defined as the percentage of patients with a recorded depression diagnosis was calculated in small areas within Cheshire and Merseyside ICS using the Quality and Outcomes Framework Indicators dataset for 2019. Strategic noise mapping for rail and road noise (LDEN) was employed to quantify noise pollution, indicating a 24-hour annual average noise level with distinct weightings for evening and night periods. The English Index of Multiple Deprivation (IMD) was utilised to represent neighbourhood deprivation. Geographical Weighted Regression and Generalised Structural Equation Spatial Modelling (GSESM) were applied to estimate relationships between transportation noise, depression prevalence, and IMD at the Lower Super Output Area (LSOA) level. While transportation noise showed a low direct effect on depression levels in Cheshire and Merseyside ICS, it significantly mediated other factors linked to depression prevalence. Notably, GSESM revealed that health deprivation and disability was strongly associated (0.62) with depression through the indirect effect of environmental noise, particularly where transportation noise exceeds 55 dB on a 24-hour basis. Comprehending variations in noise exposure across different areas is paramount. This research not only provides valuable insights for informed decision-making but also lays the groundwork for implementing noise mitigation measures. These measures are aimed at addressing mental health inequalities, enhancing the quality of life for the exposed population and supporting a healthier ageing process in urban environments. The findings also carry crucial implications for public health, specifically in tailoring targeted interventions to mitigate noise-related health risks in areas where noise burdens exceed 55 dB, and residents may experience health deprivation and disability.