bluuebunny/crossref_metadata_2025_split huggingface dataset:
ASMS: finding allele specific methylation in human genomes without phasing
Authors: Raineri Emanuele , Esteve Marco Miguel Ángel , Esteve Codina Anna 
Published: December 2024

AbstractMotivationAllele-specific methylation (ASM) refers to differential DNA methylation patterns between two alleles at a given locus. This phenomenon is often driven by genetic variants, such as single nucleotide variants (SNVs), which influence methylation incisby affecting transcription factor or methylation regulator binding, leading to allele-specific differences. Understanding ASM is critical for elucidating gene regulation, as it impacts gene expression and contributes to normal biological variation as well as disease processes, including cancer [1] and autoimmune disorders [2],[3].Another key driver of ASM is genomic imprinting, an epigenetic mechanism in which gene expression is regulated in a parent-of-origin-specific manner. Imprinted regions, marked during gametogenesis and maintained through cell divisions, are essential for growth, development, and metabolism. Dysregulation of imprinting is associated with developmental and metabolic disorders, such as Prader-Willi and Angelman syndromes, and certain cancers.Detecting ASM across the genome remains challenging due to its tissue- and cell-specific nature and the technical difficulty of phasing reads to assign methylation patterns to specific alleles. Current ASM detection pipelines (e.g., [4])) often require phasing via genetic variants, a computationally intensive process that is limited in regions with low heterozygosity.ResultsTo address these limitations, we developed asms (Allele-Specific Methylation Scanner), a tool designed to detect ASM directly from methylation data without the need for prior phasing. asms offers a faster and complementary approach to uncovering the regulatory effects of ASM, particularly in genomic regions where genetic variants or imprinting play a critical role.For demonstration purposes we leverage the fact that reads generated by Oxford Nanopore (ONT) technology measure sequence and methylation status at once, but the same software can be used with other sequencing technologies.asmscan check thousands of loci in a short time. The initial list of loci to examine can be given by the user, or generated byasmsthrough a genomic scan. Theasms clustersubcommand separates the reads based on methylation.If phasing results are available,asmscan use them to verify whether distinct alleles correspond to distinct base modifications patterns. We benchmark our software using publicly available Ashkenazi trio data [5].Implementation and availabilityasmsis implemented inrustandpython. The software is available athttps://github.com/ecmra/asms.
Pharmacophore-guided de novo drug design with diffusion bridge
Authors: Wang Conghao , Rajapakse Jagath C. 
Published: December 2024

AbstractDe novodesign of bioactive drug molecules with potential to treat desired biological targets is a profound task in the drug discovery process. Existing approaches tend to leverage the pocket structure of the target protein to condition the molecule generation. However, even the pocket area of the target protein may contain redundant information since not all atoms in the pocket is responsible for the interaction with the ligand. In this work, we propose PharmacoBridge, a phamacophore-guidedde novodesign approach to generate drug candidates inducing desired bioactivity via diffusion bridge. Our method adapts the diffusion bridge to effectively convert pharmacophore arrangements in the spatial space into molecular structures under the manner ofSE(3) -equivariant transformation, providing sophisticated control over optimal biochemical feature arrangements on the generated molecules. PharmacoBridge is demonstrated to generate hit candidates that exhibit high binding affinity with potential protein targets.
Expanding the diversity of nitroxide-based paramagnetic probes conjugated to non-canonical amino acids for SDSL-EPR applications
Authors: Bizet Maxime , Balázsi Áron , Biaso Frédéric , Byrne Deborah , Etienne Emilien , Guigliarelli Bruno , Urban Philippe , Dorlet Pierre , Truan Gilles , Gerbaud Guillaume , Kálai Tamás , Martinho Marlène 
Published: December 2024

AbstractUnderstanding protein structure requires studying its dynamics, which is critical to elucidating its functional role. Over time, biophysical techniques have revolutionized this field, offering remarkable insights into the structure-function relationship. Among these, Site-Directed Spin Labelling (SDSL) combined with Electron Paramagnetic Resonance (EPR) is a powerful method delivering structural data at the residue level, irrespective of protein size or environment. Traditional nitroxide labels, which target cysteine residues, often face limitations when these residues are essential for protein structure or function. To address this, alternatives have been proposed as the use of non-canonical amino acids (ncaa) coupled with specific nitroxide labels. This study introduces14N-HO-5223, a novel nitroxide label specific to thepAzPhe ncaa, alongside its15N-derivative. These labels were grafted at two sites of the model protein, the diflavin Cytochrome P450 reductase. For comparative purpose, two already reported labels were also used. Continuous wave (cw) EPR spectroscopy validated the HO-5223 label as an effective reporter of protein dynamics. Additionally, Double Electron-Electron Resonance (DEER) measurements provided distance distributions between the semi-quinone FMNH•state of the CPR and all nitroxide labels. These results expand the toolkit of the ncaa-nitroxide pairs, enabling EPR-based structural studies of proteins where cysteine modification is impractical, further advancing our ability to decode protein dynamics and function.
Microphysiological uremia model reveals biophysical potentiators of vascular dysfunction
Authors: Rathod Mitesh , Huang Stephanie A. , Aw Wen Yih , Doherty Elizabeth L. , Meehan Sara M. , Roy-Chaudhury Prabir , Polacheck William J. 
Published: December 2024

AbstractCardiovascular disease is a leading cause of mortality in individuals with chronic kidney disease. Hypertension, common among patients with chronic kidney disease, is a major contributor to both kidney damage and the heightened cardiovascular risk in these patients. Advanced chronic kidney disease is associated with elevated levels of circulating uremic toxins, particularly indoxyl sulfate and p-cresyl sulfate, and are known to exacerbate cardiovascular risk by promoting inflammatory processes, including monocyte adhesion, rolling, and extravasation. However, despite the established link between chronic kidney disease and cardiovascular disease, the specific role of uremic toxins in monocyte-endothelial interactions in hypertensive settings remains largely underexplored. In this study, we developed a 3D microfluidic model to examine the effects of indoxyl sulfate on monocyte adhesion and extravasation across engineered microvessels embedded in collagen hydrogels with different densities under controlled luminal pressure. We found that elevated pressure alone significantly enhanced monocyte adhesion and extravasation, regardless of matrix density, and that the uremic environment further increased these effects. Additionally, denser hydrogels primed THP-1 monocyte cells toward a pro-inflammatory like phenotype with reduced phagocytic capacity, while softer hydrogels induced an anti-inflammatory like phenotype with enhanced phagocytosis. However, exposure to the uremic environment diminished phagocytosis and shifted cells toward a pro-inflammatory like state, irrespective of matrix density. The presented approach has the potential to experimentally dissect multiple factors that contribute to elevated cardiovascular risks in chronic kidney disease patients and improve the understanding of mechanisms involved in monocyte dynamics in chronic kidney disease- related cardiovascular disease.
Sex-dependent influence of major histocompatibility complex diversity on fitness in a social mammal
Authors: Schubert Nadine , Nichols Hazel J. , Mwanguhya Francis , Businge Robert , Kyambulima Solomon , Mwesige Kenneth , Hoffman Joseph I. , Cant Michael A. , Winternitz Jamie C. 
Published: December 2024

AbstractParasite infections affect males and females differently across a wide range of species, often due to differences in immune responses. Generally, females tend to have stronger immune defenses and lower parasite loads than males. The major histocompatibility complex (MHC) plays a crucial role in the adaptive immune response, and extensive research has explored how variation in this region influences infection and fitness outcomes. However, studies of sex-specific relationships between MHC variation and infection are scarce, perhaps because MHC genes are located on the autosomes, which are shared by both sexes. Here, we provide evidence of sexually antagonistic selection in a wild, group-living mammal—the banded mongoose. Using genetic and life history data collected from over 300 individuals across 25 years, we found that particularly MHC class I (MHC-I) but also MHC class II (MHC-II) diversity influence lifetime reproductive success differently in males and females. Specifically, higher MHC diversity is linked to increased fitness in males but decreased fitness in females. Furthermore, MHC diversity did not differ between the sexes, indicating an unresolved genetic sexual conflict. Our findings demonstrate that sexually antagonistic selection acts on the MHC and may operate across both MHC classes but differently. This study contributes to the growing body of evidence that sex is a significant factor in shaping host immunity and fitness.
Unveiling unique metabolomic and transcriptomic profiles in three Brassicaceae crops
Authors: Zhang Liyong , Parkin Isobel A. P. 
Published: December 2024

AbstractBrassica napus,Camelina sativaand field pennycress (Thlaspi arvense), represent one highly economically valuable crop and two emerging oilseed crops of the Brassicaceae family, respectively. As sessile organisms, these crops are continuously exposed to various stresses when grown in the field. Interestingly, the responses of these three crops to different environmental stimuli vary to a great extent, but there is very limited knowledge about the molecular basis of these differential responses. In this study, we employed untargeted metabolomics to compare the metabolic profile of these crops, and examined the potentially related genes through further integration with transcriptomic analysis. Our data revealed distinctive overall metabolic profiles among these three crops, where in particular, a variety of phenylpropanoids showed differential accumulation and the corresponding putative genes’ expression varied significantly. The results provide a valuable resource for those studying Brassicaceae species and will provide insight into the understanding of metabolic variation among these three important oilseed crops, and provide potential targets for the future breeding of stress tolerant crops.
Association between surgical aortic valve replacement and long-term outcomes in 50 to 65-year-olds: Results of the AUTHEARTVISIT study
Authors: Florian A. , Auer J. , Reichardt B. , Krotka P. , Wagenlechner C. , Wendt R. , Mildner M. , Mascherbauer J. , Ankersmit HJ , Zimpfer D. , Graf A. 
Published: December 2024

AbstractObjectivesDuring the last years, age recommendations for the use of biological prostheses rather than mechanical prostheses for surgical aortic valve replacement (sAVR) have been lowered considerably. We evaluated survival rates, major adverse cardiac events (MACEs), and reoperation risks after surgical (sM-AVR) and biological (sB-AVR) AVR, to provide data for the optimal prosthesis choice for middle aged patients between 50 and 65 years.MethodsWe performed a population-based cohort study using Austrian Health System data from 2010–2020. Patients undergoing isolated sAVR (n=3761) were categorized into sM-AVR (n=1018) and sB-AVR (n=2743) groups. Propensity score matching (PSM) was applied to balance covariates. The primary endpoint was all-cause mortality. Secondary endpoints included MACEs, reoperation, stroke, bleeding, and survival post-reoperation. Outcomes were assessed using Cox regression and Kaplan-Meier analyses.ResultsPatients undergoing sM-AVR had significantly lower all-cause mortality compared to sB-AVR (HR=1.352, p=0.003). sB-AVR was associated with higher risks of MACEs (HR=1.182, p=0.03) and reoperation (HR=2.338, p=0.002). Stroke and bleeding rates were comparable. All results were sustained after PSM.ConclusionThe findings highlight increased mortality, MACEs and reoperation risks associated with sB-AVR compared to sM-AVR. We observed superior long-term outcomes after sM-AVR, suggesting the need to reevaluate the expanding use of sB-AVR in younger patients.Graphical Abstract
Vaccine Confidence and Intention-to-Vaccinate Children against COVID-19 among Parents in Mysore, India: Insights from the BeSD Framework
Authors: Muralidhar Kiranmayee , Ngaybe Maiya G Block , Nanjaiah Shivamma , Pope Benjamin , Coursey Kate , Jaykrishna Poornima , Ningaiah Nagalambika , Edwards Todd L. , Edwards Digna R. Velez , Madhivanan Purnima , Somaiya Devanshi , Krupp Karl 
Published: December 2024

AbstractBackgroundIndia rolled out COVID-19 vaccinations for adults in January 2021 and children aged 12-18 in early 2022. A 2021 survey indicated that 63% of Indian parents were willing to vaccinate their children against COVID-19, with few studies examining vaccine hesitancy and acceptability. The the Behavioral and Social Drivers of Vaccination (BeSD) framework helps demonstrate which factors may affect vaccination uptake. Our study examined parents’ intentions-to-vaccinate their children below 18 years of age against COVID-19 in Mysore, India and their decision-making process using the BeSD framework.MethodsFrom November 2021 to May 2022, 506 parents/guardians of children below 18 years of age living in Mysore district, India were consented and interviewed by phone or face-to-face. We assessed their own COVID-19 vaccination status, vaccine confidence (Vaccine Confidence Index), intention-to-vaccinate their child against COVID-19, and other factors affecting vaccination such as demographic variables. Multivariable ordinal logistic regression was conducted to examine the association of influencing factors based on the literature and BeSD framework using Stata version 16.1. Intention-to-vaccinate was presented as odds ratios (OR) with associated 95% confidence intervals (95%CI).ResultsThe majority (91.3%) of the 503 participants fully trusted COVID-19 vaccines for their children. The same number (91.3%) had been fully vaccinated themselves, and 78.3% reported being (very) likely to vaccinate their children against COVID-19. Vaccine-hesitant and vaccine-confident groups were not significantly different socio-demographically. As parental age increased, parents had higher odds to express intention-to-vaccinate their child (OR: 1.04, 95%CI: 1.01-1.08). Parents from urban Mysore had lower odds to vaccinate their child compared to those from rural areas (OR: 0.53, 95%CI: 0.35-0.82).ConclusionMost parents expressed vaccine confidence and intention-to-vaccinate their child against COVID-19. Exploring decision-making processes among parents is a crucial strategy to ensure effective implementation of vaccination programs.
Characterising Representations of Hue and Saturation in the Cortex Using Information Decoding
Authors: Rozman Ana , Chauhan Tushar , Martinovic Jasna 
Published: December 2024

ABSTRACTOne of the enduring questions in the field of colour vision research revolves around how features of colour appearance, such as hue and saturation are represented in the brain. While considerable progress has been made in understanding the transformation of physical colour signals during early processing stages, the mechanisms by which these signals are recombined in later processing, ultimately giving rise to our perceptual experience of colour, remain elusive. A promising avenue for capturing these representations involves decoding from EEG signals. We captured EEG signals in response to 8 evenly spaced isoluminant colours at two saturation levels, taken from a perceptually uniform CIE Lab colour space. Surprisingly, our main finding challenges the expectation that representations of colours that are perceptually more similar elicit more similar signals. Instead, our results show that isoluminant hues perceived as maximally dissimilar tend to evoke the most similar EEG signals, which is in line with predictions derived from opponent theory. Additionally, decoding performs better for lower saturation than for higher saturation hues, contrary to expectations that more distinct hue representations would be associated with highly saturated hues but in line with prediction of magnified differences in latency and amplitude of EEG signals between low-level opponent mechanisms at lower contrast levels. Finally, our findings also highlight the non- uniformity of the cortical representation space for isoluminant colour, indicating that neighbouring hues exhibit varying degrees of similarity. Put together, the results show that low-level features, such as contrast and cone-opponency, drive the EEG response to colour.
Chemogenetic tuning reveals optimal MAPK signaling for cell-fate programming
Authors: Lende-Dorn Brittany A. , Atkinson Jane C. , Bae Yunbeen , Galloway Kate E. 
Published: December 2024

AbstractCell states evolve through the combined activity of signaling pathways and gene regulatory networks. While transcription factors can direct cell fate, these factors rely on a cell state that is receptive to transitions in cell identity. How signaling levels contribute to the emergence of receptive cell states remains poorly defined in primary cells. Using a well-defined model of direct conversion, we examined how levels of the MAPK-activating oncogene HRASG12Vinfluence direct conversion of primary fibroblasts to induced motor neurons. We demonstrate that an optimal ‘Goldilocks’ level of MAPK signaling efficiently drives cell-fate programming. Rates of direct conversion respond biphasically to increasing HRASG12Vlevels. While intermediate HRASG12Vlevels increase the rate of conversion, high levels of HRASG12Vinduce senescence. Through chemogenetic tuning, we set optimal MAPK activity for high rates of conversion in the absence of HRAS mutants. As MAPK pathways influence cell-fate transitions in development and disease, our results highlight the need to tune therapeutic interventions within a non-monotonic landscape that is shaped by genetics and levels of gene expression.HighlightsMAPK signaling drives proliferation and conversion of fibroblasts to motor neuronsCell-fate programming responds biphasically to HRASG12VexpressionHigh HRASG12Vexpression induces senescence, which reduces conversionChemogenetic tuning of MAPK activity increases conversion ratesA small-molecule MAPK inducer drives high rates of conversion in the absence of HRASG12V
Investigating the performance of Oxford Nanopore long-read sequencing with respect to Illumina microarrays and short-read sequencing
Authors: Santos Renato , Lee Hyunah , Williams Alexander , Baffour-Kyei Anastasia , Breen Gerome , Iacoangeli Alfredo 
Published: December 2024

AbstractOxford Nanopore Technologies (ONT) long-read sequencing (LRS) has emerged as a promising tool for genomic analysis, but comprehensive comparisons with established platforms across diverse datasets remain limited. In this study, we present a comprehensive comparison of ONT long-read sequencing (LRS) against Illumina short- read sequencing (SRS) and microarray platforms across 14 human genomes.We performed ONT sequencing using both multiplexed and singleplexed approaches and compared the results with matched Illumina microarray and SRS data. We assessed sequencing quality metrics, variant detection performance for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), while examining the impact of sequencing depth, read length, and multiplexing.ONT LRS demonstrated competitive performance with SRS for SNV detection, particularly in low complexity regions (F-measure: 0.763 vs 0.770), though with slightly lower performance in high complexity regions (F-measure: 0.954 vs 0.968). For indel detection, LRS showed robust performance in high complexity regions (F-measure: 0.850) which, however, decreased in low complexity regions (F-measure: 0.453). LRS identified 2.82 times more structural variants than SRS and detected variants across a broader size range (8 bp to 129 Mb vs 2 bp to 6 kb). Sequencing depth strongly correlated with variant calling performance across all variant types, with correlation coefficients of 0.80 for SNVs in high complexity regions, 0.84 for SNVs in low complexity regions, and exceeding 0.9 for indels. SV detection in LRS showed strong depth dependence (r = 0.939), while SRS SV calls remained stable across depths.Our findings demonstrate that ONT LRS complements existing sequencing technologies, offering advantages in detecting structural variants and analysing low complexity regions, while maintaining competitive performance in standard variant detection. This study provides practical insights for optimising ONT sequencing strategies and highlights areas for future methodological improvement.
Cardiac Pacemaker Cells Harness Stochastic Resonance to Ensure Fail-Safe Operation at Low Rates Bordering on Sinus Arrest
Authors: Okamura Akihiro , He Isabella K , Wang Michael , Maltsev Alexander V , Maltsev Anna V , Stern Michael D , Lakatta Edward G , Maltsev Victor A 
Published: December 2024

ABSTRACTBACKGROUNDThe sinoatrial node (SAN) is primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials (APs) that exit the SAN emerge from heterogeneous signals, including subthreshold signals in non-firing (dormant) cells. This sets up a new problem in cardiac biology of how these signals contribute to heartbeat generation. Here we tested a hypothesis that pacemaker cells harness stochastic resonance to ensure their fail-safe operation, especially at low rates bordering on sinus arrest.METHODSWe measured membrane potential and Ca signals in SAN cells isolated from rabbit hearts in response to external currents in the form of sine waves or white noise. Protocols were applied via a perforated patch while cells were either in the basal state or in the presence of cholinergic receptor stimulation. Additionally, we performed multiscale model simulations at respective sub-cellular, cellular, and tissue levels.RESULTSNoise currents awakened dormant cells to fire APs and substantially improved the rate and rhythm of cells firing infrequent, dysrhythmic APs. Rhythmic AP generation in response to applications of sine wave currents of different frequencies outlined a resonance spectrum in SAN cells: their capability of responding, via stochastic resonance, to specific frequency components embedded in the noise. Cholinergic stimulation shifted the resonance spectrum towards lower frequencies, i.e. cells responded to lower frequency signals but could not process higher frequency signals. Noise currents added to SAN single cell– and tissue-models substantially expanded the parametric space of AP firing beyond the bifurcation line where cells failed to operate without noise. Both the numerical models and our simultaneous recordings of membrane potential and Ca dynamics also demonstrated that stochastic resonance in SAN cells is amplified by coupled electrical and Ca signaling, enhancing AP generation at low noise levels.CONCLUSIONSSAN cells harness stochastic resonance amplified by coupled membrane-Ca signaling to ensure rhythmic heartbeat initiation especially at low rates, providing a last-resort signaling mechanism to avoid sinus arrest when signal synchronization decreases but noise substantially increases, such as during strong parasympathetic stimulation, disease or aging when the heart slows and high-frequency signaling wanes.