bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ecological tradeoffs lead to complex evolutionary trajectories and sustained diversity on dynamic fitness landscapes
Authors: Amado André , Bank Claudia 
Published: October 2023

AbstractThe course and outcome of evolution are critically determined by the fitness landscape, which maps genotype to fitness. Most theory has considered static fitness landscapes or fitness landscapes that fluctuate according to abiotic environmental changes. In the presence of biotic interactions between coexisting genotypes, the fitness landscape becomes dynamic and frequency-dependent.Here, we introduce a fitness landscape model that incorporates ecological interactions between individuals in a population. In the model, fitness is determined by individuals competing for resources according to a set of traits they possess. An individual’s genotype determines the trait values through a Rough Mount Fuji fitness landscape model, allowing for tunable epistasis (i.e., non-additive gene interaction) and trait correlations (i.e., whether there are tradeoffs or synergies in the ability to use resources). Focusing on the effects of epistasis and trait correlations, we quantify the resulting eco-evolutionary dynamics under simulated Wright-Fisher dynamics (i.e., including genetic drift, mutation, and selection under the assumption of a constant population size) on the dynamics fitness landscape in comparison with a similar, static, fitness landscape model without ecological interactions.Whereas the non-ecological model ultimately leads to the maintenance of one main geno-type in the population, evolution in the ecological model can lead to the long-term coexistence of several genotypes at intermediate frequencies across much of the parameter range. Including ecological interactions increases steady-state diversity whenever the trait correlations are not too strong. However, strong epistasis can hinder coexistence, and additive genotype-phenotype maps yield the highest haplotype diversity at the steady state. Interestingly, we frequently observe long-term coexistence also in the absence of induced trade-offs in the ability to consume resources.In summary, our simulation study presents a new dynamic fitness landscape model that highlights the complex eco-evolutionary consequences of a (finite) genotype-phenotype-fitness map in the presence of biotic interactions.
Sinefungin, a natural nucleoside analog of S-adenosyl methionine, impairs the pathogenicity ofCandida albicans
Authors: Nayak Anushka , Chavarria Alejandro , Sanders Kyla N. , Ghalei Homa , Khoshnevis Sohail 
Published: October 2023

AbstractCandida albicans, an opportunistic fungal human pathogen, is a major threat to the healthcare system due to both infections in immunocompromised individuals and the emergence of antifungal resistance. Fungal infection caused byC. albicans, candidiasis, is a life-threatening condition in immunocompromised patients and the current treatments are mostly restricted to polyenes, azoles, and echinocandins. Use of these antifungals is limited by toxicity, drug-drug interactions, and the emergence of resistance, underscoring the importance of identifying novel therapeutic targets and the need for new treatment approaches.C. albicanscan undergo a morphological transition from yeast to hyphae and this transition is central toC. albicansvirulence. Here, we determine the impact of sinefungin, a natural nucleoside analog of S-adenosyl methionine, on the virulence ofC. albicansstrain SC5314 by evaluating treatment effects on the morphological transition, human epithelial cell adhesion, and biofilm formation. Our data indicate that sinefungin impairs pathogenic traits ofC. albicansincluding hyphal lengthening, biofilm formation and the adhesion to the human epithelial cell lines, without adversely affecting human cells, therefore highlighting sinefungin as a potential avenue for therapeutic intervention. We determine that the formation of N6-methyladenosine (m6A) is particularly disturbed by sinefungin. More broadly, this study underscores the importance of considering the post-transcriptional control mechanisms of pathogenicity when designing therapeutic solutions to fungal infection.
Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma
Authors: VanSant-Webb Chad , Low Hayden K. , Kuramoto Junko , Stanley Claire E. , Qiang Hantao , Su Audrey , Ross Alexis N. , Cooper Chad G. , Cox James E. , Summers Scott A. , Evason Kimberley J. , Ducker Gregory S. 
Published: October 2023

AbstractBackground and AimsActivating mutations in theCTNNB1gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). HCC withCTNNB1mutations show profound alterations in lipid metabolism including increases in fatty acid oxidation and transformation of the phospholipidome, but it is unclear how these changes arise and whether they contribute to the oncogenic program in HCC.MethodsWe employed untargeted lipidomics and targeted isotope tracing to quantify phospholipid production fluxes in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC.ResultsIn both models, activated β-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid flux analysis in human cells revealed a large reduction in phosphatidylcholine (PC) production rates as assayed by choline tracer incorporation. We developed isotope tracing lipid flux analysis for zebrafish and observed similar reductions in phosphatidylcholine synthesis flux accomplished by sex-specific mechanisms.ConclusionsThe integration of isotope tracing with lipid abundances highlights specific lipid class transformations downstream of β-catenin signaling in HCC and suggests future HCC-specific lipid metabolic targets.SynopsisIn this work, we show by lipid specific isotope tracing that mutations in the oncogeneCTNNB1leads to conserved changes in lipid metabolism in hepatocellular carcinoma. These include the stimulation of fatty acid oxidation and a suppression of phosphorylcholine synthesis.
5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies
Authors: Li Qianxia , Huang Chiang-Ching , Huang Shane , Tian Yijun , Huang Jinyong , Bitaraf Amirreza , Dong Xiaowei , Nevalanen Marja T. , Patel Manishkumar , Wong Jodie , Zhang Jingsong , Manley Brandon J. , Park Jong Y. , Kohli Manish , Gore Elizabeth M. , Kilari Deepak , Wang Liang 
Published: October 2023

AbstractBackgroundCurrently, no biomarkers are available to identify resistance to androgen-deprivation therapies (ADT) in men with hormone-naive prostate cancer. Since 5-hydroxymethylcytosines (5hmC) in gene body are associated with gene activation, in this study, we evaluated whether 5hmC signatures in cell-free DNA (cfDNA) predicts early resistance to ADT.ResultsWe collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at three time points including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). To quantify 5hmC abundance across the genome, we used selective chemical labeling sequencing and mapped sequence reads to individual genes. Differential methylation analysis in baseline samples identified significant 5hmC difference in 1,642 of 23,433 genes between patients with and without progression (false discovery rate, FDR<0.1). Patients with disease progression showed significant 5hmC enrichments in multiple hallmark gene sets with androgen responses as top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients featuring a significant 5hmC hypermethylation in the gene sets involvingAR,FOXA1andGRHL2. To quantify overall activities of these gene sets, we developed a gene set activity scoring algorithm and observed significant association of high activity scores with poor progression-free survival (P<0.05). Longitudinal analysis showed that the high activity scores were significantly reduced after 3-months of initiating ADT (P<0.0001) but returned to higher levels when the disease was progressed (P<0.05).ConclusionsThis study demonstrates that 5hmC-based activity scores from gene sets involved inAR,FOXA1andGRHL2may be used as biomarkers to determine early treatment resistance, monitor disease progression, and potentially identify patients who would benefit from upfront treatment intensification.
Early Real-world Implant Experience with a Helix-fixation Ventricular Leadless Pacemaker
Authors: Nair Devi G. , Exner Derek V. , Reddy Vivek Y. , Badie Nima , Ligon David , Miller Marc A. , Lee Bridget , Doty Brandon , Thomaides Athanasios , Eldadah Zayd , Islam Malick , Hadadi Cyrus 
Published: October 2023

AbstractBackgroundRoughly 1 in 6 patients receiving conventional transvenous pacemaker systems experience significant complications within 1 year of implant, mainly due to the transvenous lead and subcutaneous pocket. A new helix-fixation single-chamber ventricular leadless pacemaker (LP) system capable of pre-deployment exploratory electrical mapping is commercially available. Such an LP may mitigate complications while streamlining the implantation.ObjectivesEvaluate the initial real-world implant experience of the helix-fixation LP following its commercial release.MethodsIn patients indicated for single-chamber right ventricular pacing, helix-fixation Aveir VR LPs (Abbott, Abbott Park, IL) were implanted using the dedicated loading tool, introducer, and delivery catheter. Implant procedural characteristics, electrical parameters, and any 30-day procedure-related adverse events of consecutive implant attempts were retrospectively evaluated.ResultsA total of 167 patients with Class I indication for permanent pacing received implants in 4 North American centers (57% male, 70 years old). Pre-fixation electrical mapping of potential sites allowed repositioning to be avoided in 95.7% of patients. Median [interquartile range] LP procedure and fluoroscopy durations were 25.5 min [20.0, 35.0] and 5.7 min [4.0, 9.2], respectively. Pacing capture threshold, sensed R-wave amplitude, and impedance were 0.8 V [0.5, 1.3], 9.0 mV [6.0, 12.0], and 705 Ω [550, 910], respectively. Implantation was successful in 98.8% of patients, with 98.2% free from acute adverse events.ConclusionThe initial, real-world experience of the helix-fixation ventricular leadless pacemaker demonstrated safe and efficient implantation with minimal repositioning, viable electrical metrics, and limited acute complications.
TEclass2: Classification of transposable elements using Transformers
Authors: Bickmann Lucas , Rodriguez Matias , Jiang Xiaoyi , Makalowski Wojciech 
Published: October 2023

AbstractMotivationTransposable elements (TEs) are interspersed repetitive sequences that are major constituents of most eukaryotic genomes and are crucial for genome evolution. Despite the existence of multiple tools for their classification and annotation, none of them can achieve completely reliable results making it a challenge for genomic studies. In this work, we introduce TEclass2, a new software that uses a deep learning approach based upon a linear Transformer architecture with a k-mer to-kenizer and further adaptations to handle DNA sequences. This software has an easy configuration that allows training models on new datasets and the classification of TE models providing multiple metrics for a reliable evaluation of the results.ResultsThis work shows a successful adaptation of deep learning with Transformers for the classification of TE models from consensus sequences, and these results lay a foundation for novel methodologies in bioinformatics. We provide a tool for the training of models and the classification of consensus sequences from TE models on custom data and a web page interface with a pre-trained dataset based on curated and non-curated TE libraries allowing a fast and simple classification of TEs.Availabilityhttps://bioinformatics.uni-muenster.de/tools/teclass2/index.plContactwojmak@uni-muenster.deSupplementary informationSupplementary data are available atBioinformaticsonline.
TEPEAK : A novel method for identifying and characterizing polymorphic transposable elements in non-model species populations
Authors: Burke Devin , Chuong Edward , Taylor William , Layer Ryan 
Published: October 2023

AbstractTransposable elements (TEs) replicate within genomes and are an active source of genetic variability in many species. Their role in immunity and domestication underscores their biological significance. However, analyzing TEs, especially within lesser-studied and wild populations, poses considerable challenges. To address this, we introduce TEPEAK, a simple and efficient approach to identify and characterize TEs in populations without any prior sequence or loci information. In addition to processing user-submitted genomes, TEPEAK integrates with the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) to increase cohort sizes or incorporate proximate species. Our application of TEPEAK to 256 horse genomes spanning 11 groups reaffirmed established genetic histories and highlighted disruptions in crucial genes. Some identified TEs were also detectable in species closely related to horses. TEPEAK paves the way for comprehensive genetic variation analysis in traditionally understudied populations by simplifying TE studies. TEPEAK is open-source and freely available athttps://github.com/mrburke00/TEPEAK.
Omicron COVID-19 Immune Correlates Analysis of a Third Dose of mRNA-1273 in the COVE Trial
Authors: Zhang Bo , Fong Youyi , Fintzi Jonathan , Chu Eric , Janes Holly E. , Carpp Lindsay N. , Kenny Avi , Carone Marco , Benkeser David , van der Laan Lars W. P. , Deng Weiping , Zhou Honghong , Wang Xiaowei , Lu Yiwen , Yu Chenchen , Borate Bhavesh , Houchens Christopher R. , Martins Karen , Jayashankar Lakshmi , Huynh Chuong , Fichtenbaum Carl J. , Kalams Spyros , Gay Cynthia L. , Andrasik Michele P. , Kublin James G. , Corey Lawrence , Neuzil Kathleen M. , Priddy Frances , Das Rituparna , Girard Bethany , El Sahly Hana M. , Baden Lindsey R. , Donis Ruben O. , Koup Richard A. , Gilbert Peter B. , Follmann Dean ,   Moderna, Inc. Team,   Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team,   USG/CoVPN Biostatistics Team
Published: October 2023

AbstractIn the coronavirus efficacy (COVE) phase 3 efficacy trial of the mRNA-1273 vaccine, IgG binding antibody (bAb) concentration against Spike (BA.1 strain) and neutralizing antibody (nAb) titer against Spike (BA.1 strain) pseudovirus were assessed as correlates of risk of Omicron COVID-19 and as correlates of relative boost efficacy in per-protocol recipients of a third (booster) dose. Markers were measured on the day of the boost (BD1) and 28 days later (BD29). For SARS-CoV-2 naive individuals, BD29 Spike IgG-BA.1 strain bAbs and BD29 BA.1-strain nAbs inversely correlated with Omicron COVID-19: hazard ratio (HR) per 10-fold marker increase [95% confidence interval (CI)] = 0.16 (0.03, 0.79); P=0.024 and 0.31 (0.10, 0.96); P = 0.042, respectively. These markers also inversely correlated with Omicron COVID-19 in non-naive individuals: HR = 0.15 (0.04, 0.63); P = 0.009 and 0.28 (0.07, 1.08); P = 0.06, trend. Fold-rise in markers from BD1 to BD29 had similarly strong inverse correlations. For SARS-CoV-2 naive individuals, overall booster relative (three-dose vs two-dose) efficacy was 46% (95% CI: 20%, 64%) and correlated with BA.1 strain nAb titer at exposure. At 56, 251, and 891 arbitrary units (AU)/ml (10th, 50th, and 90thpercentile), the booster relative efficacies were −8% (95% CI: −126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), respectively. Similar relationships were observed for Spike IgG-BA.1 strain bAbs and for the markers measured at BD29. The performance of bAb and nAb markers as correlates of protection against Omicron COVID-19 supports their continued use as surrogate endpoints for mRNA vaccination against Omicron COVID-19.
Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
Authors: Al-Azab Mahmoud , Idiiatullina Elina , Lin Meng , Hrovat-Schaale Katja , Xian Huifang , Zhu Jianheng , Yang Mandy , Lu Bingtai , Liu Ziyang , Zhao Zhiyao , Liu Yiyi , Chang Jingjie , Li Xiaotian , Guo Caiqin , Zeng Ping , Cui Jun , Gao Xia , Zhang Yan , Zhang Yuxia , Masters Seth L. 
Published: October 2023

AbstractRare genetic variants in TLR7 are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localisation into endosomes, however it has only been genetically linked to lupus in mice and dogs. We now identify a novel variant in UNC93B1 (T314A) located proximally to the TLR7 transmembrane domain, in a patient with childhood-onset systemic lupus erythematosus (SLE). Further examination in a cohort of East Asian patients revealed seven who encode UNC93B1 (V117L), which is a rare but highly significant risk factor for this disease, when compared to the corresponding general population. The variant is associated with increased expression of type I IFNs and NF-kB cytokines in patients plasma and PBMC. This was confirmed using cell line models, with exaggerated responses to stimulation of TLR7/8, but not TLR3 or TLR9, and the process can be inhibited by targeting the TLR signaling molecules IRAK1/4. For UNC93B1 (V117L) we then created the orthologous mutation in mice (V138L), which results in a spontaneous lupus-like disease in heterozygotes, that is more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset SLE.One sentence summaryRare genetic variants in UNC93B1 predispose to childhood-onset lupus via TLR7-IRAK1/4, validated with a corresponding mouse model.
Hyperglycemia-induced cathepsin L maturation: Linking to diabetic comorbidities and COVID-19 mortality
Authors: He Qiong , Zhao Miao-Miao , Li Ming-Jia , Li Xiao-Ya , Jin Jian-Min , Feng Ying-Mei , Zhang Li , Huang Wei-Jin , Yang Fang-Yuan , Yang Jin-Kui 
Published: October 2023

ABSTRACTDiabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals.In vitrostudies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, withCTSLknockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside db/db diabetic and control mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.
Double data extraction was insufficient for minimizing errors in evidence synthesis: a randomized controlled trial
Authors: Tang Lijun , Wang Ruoxi , Doi Suhail A.R. , Furuya-Kanamori Luis , Lin Lifeng , Qin Zongshi , Tao Fangbiao , Xu Chang 
Published: October 2023

AbstractObjectivesThe objective was to investigate the role of double extraction in reducing data errors in evidence synthesis for pharmaceutical and non-pharmaceutical interventions.DesignCrossover randomized controlled trial (RCT).SettingUniversity teaching center and hospital evidence-based medicine center.ParticipantsEligible 100 participants were 2ndyear or above post-graduate students (e.g., masters, doctoral program), who were randomly (1:1) assigned for data extraction tasks of either 10 RCTs of pharmaceutical interventions or 10 of non-pharmaceutical interventions, followed by a cross-over pattern and a further double-checking process.InterventionThe intervention of this trial was double-checking process for data extraction.Primary and secondary outcome measuresThe primary outcome was the error rates for RCTs in the pharmaceutical versus non-pharmaceutical intervention group, in terms of both study level and cell level (2 by 2 table). The secondary outcome was the absolute difference in the error rates before and after the double-checking process for both the pharmaceutical and non-pharmaceutical intervention groups, again, in terms of both study level and cell level (2 by 2 table).ResultsThe error rates in RCTs of pharmaceutical and non-pharmaceutical groups were 64.65% and 59.90%, with an absolute difference of 4.75% and an odds ratio (OR) of 1.29 [95% confidence interval (CI): 1.06 to 1.57,P= 0.01] when measured at the study level. After double-checking, the error rates decreased to 44.88% and 39.54%, and the difference between the two groups remained at 5.34%, with the OR of 1.27 (95%CI: 1.1 to 1.46;P< 0.01). Similar results were observed when measured at the cell level.ConclusionDouble-checking reduced data extraction errors, but the error rate still remained high after the process. Further evidence synthesis research may consider to use triple data extraction or else effective methods to minimize potential errors.Trial registration numberChinese Clinical Trial Registry Center (Identifier: ChiCTR2200062206)Strengths and limitations of the studyThis is the third randomized trial focusing on data extraction strategies and the first one in the Asia-Pacific region.This is the first randomized trial that compares error rates of data extraction in trials of pharmaceutical interventions and non-pharmaceutical interventions.We validated the effectiveness of double data extraction while also identifying its limitations, providing valuable evidence for future data extraction strategies.To ensure the feasibility of the trial, we restricted subjects to 2 post-graduate students or above, which may affects the representativeness of the sample.The readability of the chosen randomized controlled trials for pharmaceutical and non-pharmaceutical interventions may vary, potentially resulting in selection bias that can distort the outcomes.
Disease and Economic Burden of Stillbirths in India in 2019
Authors: Wadhwani Vidhi , Shrinivas Divya , Dubey Sweta , Zadey Siddhesh 
Published: October 2023

ABSTRACTBackgroundIndia has the highest number of stillbirths worldwide. However, disease and economic burdens assessment of stillbirths in India remain missing.MethodsWe conducted a retrospective analysis using stillbirth data from the health management information system (HMIS), and civil and sample registration systems (CRS and SRS) for India and its 21 states. We calculated disease burden in terms of disability-adjusted life years (DALYs) and economic burden in value of life-years (VLYs). We conducted multiple sensitivity analyses for DALY and VLY assessments.ResultsIndian HMIS reported 263,342 stillbirths in 2019. Stillbirths led to 18.3 million DALYs and a monetary loss of INR 6.4 trillion. Five states contributed to more than 40% burden. Sensitivity analyses showed consistency in findings.ConclusionDue to their disease and economic burdens, stillbirths should be prioritized in the public health agenda.