bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three-Dimensional Efficacy Evaluation of Nasal Symmetry in Unilateral Cleft Lip Primary Repair: A Modified Rotation Advancement Technique
Authors: Xu Yulang , Yao Meilin , Li Chenghao , Shi Bing , Li Jingtao , Zheng Qian , Zeng Ni 
Published: January 2025

Objective:
Objective assessment of the long-term postoperative outcomes of a modified rotation advancement combined with force balance orbicularis oris muscle reconstruction in patients with unilateral complete cleft lip and palate.

Methods:
Consecutive patients undergoing cleft lip primary repair were included (n=90). Three-dimensional images preoperatively (n=90), postoperatively (n=90), and at 5 years follow-up (n=57) were assessed and compared to age-matched controls.

Results:
In preoperative measurement, the subnasale and pronasale both exhibited a significant deviation. The cleft subalare was displaced both medially and posteriorly in comparison to the controls. Conversely, the noncleft subalare demonstrated a lateral drift. These observations collectively indicated an overall lateral drift of the nasal base towards the noncleft side. Surgical intervention successfully resulted in landmark positions that closely mirrored those of the controls. The symmetry of the nasal base was maintained at late follow-up within the cleft lip group. However, there was a significant downward and retrusive displacement of the cleft alar base, along with a notable lateral displacement of the subnasale and the noncleft alar base in both the cleft lip and alveolus/palate groups.

Conclusion:
The modified rotation advancement technique combined with force balance reconstruction of orbicularis oris results in promising symmetry of nasal base in patients with unilateral complete cleft lip. The alar base retrusion in patients with cleft lip and alveolus/palate is probably due to bony defect, which might be addressed by secondary alveolar bone grafting.
Learning robust gene expression embeddings for disease subtyping, biomarker
identification and cross-species alignment
Authors: Chen Xin , Smith Kathleen M , Bi Yingtao 
Published: January 2025

Abstract
High dimension gene expression measurements such as microarray and RNA-seq
data, are often plagued by sources of unwanted variation. This variability can
lead to the obscuring of meaningful biological signal by technical noise and
non-interesting biological variation, thus resulting in failure to identify the
same set of targets and biomarkers in independent studies. This phenomenon
contributes to the so-called reproducibility crisis and makes preclinical drug
development more challenging. There is an urgent need for an improved process to
identify shared biological signals in large datasets from independent cohorts.
In this article, we propose an innovative method called Joint-Embedding via
Canonical Correlation Analysis (JECCA), which aims to capture relevant
biological variation by learning of shared lower dimension embedding across
multiple datasets.
We demonstrate the efficacy of JECCA in analyzing multiple human cancer and
inflammatory disease gene expression datasets, showcasing its ability to
identify robust, biologically relevant signals. By leveraging these embeddings,
our approach enables several important applications: (1) robust disease endotype
identification by joint unsupervised analysis of multiple independent gene
expression datasets (2) reproducible and biologically meaningful biomarker
identification to enhance prediction of treatment outcome (3) cross-platform
analysis, such as integration of RNA-seq and microarray data, which are
accumulating exponentially in public databases (4) cross-species analysis to
identify conserved molecular features between human and mouse. We provide
comparative analyses that highlight the superior performance of JECCA over other
approaches such as batch value-corrected methods based on joint analysis. As
analysis of publicly available datasets becomes more prevalent, we foresee JECCA
being employed in multiple disease contexts.
Determinants of COPD Stage Progression and Regression: a Markov Transition Analysis of The COPDGene Cohort
Authors: Sánchez-Romero Luz M. , Brouwer Andrew F. , Meza Rafael , Levy David T. , Torres-Alvarez Rossana , Han MeiLan K. 
Published: January 2025

ABSTRACTRationaleChronic obstructive pulmonary disease (COPD) is a leading cause of death but with variable progression.ObjectiveEstimate factors influencing transition rates between PRISm and GOLD stages.MethodsUsing a Markov multistate model, transition rates between GOLD-0, PRISm and GOLD-1, GOLD-2 and GOLD 3-4 were estimated for 5,728 US adult ever cigarette users from the COPDGene cohort over 10-years. We calculated one and five-year transition probabilities for progressive and regressive transitions and estimated the mean sojourn time for severity states.Main ResultsGOLD-1 and PRISm individuals spent the least time in any single stage (GOLD-1: 6 years; PRISm: 7 years). PRISm and GOLD-1 individuals were equally likely to transition to GOLD-2 vs. GOLD-0 (PRISm: HR 1.09, 95% confidence interval [CI] 0.90-1.33, GOLD-1 (HR 1.15, 95%CI 0.93-1.42) per five-year period, but rarely transition between PRISm and GOLD-1. Individuals at GOLD-0 were equally likely to progress to GOLD-1 or PRISm (HR 1.11, 95%CI 0.93-1.31) but the transient time for this stage was the longest of any GOLD stage (16 years, 95%CI 15.2-17.3). GOLD-2 was the most likely stage to progress (HR 2.4, 95%CI 1.9-3.02) to GOLD 3-4 vs. regress to GOLD-1. For GOLD-2 individuals, current smoking status (HR 0.84, 95%CI 0.67-1.06) or intensity (HR 0.84, 95%CI 0.54-1.29) was not associated with disease progression.ConclusionsGOLD-1 and PRISm are the most transient stages equally likely to regress to GOLD-0 or progress to GOLD-2 and may benefit from smoking cessation interventions. GOLD-2 individuals are the most likely to progress and may benefit most from targeted disease interventions.
Detecting and avoiding homology-based data leakage in genome-trained sequence models
Authors: Rafi Abdul Muntakim , Kiyota Brett , Yachie Nozomu , de Boer Carl 
Published: January 2025

AbstractModels that predict function from DNA sequence have become critical tools in deciphering the roles of genomic sequences and genetic variation within them. However, traditional approaches for dividing the genomic sequences into training data, used to create the model, and test data, used to determine the model’s performance on unseen data, fail to account for the widespread homology that permeates the genome. Using models that predict human gene expression from DNA sequence, we demonstrate that model performance on test sequences varies by their similarity with training sequences, consistent with homology-based ‘data leakage’ that influences model performance by rewarding overfitting of homologous sequences. Because the sequence and its function are inexorably linked, even a maximally overfit model with no understanding of gene regulation can predict the expression of sequences that are similar to its training data. To prevent leakage in genome-trained models, we introduce ‘hashFrag,’ a scalable solution for partitioning data with minimal leakage. hashFrag improves estimates of model performance and can actually increase model performance by providing improved splits for model training. Altogether, we demonstrate how to account for homology-based leakage when partitioning genomic sequences for model training and evaluation, and highlight the consequences of failing to do so.
Phenotypic and Developmental Dissection of an Instance of the Island Rule
Authors: Nolte Mark J. , Payseur Bret A. 
Published: January 2025

AbstractOrganismal body weight correlates with morphology, life history, physiology, and behavior, making it perhaps the most telling single indicator of an organism’s evolutionary and ecological profile. Island populations provide an exceptional opportunity to study body weight evolution. In accord with the “island rule,” insular small-bodied vertebrates often evolve larger sizes, whereas insular large-bodied vertebrates evolve smaller sizes. To understand how island populations evolve extreme sizes, we adopted a developmental perspective and compared a suite of traits with established connections to body size in the world’s largest wild house mice from Gough Island and mice from a smaller-bodied mainland strain. We pinpoint 24-hour periods during the third and fifth week of age in which Gough mice gain exceptionally more weight than mainland mice. We show that Gough mice accumulate more visceral fat beginning early in postnatal development. During a burst of weight gain, Gough mice shift toward carbohydrates and away from fat as fuel, despite being more active than and consuming equivalent amounts of food as mainland mice. Our findings showcase the value of developmental phenotypic characterization for discovering how body weight evolves in the context of broader patterns of trait evolution.
Host microRNA-31-5p represses oncogenic herpesvirus lytic reactivation by restricting the RNA-binding protein KHDRBS3-mediated viral gene expression
Authors: Lee Soo Mi , Avalos Christopher L. , Miliotis Christos , Doh Hanna M. , Chan Erica , Kaye Kenneth M. , Slack Frank J. 
Published: January 2025

AbstractOncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), an etiological agent of Kaposi’s sarcoma and primary effusion lymphoma, employs a biphasic life cycle consisting of latency and lytic replication to achieve lifelong infection. Despite its essential role in KSHV persistence and tumorigenicity, much remains unknown about how KSHV lytic reactivation is regulated. Leveraging high-throughput transcriptomics, we identify microRNA-31-5p (miR-31-5p) as a key regulator of KSHV lytic reactivation capable of restricting KSHV entry into the lytic replication cycle. Ectopic expression of miR-31-5p impairs KSHV lytic gene transcription and production of lytic viral proteins, culminating in dramatic reduction of infectious virion production during KSHV reactivation. miR-31-5p overexpression also markedly reduces the expression of critical viral early genes, including the master regulator of the latent-lytic switch, KSHV replication and transcription activator (RTA) protein. Through mechanistic studies, we demonstrate that miR-31-5p represses KSHV lytic reactivation by directly targeting the KH domain protein KHDRBS3, an RNA-binding protein known to regulate RNA processing including alternative splicing. Our study highlights KHDRBS3 as an essential proviral host factor that is key to the successful completion of KSHV lytic replication and suggests its novel function in viral lytic gene transcription during KSHV reactivation. Taken together, these findings reveal a previously unrecognized role for the miR-31-5p/KHDRBS3 axis in regulating the KSHV latency-lytic replication switch and provide insights into gene expression regulation of lytic KSHV, which may be leveraged for lytic cycle-targeted therapeutic strategies against KSHV-associated malignancies.
Deleterious mutations and selection for sex in spatially structured, diploid populations
Authors: Fouqueau Louise , Roze Denis 
Published: January 2025

ABSTRACTBy increasing local genetic drift and generating inbreeding, population spatial structure may have important effects on the evolutionary benefits of sexual reproduction. In this article, we consider a population structured according to the island model, and use two and three-locus analytical models and multilocus simulations to explore the selective forces acting on a modifier locus affecting the rate of sexual reproduction of facultatively sexual organisms, in the presence of recurrent deleterious mutations. The results show that population structure and selection combine to generate a local excess of heterozygotes at selected loci (negativeFIS), for both partially recessive and partially dominant deleterious alleles. The linkage disequilibrium between deleterious alleles may be either negative or positive depending on their dominance coefficient, the degree of population structure and the rate of sex. These genetic associations combine with many other ones to generate indirect selection at the sex modifier locus, generally favoring intermediate rates of sex even when sex entails direct fitness costs. Multilocus simulations show that the equilibrium rate of sex increases moderately as the degree of population structure increases. However, population structure may also prevent the irreversible spread of asexual mutants when the cost of sex is strong.
Anopheles stephensilarval habitat superproductivity and its relevance for larval source management in Africa
Authors: Yared Solomon , Dengela Dereje , Mumba Peter , Chibsa Sheleme , Zohdy Sarah , Irish Seth R , Yoshimizu Melissa , Balkew Meshesha , Akuno Albert , Perkins T. Alex , Vazquez-Prokopec Gonzalo M 
Published: January 2025

AbstractThe invasion of Africa byAnopheles stephensiposes a significant threat to malaria elimination. AsAn. stephensiexploits a wide array of urban artificial larval habitats, it may be less impacted by rainfall variability compared to other nativeAnophelesspecies. We empirically investigated this assumption by quantifying the seasonal transition of an established population from eastern Ethiopia between rainy and dry periods. Monthly larval surveys generated evidence of significant heterogeneity between seasons in the type of habitat and their productivity. As the dry season progressed,An. stephensiproductivity significantly concentrated in large water reservoirs (for drinking and construction) to a point in which up to 77% of all larvae originated from 23% of the sites. Such superproductive sites were primarily water cisterns used for residential or construction purposes. A two-patch metapopulation model ofAn. stephensilinked to rainfall data recreated the seasonal larval dynamics observed in the field and predicted that larval control targeted on superproducer water reservoirs, when implemented at coverages higher than 60%, may lead toAn. stephensielimination. Our findings highlight the role of environmental variability in regulatingAn. stephensipopulations and open the window for the deployment of control strategies that exploit major mosquito population bottlenecks.
Drug-Resistance Biomarkers inLeishmania infantumthrough Nanopore-Based Detection of Aneuploidy and Gene Copy Number Variations with LeishGenApp
Authors: Carrasco Marina , Martí-Carreras Joan , Gómez-Ponce Marcel , Alcover Maria Magdalena , Roura Xavier , Ferrer Lluís , Baneth Gad , Bruno Federica , Chicharro Carmen , Cordeiro-da-Silva Anabela , Cristovão José , Di Muccio Trentina , Maia Carla , Moreno Javier , Priego Anabel , Roca-Geronès Xavier , Santarem Nuno , Vila Soriano Anna , Vitale Fabrizio , Yasur-Landau Daniel , Francino Olga 
Published: January 2025

AbstractThe emergence of drug-resistant strains ofLeishmania infantum,a parasite that infects dogs and humans, poses an increasing threat, underscoring the need for a One Health framework for adequate control. Aneuploidy and gene copy-number variation (CNV) are associated with resistance to first-line drugs. We analyzed aneuploidies, genome plasticity, and 15 CNVs as drug-resistance biomarkers in 35L. infantumisolates from human and canine host across the Mediterranean by nanopore-only whole-genome sequencing and the automated diagnostic platform LeishGenApp. Results highlighted different levels of aneuploidy turnover among chromosomes and characterized the structural organization of resistance-associated genomic regions, emphasizing the role of genomic repeated sequences in the extended H-locus, METK and SMT locus. At least one genomic resistance biomarker was detected in 80% of the Mediterranean isolates, being the most prevalent to antimonials (50%) and allopurinol (50%) in canine isolates and to antimonials (61%) and paramomycin (38%) in human isolates. Monoresistance (50%) predominates in dogs, while resistance to two drugs is most common in human isolates (38%). Differences in genomic resistance biomarkers prevalence in our cohort underscore the importance of targeted drug policies to mitigate resistance dissemination. Our results provide an effective approach for detecting aneuploidies and CNVs as drug-resistance biomarkers inLeishmaniaparasites by nanopore-only whole-genome sequencing. This powerful tool is significant for monitoring resistantL. infantumstrains, particularly in dogs, the primary reservoir, lessening resistance-related relapses, limiting resistantLeishmaniatransmission by sand flies, and shaping One Health strategies.
Needle in a haystack: A droplet digital polymerase chain reaction assay to detect rare helminth parasites infecting natural host populations
Authors: Fouilloux Chloe A. , Neeno-Eckwall Eric , Srinivas Ipsita , Compton Jonathan , Sampson Josh , Weber Jesse , Wolf Cole , Hund Amanda , Berini John , Alexander Heather , Choi Emma , Bolnick Daniel I. , Hite Jessica L. 
Published: January 2025

AbstractHelminths infect humans, livestock, and wildlife, yet remain understudied despite their significant impact on public health and agriculture. Because many of the most prevalent helminth-borne diseases are zoonotic, the health of diverse host species are closely interconnected. Therefore, understanding helminth transmission among wildlife could improve predictions and management of infection risks across species. A key challenge to understanding helminth transmission dynamics in wildlife is accurately and quantitatively tracking infection levels across hosts and environments. Traditional methods, such as visual parasite identification from environmental samples or infected hosts, are time-consuming, while standard molecular techniques (e.g., PCR and qPCR) often lack the sensitivity to reliably detect lower parasit burdens. These limitations often underestimate the prevalence and severity of infection, hindering efforts to manage infectious diseases. Here, we developed a multiplexed droplet digital PCR (ddPCR) assay to quantify helminth levels in aquatic habitats using 18S rRNA target genes. UsingSchistocephalus solidusand their copepod hosts as a case study, we demonstrate ddPCR’s sensitivity and precision. By establishing a 1:1 infection standard in the lab, we contextualize ddPCR gene concentration data to quantify both host and parasite numbers in field samples. The assay is highly reproducible, reliably detecting target genes at concentrations as low as 1 picogram of DNA in lab standards and field samples (multi-species and eDNA). Thus, we provide a toolkit for quantifying infection loads in intermediate hosts and monitoring infection dynamics across spatio-temporal scales in multiple helminth systems of concern for public health, agriculture, and conservation biology.Graphical abstractApplications of ddPCR probe-primer design to parallel systems.Cyclopoid copepods serve as initial hosts for diverse helminthic diseases distributed globally. The primers designed in this assay are suitable for other systems, with minimal work required for probe design specific to each helminth species.
Population history across timescales in an urban archipelago
Authors: Howell Emma K. , Nolfo-Clements Lauren E. , Payseur Bret A. 
Published: January 2025

AbstractContemporary patterns of genetic variation reflect the cumulative history of a population. Population splitting, migration, and changes in population size leave genomic signals that enable their characterization. Existing methods aimed at reconstructing these features of demographic history are often restricted in their temporal resolution, leaving gaps about how basic evolutionary parameters change over time. To illustrate the prospects for extracting insights about dynamic population histories, we turn to a system that has undergone dramatic changes on both geological and contemporary timescales – an urbanized, near-shore archipelago. Using whole genome sequences, we employed both common and novel summaries of variation to infer the demographic history of three populations of endemic white-footed mice (Peromyscus leucopus) in Massachusetts’ Boston Harbor. We find informative contrasts among the inferences drawn from these distinct patterns of diversity. While demographic models that fit the joint site frequency spectrum (jSFS) coincide with the known geological history of the Boston Harbor, patterns of linkage disequilibrium reveal collapses in population size on contemporary timescales that are not recovered by our candidate models. Historical migration between populations is also absent from best-fitting models for the jSFS, but rare variants show unusual clustering along the genome within individual mice, a pattern that is reproduced by simulations of recent migration. Together, our findings indicate that these urban archipelago populations have been shaped by both ancient geological processes and recent human influence. More broadly, our study demonstrates that the temporal resolution of demographic history can be extended by examining multiple facets of genomic variation.Significance StatementDetailed information about a population’s history can be obtained by studying patterns of genomic variation, but these insights can be limited in their temporal scope. Our investigation of white-footed mice in the urban Boston Harbor archipelago demonstrates how combining multiple summaries of genomic variation enables a more complete reconstruction of population history over both the recent and distant past.