bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of 5mC within heterogenous tissue usingde-novosomatic mutations
Authors: Wilcox Justin Jon Schader , Foucault Quentin Jean Robert , Gossmann Toni Ingolf 
Published: June 2024

AbstractTissues represent a fundamental evolutionary interface at the junction of genotype and phenotype. Indeed, gene regulation often occurs at the tissue level and manifests itself through tissue-specific epigenetic modifications. Studies investigating tissue epigenetics are limited by access to pure tissues. Tissues not only differ epigenetically, they are also subject to genetic differentiation through somatic mutations. As somatic mutations follow predictable patterns of inheritance, the application of population genomic approaches to inter- and intra-tissue variation could allow for the efficient detection of epigenetic modifications, even when tissue samples are convoluted. Here, we present an approach that usesde-novosomatic mutations to deconvolute 5mC methylation patterns through analysis of shifts in tissue-specific allele frequencies. We use simulations and bisulfite sequencing data to show that somatic mutations are common and detectable in next-generation sequencing data. We then use changes in mutation frequencies to accurately derive the proportional tissue of origin along a gradient ofin silicosubsamples of mixed-tissue bisulfite reads. We confirm that mixed tissues bias estimates of methylation levels and prevent detection of methylation differences at high levels of mixture. Our derived estimates of tissue contamination allow for unbiased and accurate deconvolution of mixed-tissue methylations in CpG and non-CpG context. We are ultimately able to recover 15-30% of differentially-methylated sites, and approximately 40-90% of differentially-methylated CpG islands and gene bodies in any cytosine context at contamination levels up to 90%. Our findings highlight the utility of population genomic approaches across scales, and expand the accessibility of epigenetics studies within evolutionary biology.
Identification and characterization of a human MORC2 DNA binding region that is required for gene silencing
Authors: Fendler Nikole L. , Ly Jimmy , Welp Luisa , Urlaub Henning , Vos Seychelle M. 
Published: June 2024

AbstractThe eukaryotic microrchidia (MORC) protein family are DNAgyrase,Hsp90, histidinekinase, MutL(GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here we studied the full-length human MORC2 protein biochemically. We identified a DNA binding site in the C-terminus of the protein, and we observe that this region is heavily phosphorylated in cells. Phosphorylation of MORC2 reduces its affinity for DNA and appears to exclude the protein from the nucleus. We observe that DNA binding by MORC2 reduces its ATPase activity and that MORC2 can topologically entrap multiple DNA substrates between its N-terminal GHKL and C-terminal coiled coil 3 dimerization domains. Finally, we observe that the MORC2 C-terminal DNA binding region is required for gene silencing in cells. Together, our data provide a model to understand how MORC2 engages with DNA substrates to mediate gene silencing.
Large Language Model Uncertainty Measurement and Calibration for Medical Diagnosis and Treatment
Authors: Savage Thomas , Wang John , Gallo Robert , Boukil Abdessalem , Patel Vishwesh , Ahmad Safavi-Naini Seyed Amir , Soroush Ali , Chen Jonathan H 
Published: June 2024

AbstractIntroductionThe inability of Large Language Models (LLMs) to communicate uncertainty is a significant barrier to their use in medicine. Before LLMs can be integrated into patient care, the field must assess methods to measure uncertainty in ways that are useful to physician-users.ObjectiveEvaluate the ability for uncertainty metrics to quantify LLM confidence when performing diagnosis and treatment selection tasks by assessing the properties of discrimination and calibration.MethodsWe examined Confidence Elicitation, Token Level Probability, and Sample Consistency metrics across GPT3.5, GPT4, Llama2 and Llama3. Uncertainty metrics were evaluated against three datasets of open-ended patient scenarios.ResultsSample Consistency methods outperformed Token Level Probability and Confidence Elicitation methods. Sample Consistency by Sentence Embedding achieved the highest discrimination performance (ROC AUC 0.68–0.79) with poor calibration, while Sample Consistency by GPT Annotation achieved the second-best discrimination (ROC AUC 0.66-0.74) with more accurate calibration. Nearly all uncertainty metrics had better discriminative performance with diagnosis rather than treatment selection questions. Furthermore, verbalized confidence (Confidence Elicitation) was found to consistently over-estimate model confidence.ConclusionsSample Consistency is the most effective method for estimating LLM uncertainty of the metrics evaluated. Sample Consistency by Sentence Embedding can effectively estimate uncertainty if the user has a set of reference cases with which to re-calibrate their results, while Sample Consistency by GPT Annotation is more effective method if the user does not have reference cases and requires accurate raw calibration. Our results confirm LLMs are consistently over-confident when verbalizing their confidence through Confidence Elicitation.
Bone marrow S-phase is Associated with Risk assessment and Shows Differential Correlation with levels of CD34+Blasts and CD16−Granulocytes in Patients with Myelodysplastic syndromes
Authors: Azoulay David , Paz Avigail , Stemer Galia 
Published: June 2024

AbstractIntroductionIncluding of proliferative parameters in the routine clinical flow-cytometry (FC) workup may be important for better evaluation of prognosis and risk assessment in patients with myelodysplastic syndromes (MDS). However, supportive data are still contradicting.AimTo assess the levels of FC based proliferative parameters in patients with MDS using propidium Iodide, and to study their correlation with risk assessment and the incidences of CD34+blasts and CD16-and CD16+granulocytes.MethodsData was retrospectively collected and analysed from 40 specimens of bone marrow (BM) aspiration of MDS patients, 14 specimens of hypocellular BM with no evidence of malignancy, and 16 specimens of reactive BM as determined by pathological examination. IPSS-R scores were calculated for MDS patients then divided to high-risk (IPSS-R score >4.5) and low-risk (IPSS-R score <3). The levels of proliferative parameters and their correlation with incidence of CD34+blasts and CD16-and CD16+granulocytes were compared between high and low risk MDS patients.ResultsMDS and reactive BM specimens showed similar whole sample S-phase percentage that was significantly higher than hypocellular BM specimens. As compared to MDS, reactive BM show a greater S-phase percentage in the erythroid fraction. In MDS, the whole sample S-phase percentage was significantly high in a subset of high-risk patients. Increased S-phase percentage in these patients was attributed to high S-phase percentage in granulocytes and monocytes. S-phase percentage correlated with the level of CD34+blasts in the low-risk group but not in the high-risk group. In contrast to CD34+blasts, the S-phase percentage correlated with the level of CD16-granulocytes in the high-risk group but not in the low-risk group.ConclusionsOur observations confirm the association of increased proliferative parameters and adverse prognosis in MDS, and suggest differential proliferation pattern of CD34+and CD16-granulocytes in low and high-risk MDS patients.
Impact of Effective Refractory Period Personalization on Arrhythmia Vulnerability in Patient-Specific Atrial Computer Models
Authors: Díaz Patricia Martínez , Dasí Albert , Goetz Christian , Unger Laura , Haas Annika , Luik Armin , Rodríguez Blanca , Dössel Olaf , Loewe Axel 
Published: June 2024

AbstractBackground and AimsThe effective refractory period is one of the main electrophysiological properties governing arrhythmia maintenance, yet effective refractory period personalisation is rarely performed when creating patient-specific computer models of the atria to inform clinical decision-making. The aim of this study is to evaluate the impact of incorporating clinical effective refractory period measurements when creatingin silicopersonalised models on arrhythmia vulnerability.MethodsClinical effective refractory period measurements were obtained in seven patients from multiple locations in the atria. The atrial geometries from the electroanatomical mapping system were used to generate personalised anatomical atrial models. To reproduce patient-specific refractory period measurements, the Courtemanche cellular model was gradually reparameterised from control conditions to a setup representing atrial fibrillation-induced remodelling. Four different modelling approaches were compared: homogeneous (A), heterogeneous (B), regional (C), and continuous (D) distribution of effective refractory period. The first two configurations were non-personalised based on literature data, the latter two were personalised based on patient measurements. We evaluated the effect of each modelling approach by quantifying arrhythmia vulnerability and tachycardia cycle length. We performed a sensitivity analysis to assess the influence of effective refractory period measurement uncertainty on arrhythmia vulnerability.ResultsThe mean vulnerability was 3.4±4.0%, 7.7±3.4%, 9.0±5.1%, 7.0±3.6% for scenarios A to D, respectively. The mean tachycardia cycle length was 167.1±12.6ms, 158.4±27.5ms, 265.2±39.9ms, and 285.9±77.3ms for scenarios A to D, respectively. Incorporating perturbations to the measured effective refractory period in the range of 2, 5, 10 and 20ms, had an impact on the vulnerability of the model of 5.8±2.7%, 6.1±3.5%, 6.9±3.7%, 5.2±3.5%, respectively.ConclusionIncreased dispersion of the effective refractory period had a greater effect on reentry dynamics than on mean vulnerability values. The incorporation of personalised effective refractory period in the form of gradients had a greater impact on vulnerability than had a homogeneously reduced effective refractory period. Effective refractory period measurement uncertainty up to 20ms slightly influences arrhythmia vulnerability. Electrophysiological personalisation of atrialin silicomodels appears essential and warrants confirmation in larger cohorts.
Socioeconomic Inequalities in the Visual Assessment of Older Adults with Cataracts in Peru
Authors: Intimayta-Escalante Claudio , Vitteri-Soto Gino 
Published: June 2024

ABSTRACTIntroductionIn Peru, one in six adults over 50 years old has cataracts. This proportion increases due to the lack of routine visual assessments among older adults. Therefore, the objective of this research was to evaluate the socioeconomic inequalities in visual assessments among older adults with cataracts in Peru.MethodsThis analytical cross-sectional study was conducted using data from the Demographic and Family Health Survey in Peru from 2013 to 2023. Socioeconomic conditions such as gender, age, educational level, wealth quintile, area or place of residence, health insurance status, and comorbidities were evaluated. Inequalities were estimated using the concentration index (CI) and Erreyger’s modification (ECI).ResultsOf the 6,367 older adults with cataracts included in the study, 93.1% (95%CI: 92.2–93.9) had a visual assessment. The average age of the participants was 76.7 years, with over half of them being women (56.2%). Conditions such as educational level, wealth quintile, area or place of residence, and comorbidities mediated differences in the proportion of adults with cataracts who had visual assessments (p<0.001). Adults without education (ECI: -0.16), residents of rural areas (ECI: -0.41), or those outside Lima (ECI: -0.51) exhibited greater inequalities in receiving visual assessments.ConclussionAmong older adults with cataracts, living in rural areas or outside Lima and having a low educational level were identified as key factors mediating greater inequality in visual assessments.
Cardiovascular outcomes in adult patients with atrial septal defect: a nationwide population-based study
Authors: Lee Jue Seong , Park Man Young , Jung Jin-Man , Shin Hong Ju 
Published: June 2024

AbstractBackgroundThe beneficial effects of atrial septal defect (ASD) closure on cardiovascular events and mortality in adults remain undetermined. Therefore, this study aimed to investigate the long-term effects of different ASD closure methods on cardiovascular events in adults.MethodsA retrospective analysis was conducted using data obtained from the Korean National Health Insurance Service from 2002 to 2020, focusing on patients aged ≥20 years diagnosed with ASD based on the codes provided by the Tenth revision of International Classification of Diseases codes between 2004 and 2015. Participants were categorized into the observation, device closure, and surgery groups. Propensity score matching (PSM) of variables such as sex, age, comorbidities, and medications was employed at a 2:1:1 ratio to mitigate imbalances among the groups. The Cox proportional hazards model was utilized to compare the occurrence of major adverse cardiovascular events (MACE), including stroke, myocardial infarction (MI), coronary revascularization, and all-cause death, and each individual component among the three groups.ResultsIn total, 20,643 patients with ASD were included in this study. After PSM, there were 6,636 in the observation group and 3,318 each in the device closure and surgery group. Over a 5-year follow-up period, the adjusted hazard ratios for MACE were significantly lower in the surgery (0.72; 95% CI: 0.66–0.79) and device closure groups (0.85; 95% CI: 0.78–0.92) than in the observation group. Beneficial effects on stroke and all-cause mortality were observed in both intervention groups. Additionally, a beneficial effect on coronary revascularization was observed in the surgery group, whereas the impact on MI was not significantly different between the groups.ConclusionsASD closure, whether by surgery or using a device, is associated with a decreased incidence of cardiovascular outcomes in adults. The benefits on cardiovascular outcomes vary with the type of closure method, underscoring the need for a tailored approach to manage ASD in adults.Clinical PerspectivesWhat is new?Compared with no intervention, surgery exhibited a more beneficial effect in terms of MACE, followed by device closure.Device closure appears to be more beneficial in terms of all-cause death.Surgery reduced the occurrence of coronary revascularization.What are the clinical implications?Cardiovascular preventive effects after ASD closure (through surgery or device) were observed in adult patients with ASD when compared to the untreated individuals.The benefits on cardiovascular outcomes vary with the type of closure method, underscoring the need for a tailored approach to manage ASD in adults.
Prevalence of Depression in pre- and post-operative CABG (Coronary Artery Bypass Graft) patients
Authors: Tariq Maheen , Mazhar Ismail , Rai Mir Muhammad , Khan Qudsia Umaira , Daniyal Muhammad , Faisal Danyal 
Published: June 2024

AbstractDepression in post-surgical patients is a common occurrence. It is likely to occur in cardiac surgery like Coronary Artery Bypass Grafting. This condition could significantly prolong recovery time and could result in complications. Therefore, this study aimed to study the prevalence of Post-Operative Depression amongst Coronary Artery Bypass Graft patients. The undertaken research was conducted amongst patients who had undergone CABG at CMH Lahore and Punjab Institute of Cardiology. A survey was conducted on a sample size of 150 patients, out of which 147 gave consent to participation. The sample size was calculated using WHO Formula. The severity of depression was analyzed through questions in the Becks Depression Inventory. Data was analyzed using SPSS software (25.0 version). Out of 147 patients, 110 were males and 37 were females. The results depicted greater depression amongst females than in males both pre-operatively and post-operatively, with a mean score of 1.41 and 1.08 respectively. A significant difference (p<0.01) was obtained between the correlation of Pre-Operative Scores (in percentages and frequency) and Post-Operative Scores (in percentages and frequency). An insignificant difference (p=0.125) was obtained between the correlation between Preoperative Scores and Gender. A greater Mean Score (1.41) was seen in females, indicating more post-operative depression than males (1.05). An insignificant difference (p=0.239) was obtained between the correlation between Preoperative Scores and Gender. A greater Mean Score (1.08) was seen in females, indicating more post-operative depression than males (0.84). The study concluded that the prevalence of postoperative depression among patients was not significant.
STIPS algorithm enables tracking labyrinthine patterns and reveals distinct rhythmic dynamics of actin microridges
Authors: Bhavna Rajasekaran , Sonawane Mahendra 
Published: June 2024

SUMMARYTracking and motion analyses of semi-flexible biopolymer networks from time-lapse microscopy images are important tools that enable quantitative measurements to unravel dynamical and mechanical properties of biopolymers in living tissues important for understanding their organization and function. Biopolymer networks pose tracking challenges as they exhibit continuous stochastic transitions in the form of merges/splits resulting in local neighborhood rearrangements over short time/length scales. We propose the STIPS algorithm (SpatioTemporalInformation onPixelSubsets) that tracks merging/splitting events in self-organizing patterning systems, by creating pixel subsets to link trajectories across consecutive frames. We demonstrate our method on actin-enriched protrusions, the ‘microridges’ that form dynamic labyrinthine patterns on outer surfaces of squamous cell epithelia, mimicking ‘active Turing-patterns’. We uncovered two distinct actomyosin based rhythmic dynamics within neighboring cells; common pulsatile mechanism between 2-5.9 mins period governing both fusion and fission contributing to pattern maintenance and cell area pulses predominantly exhibiting ∼10 mins period.
Alarm functions of PD-1+ brain resident memory T cells
Authors: Musial Shawn C. , Kleist Sierra A. , Degefu Hanna N. , Ford Myles A. , Chen Tiffany , Isaacs Jordan F. , Boussiotis Vassiliki A. , Skorput Alexander G. J. , Rosato Pamela C. 
Published: June 2024

ABSTRACTResident memory T cells (TRM) have been described in barrier tissues as having a ‘sensing and alarm’ function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain TRM, which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that TRMare sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that while PD-1 restrains granzyme B expression by reactivated brain TRM, it has no effect on cytotoxicity or downstream alarm responses. We conclude that TRMare sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.
ERH Enables Early Embryonic Differentiation and Overlays H3K9me3 Heterochromatin on a Cryptic Pluripotency H3K9me3 Landscape in Somatic Cells
Authors: Katznelson Andrew , Hernandez Blake , Fahning Holly , Tapia Kylea , Burton Adam , Zhang Jingchao , Torres-Padilla Maria-Elena , Plachta Nicolas , Zaret Kenneth S. , McCarthy Ryan L. 
Published: June 2024

AbstractEnhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized in fission yeast1and recently shown to maintain H3K9me3 in human fibroblasts2. Here, we find that ERH depletion in fibroblasts reverts the H3K9me3 landscape to an embryonic stem cell (ESC) state and enables activation of naïve and pluripotency genes and transposable elements during induced pluripotent stem cell (iPSC) reprogramming. We find that ERH similarly represses totipotent and alternative lineage programs during mouse preimplantation development and is required for proper segregation of the inner cell mass and trophectoderm cell lineages. During human ESC differentiation into germ layer lineages, ERH silences naïve and pluripotency genes, transposable elements, and alternative lineage somatic genes. As in fission yeast, we find that mammalian ERH interacts with RNA-binding proteins to engage and repress its chromatin targets. Our findings reveal a fundamental role for ERH in cell fate specification via the initiation and maintenance of early developmental gene repression.
Evolutionary genomics of a zoonotic parasite across the Neotropical Realm
Authors: Heeren Senne , Sanders Mandy , Shaw Jeffrey Jon , Brandão-Filho Sinval Pinto , Boité Mariana Côrtes , Cantanhêde Lilian Motta , Chourabi Khaled , Maes Ilse , Llanos-Cuentas Alejandro , Arevalo Jorge , Marco Jorge D. , Lemey Philippe , Cotton James A. , Dujardin Jean-Claude , Cupolillo Elisa , Van den Broeck Frederik 
Published: June 2024

ABSTRACTThe Neotropical realm, one of the most biodiverse regions on Earth, houses a broad range of zoonoses that pose serious public health threats. Protozoan parasites of theLeishmania(Viannia)braziliensisspecies complex cause zoonotic leishmaniasis in Latin America with clinical symptoms ranging from simple cutaneous to destructive, disfiguring mucosal lesions. We present the first comprehensive genome-wide continental study including 257 cultivated isolates representing most of the geographical distribution of this major human pathogen. TheL. braziliensisspecies complex is genetically highly heterogeneous, consisting of divergent parasite groups that are associated with different environments and vary greatly in diversity. Apart from several small ecologically isolated groups with little diversity, our sampling identifies two major parasite groups, one associated with the Amazon and the other with the Atlantic Forest biomes. These groups show different recombination histories, as suggested by high levels of heterozygosity and effective population sizes in the Amazonian group in contrast to high levels of linkage and clonality in the Atlantic group. We argue that these differences are linked to strong eco-epidemiological differences between the two regions. In contrast to geographically focused studies, our study provides a broad understanding of the molecular epidemiology of zoonotic parasites circulating in tropical America.