bluuebunny/crossref_metadata_2025_split huggingface dataset:
MitoEdit: a pipeline for optimizing mtDNA base editing and predicting bystander effects
Authors: Shah Devansh , McCastlain Kelly , Chang Ti-Cheng , Wu Gang , Kundu Mondira 
Published: January 2025

Short Structured AbstractMotivationHuman mitochondrial DNA (mtDNA) mutations are causally implicated in maternally inherited mitochondrial respiratory disorders; however, the role of somatic mtDNA mutations in both late-onset chronic diseases and cancer remains less clear. Although recent advances in mtDNA base editing technology have the potential to model and characterize many of these mutations, current editing approaches are complicated by the potential for multiple unintentional edits (bystanders) that are only identifiable through empirical ‘trial and error’, thereby sacrificing valuable time and effort towards suboptimal construct development.ResultsWe developed MitoEdit, a novel tool that incorporates empirical base editor patterns to facilitate identification of optimal target windows and potential bystander edits. MitoEdit allows users to input DNA sequences in a text-based format, specifying the target base position and its desired modification. The program generates a list of candidate target windows with a predicted number of bystander edits and their functional impact, along with flanking nucleotide sequences designed to bind TALE (transcription activator-like effectors) array proteins.In silicoevaluations indicate that MitoEdit can predict the majority of bystander edits, thereby reducing the number of constructs that need to be tested empirically. To the best of our knowledge, MitoEdit is the first tool to automate prediction of base edits.Availability and implementationMitoEdit is freely available at Kundu Lab GitHub (https://github.com/Kundu-Lab/mitoedit).ContactCorresponding email:Gang.Wu@stjude.org;Mondira.Kundu@stjude.orgSupplementary informationSupplementary data are available atBioinformaticsonline.
Structured simulation-based training with frugal ophthalmic instruments rapidly equips non-ophthalmologists to identify malarial retinopathy
Authors: Wilson Kyle J , Kousha Obaid , Nkume Harold , Liomba Alice M , Beare Nicholas AV , Blaikie Andrew 
Published: January 2025

AbstractBackgroundMalaria, particularly cerebral malaria, poses a significant health threat, especially for children in sub-Saharan Africa. Identification of malarial retinopathy (MR) has diagnostic value in cerebral malaria but can be impractical due to lack of availability of trained and equipped ophthalmic specialists. Recent developments in low-cost simulation tools and ophthalmoscopes offer the potential to train non-ophthalmologists to offer fundus assessments in low-resource settings.MethodsTwenty non-ophthalmologist healthcare providers in Malawi attended a training program focused on identification of MR using direct and binocular indirect ophthalmoscopy. The curriculum included didactic sessions, hands-on practice with simulation eyes, and assessment of skill acquisition with immediate feedback. Pre- and post-training confidence surveys were conducted.ResultsParticipants demonstrated significant improvement in identification of malarial retinopathy after completing the training, with a mean accuracy of 83%. Clinician confidence levels increased across all domains of retinal examination covered in the course.ConclusionStructured simulation-based training using frugal ophthalmoscopes can equip non-ophthalmologists with skills to identify MR in simulation eyes. Future work should focus on long-term skill retention and validation in a real-world clinical setting.
Automated Oxygen Delivery in Home Setting for Patients with COPD on Long-Term Oxygen Therapy – a randomized crossover feasibility trial
Authors: Kofod Linette Marie , Hansen Ejvind Frausing , Kristensen Morten Tange , Brocki Barbara Cristina , Westerdahl Elisabeth 
Published: January 2025

AbstractRationalePatients with COPD on long-term oxygen therapy (LTOT) have an unmet need for oxygen adjustments during sleep, rest, and activity, documented by continuous monitoring of oxygen saturation. While emerging technology enables automated adjustments, its feasibility in home settings remains uncertain. This randomized crossover trial evaluated the feasibility and preliminary effects of continuous automated oxygen titration in the homes of patients on LTOT.MethodsThe intervention involved four days of automated oxygen titration targeting a SpO₂ of 90-94% using a Bluetooth-connected electronic device and wrist pulse oximeter, forming a closed-loop system. Oxygen flow (0.9-6.8 L/min) was continuously adjusted based on SpO₂. During the control period, patients received their usual fixed dose oxygen. Feasibility was defined as successful automated titration time and time spent with normoxia. Changes in health status were measured using the Clinical COPD Questionnaire (CCQ).ResultsTwelve patients on LTOT (2.0±0.8 L/min) were included, with more than 217,000 paired SpO2and oxygen flow data points collected per patient. Oxygen flow was automatically adjusted for a median (IQR) of 77 (68.0–84.3) hours, covering 83% of the time. Time within target saturation increased significantly from 52% (42–63) to 86% (75–90) during intervention, with all patients utilizing the full available flow range. The CCQ score improved by 0.74±0.47 points, p <0.001.ConclusionAutomated home oxygen titration is feasible, achieving more time with normoxia, but it required a wide flow range and continuous monitoring. The patients reported notable reductions in COPD symptoms.
TICTAC: Target Illumination Clinical Trial Analytics with Cheminformatics
Authors: Abok Jeremiah I , Edwards Jeremy S , Yang Jeremy J 
Published: January 2025

AbstractIntroductionIdentifying disease–target associations is a pivotal step in drug discovery, offering insights that guide the development and optimization of therapeutic interventions. Clinical trial data serves as a valuable source for inferring these associations. However, issues such as inconsistent data quality and limited interpretability pose significant challenges. To overcome these limitations, an integrated approach is required that consolidates evidence from diverse data sources to support the effective prioritization of biological targets for further research.MethodsWe developed a comprehensive data integration and visualization pipeline to infer and evaluate associations between diseases and known and potential drug targets. This pipeline integrates clinical trial data with standardized metadata, providing an analytical workflow that enables the exploration of diseases linked to specific drug targets as well as facilitating the discovery of drug targets associated with specific diseases. The pipeline employs robust aggregation techniques to consolidate multivariate evidence from multiple studies, leveraging harmonized datasets to ensure consistency and reliability. Disease–target associations are systematically ranked and filtered using a rational scoring framework that assigns confidence scores derived from aggregated statistical metrics.ResultsOur pipeline evaluates disease–target associations by linking protein-coding genes to diseases and incorporates a confidence assessment method based on aggregated evidence. Metrics such as meanRank scores are employed to prioritize associations, enabling researchers to focus on the most promising hypotheses. This systematic approach streamlines the identification and prioritization of biological targets, enhancing hypothesis generation and evidence-based decision-making.DiscussionThis innovative pipeline provides a scalable solution for hypothesis generation, scoring, and ranking in drug discovery. As an open-source tool, it is equipped with publicly available datasets and designed for ease of use by researchers. The platform empowers scientists to make data-driven decisions in the prioritization of biological targets, facilitating the discovery of novel therapeutic opportunities.
Comparing Esri ArcGIS and SAS Geocoding Approaches: Test case with 3,238 Wisconsin addresses
Authors: Johnson Hannah K. , Hampton John M. , Arroyo Natalia , Schultz Amy , Gangnon Ronald E. , Malecki Kristen M. , Trentham-Dietz Amy 
Published: January 2025

SUMMARYThis report describes a comparison of two geocoding methods used by the Cohorts for Environmental Exposures and Cancer Risks (CEECR) consortium: ArcGIS Geocoding by Esri and the SAS GEOCODE Procedure. The goal of this report is to determine the comparability of data sets that employ different approaches for linking survey data with spatial surrogates of exposure to environmental and socioeconomic factors. ArcGIS and SAS GEOCODE were selected as two platforms for this comparison because both programs are being used by one or more CEECR cohort study teams and they can be used locally offline. The latter minimizes confidentiality issues related to online data linkages. Residential addresses from 3,238 Wisconsin residents in theCancer & COVID Studyand theWisconsin in situ Cohort(WISC) were geocoded and linked to eight different publicly available datasets of environmental and socioeconomic factors at various geographic scales using both geocoding platforms. Since the two analytic platforms vary in geocoding approaches, the validity and accuracy of both platforms were compared to examine differences when assigning surrogate measurements of exposure based on spatial locations. ArcGIS offered a higher specificity for matched addresses with slightly more latitude/longitude point and street matches (97.7%) than SAS (95.9%), with the remainder matching at the zip code level. The two geocoding platforms showed high concordance in assignment at the county (99.6%), census tract (96.5%), and census block group (94.7%). As a result, the correlations based on census tracts and block groups were very strong for linked exposure measures of socioeconomic status, environmental justice, urban/rural residence, air pollution, proximity to industrial sites, and cancer risk (all intraclass correlation coefficients ≥98%). Slightly lower concordance was observed for point source linkages (intraclass correlation coefficients 96-97%). Approximately ~4% of addresses were mis-matched largely in rural areas where census areas are larger and accurate geocoding base-layers are less widely available than in urban areas. For researchers that are already utilizing SAS, the GEOCODE procedure can be a logical choice as it is included in base SAS software and does not require an additional cost. However, SAS and ArcGIS provide similar options for the vast majority of study address locations.
Genomic Analysis of Trichotillomania
Authors: Halvorsen Matthew W. , Garrett Melanie E. , Cuccaro Michael L. , Ashley-Koch Allison E. , Crowley James J. 
Published: January 2025

AbstractTrichotillomania (TTM) is a psychiatric condition in which people feel an overwhelming urge to pull out their hair, resulting in noticeable hair loss and significant distress. Twin, family and candidate gene studies suggest that TTM is at least partly genetic, but no genome-wide analyses have been completed. To fill the gap in this field, we have conducted a case-control study of genotype array data from 101 European ancestry TTM cases and 488 ancestry-matched unaffected controls. TTM cases were ascertained in the USA through web-based recruitment, patient support groups, and conferences organized by the Trichotillomania Learning Center. Following clinical confirmation of a TTM diagnosis, patients completed self-report assessments of frequency and duration of hair pulling, other psychiatric symptoms, and family history. Unaffected controls were also ascertained in the USA and were matched to cases by ancestry. In the first formal genome-wide association study of TTM, we did not identify any common variants with a genome-wide significant (P < 5×10−8) association level with case status. We found that TTM cases carry a higher load of common polygenic risk for psychiatric disorders than unaffected controls (P= 0.008). We also detected copy number variants previously associated with neuropsychiatric disorders in TTM cases (specifically, deletions inNRXN1, CSMD1, and 15q11.2). These results further support genetics’ role in the etiology of TTM and suggest that larger studies are likely to identify risk variation and, ultimately, specific risk genes associated with the condition.
Whole Genome Sequencing in Adolescent Idiopathic Scoliosis Cohort Indicates Polygenic Disease Involving Multiple Biological Pathways
Authors: Tuncay Islam Oguz , Lee Eun Kyoung , Gustafson Anxhela , Lee Yoonsuh , Jung Dawoon , Koh June-Young , Lee Wonchul , Lee Sangmoon , Shazand Kamran 
Published: January 2025

ABSTRACTAdolescent idiopathic scoliosis (AIS) is the most common nondegenerative spinal abnormality. Research indicates a strong correlation between genetics and AIS, with heritability estimates of 87.5%. However, the rarity of shared causative genes among patients, and the difficulty of replication between studies suggest that AIS is a highly complex polygenic disease. In this study, we utilized whole-genome sequencing (WGS) to comprehensively explore the genetic landscape of 119 AIS patients from 103 families. We implemented an automated WGS analysis pipeline powered by RareVisionTMconsisting of automated algorithms and manual curation. We identified clinically relevant candidate variants in 20/119 (16.8%) patients and potentially relevant strong or moderate candidate variants in another 73/119 (61.3%) patients. Candidate variants included coding and noncoding point mutations, along with structural variants and large indels, showing the utility of WGS. Candidate genes included AIS-associated genes (e.g.CHD7,COL11A1/2,FBN1/2,HSPG2,KIF7), as well as genes associated with other musculoskeletal and developmental syndromes where scoliosis is a known symptom (e.g.RYR1,GJB2,MYH2,MYH7). Association analysis showed 4 known AIS single nucleotide polymorphisms (rs12946942, rs10756785, rs3904778, rs7633294) also correlated with AIS in our cohort. Finally, through gene set enrichment analysis, we were able to identify 3 gene clusters involved in skeletal muscle contraction, extracellular matrix composition, and gene expression regulation. In summary, through scalable WGS-based familial testing we were able to (1) find clinically relevant genetic variations in the majority of our patients and (2) create a large dataset that allowed us to identify biological pathways relevant to AIS etiopathogenesis.
Known Group Validity of Assessment of Work Performance for Thai Homeless People
Authors: Thanapet Uthaikan , Ammawat Watthanaree , Rueankam Maliwan , Chatthong Winai , Khemthong Supalak 
Published: January 2025

AbstractBackgroundSubstance use and mental disorders are highly prevalent in Thai homeless people living with no mental health recovery. The lack of psychosocial occupational therapists may be one huge problem for none of the measurement outcomes for clinical utility. We aimed to determine the known-group validity of the Assessment of Work Performance (AWP) with good content and internal consistency reliability.MethodsParticipants (N = 60) were recruited by screening with no cognitive impairment, no psychiatric symptoms, independent self-care, and on-the-job assignment at Nonthaburi’s destitute home. Mann–Whitney U tests firstly found a significant difference in process skills between males and females (p < .05). Data analysis of the ceiling effect was then conducted to design using cleaned samples (N = 22), and the Mann–Whitney U tests secondly found a significant difference in communication skills between males and females (p < .05).ResultsThere were no associations between the frequency of genders and substance abusers were computed using cross-tabulation (N = 60 versus N = 22). Besides a corrected sample, natural contexts of too easy job selection, no preparatory of supported employment, and non-purposeful living activities may be confounding factors of avolition, poor habit, and inactive life roles without wellness at the end of life.ConclusionThese preliminary results suggest a useful AWP with good known-group validity for measuring outcomes among vulnerable people and describing how to improve motor, process, and interactive communication skills based on the Model of Human Occupation (MOHO) in occupational therapists and Mental Health Recovery (MHR) workers.
Simulating The Effect of the Radiotherapy on Cancer Stem Cell Evolution
Authors: Heryanto Yusri Dwi , Imoto Seiya 
Published: January 2025

ABSTRACTRadiotherapy is one of the most effective treatments for cancer. However, the radiation on cancer often leads to further tumor evolution and resistance. Accumulating evidence suggests that the cancer stem cells (CSCs) play a significant role in the tumor’s radioresistance and invasiveness. Therefore, we set out to investigate the aggressiveness and radioresistance that emerge because of radiation-induced selective pressures on CSCs. We developed an agent-based model (ABM) that tracks the evolution and growth of the cancer after treated by different regimens of radiotherapy. In the ABM, each cell is an agent that follows some predefined rules for their behaviors and interactions with other agents. We showed that the radiotherapy treatment increased the resistance, proliferation rate, and the CSC proportion of the tumor. Our simulation also showed that the CSC-targeted treatment is important for eliminating tumor completely.
Unraveling Dengue Serotype 3 Transmission in Brazil: Evidence for Multiple Introductions of the 3III_B.3.2 Lineage
Authors: Pereira James Siqueira , Slavov Svetoslav Nanev , Brcko Isabela Carvalho , Ribeiro Gabriela , de Souza Vinicius Carius , Ribeiro Igor Santana , De Lima Iago Trezena T. , Lima Borges Gleissy Adriane , de Lima Furtado Katia Cristina , da Silva Chagas Shirley Moreira , Barros da Costa Patricia Miriam Sayuri Sato , Adelino Talita , de Melo Iani Felipe C. , Junior Alcantara Luiz Carlos , Hill Verity , Grubaugh Nathan D. , Sampaio Sandra Coccuzzo , Elias Maria Carolina , Giovanetti Marta , Lima Alex Ranieri J. 
Published: January 2025

SummaryDengue, caused by DENV 1-4, remains a global public health concern, with Brazil experiencing some of the largest epidemics. The reemergence of DENV-3 in Brazil between 2023 and 2024 has raised concerns about new outbreaks due to the absence of sustained circulation of this serotype in recent years. This study investigates the dynamics of DENV-3 in Brazil, focusing on the spread of the 3III_B.3.2 lineage within genotype 3III and its introduction routes. We analyzed 1,536 DENV-3 genomes, all classified as genotype 3III, the dominant DENV-3 genotype in Brazil since 2001. Phylogenetic analysis identified the 3III_B.3.2 lineage in all recent Brazilian cases, with detections also reported in Central America, the United States, and Europe. At least six independent introduction events of this lineage into Brazil were identified, with the Caribbean region and Costa Rica as the primary sources. The earliest introduction likely occurred in late 2022 in Roraima, followed by introductions in São Paulo, Minas Gerais, and Pará. While one instance of interstate transmission was detected — from São Paulo to Minas Gerais — our findings indicate that external introductions, rather than domestic spread, were the primary drivers of DENV-3 circulation during this period. These results underscore the importance of continued genomic surveillance and coordinated public health strategies to monitor and mitigate future outbreaks.
Carbonic anhydrase 4 disruption and pharmacological inhibition reduce synaptic and behavioral adaptations following oxycodone withdrawal
Authors: Gupta Subhash C , Taugher-Hebl Rebecca J. , Ghobbeh Ali , Jahnke Marshal T. , Fan Rong , LaLumiere Ryan T. , Wemmie John A. 
Published: January 2025

AbstractThe ongoing opioid crisis underscores the need for innovative treatments targeting neurobiological mechanisms underlying opioid-seeking behaviors and relapse. Here we explored the role of carbonic anhydrase 4 (CA4) in modulating synaptic adaptations to oxycodone withdrawal in mice. We disrupted CA4 genetically and inhibited it pharmacologically with acetazolamide (AZD), a carbonic anhydrase inhibitor used clinically. We found that oxycodone withdrawal increased AMPAR/NMDAR ratio and synaptic recruitment of calcium-permeable AMPARs in nucleus accumbens core (NAcC) medium spiny neurons (MSNs). Synaptic changes required an extended period of abstinence, generalized across opioids including morphine and heroin, were specific to D1 dopamine receptor-expressing MSNs, and were prevented by CA4 disruption. AZD administrationin vitroandin vivoreversed the synaptic alterations, and effects of AZD depended on CA4 and acid sensing ion channel 1A (ASIC1A). Interestingly, abstinence from oxycodone did not affect dendritic spine density in NAcC MSNs, in contrast to previously observed effects of abstinence from cocaine. Finally, in an oxycodone self-administration paradigm, CA4 disruption and AZD reduced drug-seeking behaviors following 30 days of forced abstinence. Together, these findings identify a critical role for CA4 in synaptic adaptations in opioid withdrawn mice and drug-seeking behavior. Moreover, they suggest pharmacological inhibitors of CA4 may hold therapeutic potential for reducing opioid-seeking and relapse in opioid use disorder.
The cost of diarrhoea: a household perspective from seven countries in the Global Enteric Multicenter Study (GEMS)
Authors: Al Fidah Md Fuad , Islam Md Ridwan , Amin Rukaeya , Nuzhat Sharika , Ahmed Tahmeed , Faruque ASG 
Published: January 2025

AbstractBackgroundThe burden of diarrhoeal diseases is considerable in South Asia, as well as in sub-Saharan Africa (SSA). Its economic impact is more profound in resource-limited settings like low- and middle-income countries (LMICs). In this study, we aimed to estimate the direct and indirect cost reported by the caregivers of participants from seven LMICs.MethodsThe current study used data from the multicenter, Global Enteric Multicenter Study (GEMS) which enrolled under-5 children (U5C). This prospective case-control study was conducted in 7 sites, all of them located in LMICS. Cost data was collected from the caregivers and after adjustment for inflation, were converted into International Dollar (I$). Quantile regression models were developed after adjusting for age, sex and country.ResultsThis study analyzed data from 4,592 participants. The median (IQR) total direct cost (TDC) and total indirect cost (TIC) were 8.4 (11.0) I$ and 10.2 (14.3) I$, respectively. Statistically significant differences were found across continents for multiple variables. The highest median TDC and TIC was in Bangladesh (13.6 I$ and 23.2 I$ respectively), while Mozambique reported the lowest (0.4 I$ and 4.9 I$ respectively) with medication accounting for 60.9% of TDC. Quantile regression analysis showed TDC was positively associated with factors like family size, urban residence, moderate-to-severe disease, caregiver education, and use of rehydration methods, while treated drinking water and overweight status were negatively associated. TIC was significantly associated with seeking prior care.ConclusionThe indirect cost of diarrhoea was higher than the direct cost which indicates the impact of lost productivity due to the disease. Bolstering the healthcare financing systems, ensuring affordable medication, promoting WASH initiative and timely healthcare-seeking can reduce the economic burden.