bluuebunny/crossref_metadata_2025 huggingface dataset:
The Morphologic and Molecular Heterogeneity of Fumarate Hydratase–deficient Leiomyomas: Integrative Molecular Profiling of Uterine Smooth Muscle Tumors With Histologic Feature Correlation
Authors: Szczepanski Julianne M. , Chapel David B. , Huang Tao , Pham Trinh , Mannan Rahul , Mehra Rohit , Sciallis Andrew P. , Tomlins Scott , Skala Stephanie L. , Udager Aaron M.
Published: January 2025

The morphologic features of uterine smooth muscle tumors (USMTs) are subject to interobserver variability and are complicated by consideration of features of fumarate hydratase deficiency (FHd) and other morphologic subtypes, with difficult cases occasionally diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP). We compare immunohistochemical findings and detailed morphologic analysis of 45 USMTs by 4 fellowship-trained gynecologic pathologists with comprehensive molecular analysis, focusing on FHd leiomyomas (n=15), compared to a variety of other USMTs with overlapping morphologic features, including 9 STUMPs, 8 usual-type leiomyomas (ULM), 11 apoplectic leiomyomas, and 2 leiomyomas with bizarre nuclei (LMBN). FHd leiomyomas, defined by immunohistochemical (IHC) loss of FH and/or 2SC accumulation, showed FH mutations and/or FH copy loss in all cases, with concurrent TP53 mutations in 2 tumors. Severe and/or symplastic-type cytologic atypia was seen more often in FHd leiomyomas with only FH copy loss (6/8, and 2/2 with concurrent TP53 mutations) compared to those with FH mutations (2/7) and typically showed increased genomic instability. This subset of FHd tumors often showed morphologic overlap with STUMPs and LMBN, but all cases of FHd tumors showed 2SC accumulation and/or FH loss by IHC. In conclusion, we highlight the importance of investigating USMTs with severe and/or symplastic-type cytologic atypia with FH and 2SC IHC, as many of these tumors are FH-deficient via focal deep deletion (2-copy loss) of the FH locus. In addition, we report the presence of concurrent TP53 mutations in FHd tumors with more severe cytologic atypia; further data about clinical outcomes for these tumors are needed.
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.
Evaluation of nationwide analysis surveillance for methicillin-resistant Staphylococcus aureus within Genomic Medicine Sweden
Authors: Tång Hallbäck Erika , Björkman Jonas T. , Dyrkell Fredrik , Welander Jenny , Fang Hong , Sylvin Isak , Kaden Ren , Eilers Hinnerk , Söderlund Strand Anna , Mernelius Sara , Berglind Linda , Campillay Lagos Amaya , Engstrand Lars , Sikora Per , Mölling Paula
Published: January 2025

Background. National epidemiological investigations of microbial infections greatly benefit from the increased information gained by whole-genome sequencing (WGS) in combination with standardized approaches for data sharing and analysis.

Aim. To evaluate the quality and accuracy of WGS data generated by different laboratories but analysed by joint pipelines to reach a national surveillance approach.

Methods. A national methicillin-resistant Staphylococcus aureus (MRSA) collection of 20 strains was distributed to nine participating laboratories that performed in-house procedures for WGS. Raw data were shared and analysed by three pipelines: 1928 Diagnostics, JASEN (GMS pipeline) and CLC-Genomics Workbench. The outcomes were compared according to quality, correct strain identification and genetic distances.

Results. One isolate contained intraspecies contamination and was excluded from further analysis. The mean sequencing depth varied between sites and technologies. However, all analysis methods identified 12 strains that belonged to one of five outbreak clusters. The cut-off definition was set to <10 allele differences for core genome multilocus sequence typing (cgMLST) and <20 genetic differences for SNP analysis in a pairwise comparison.

Conclusions. MRSA isolates, which are whole genome sequenced by different laboratories and analysed using the same bioinformatic pipelines, yielded comparable results for outbreak clustering for both cgMLST and SNP, using the 1928 analysis pipeline. In this study, JASEN was best suited to analyse Illumina data and CLC to analyse within respective technology. In the future, real-time sharing of data and harmonized analysis within the Genomic Medicine Sweden consortium will further facilitate investigations of outbreaks and transmission routes.
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

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

Rationale

Chronic obstructive pulmonary disease (COPD) is a leading cause of death but with variable progression.

Objective

Estimate factors influencing transition rates between PRISm and GOLD stages.

Methods

Using 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 Results

GOLD-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.

Conclusions

GOLD-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

Models 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

Organismal 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

Oncogenic 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

By 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

The 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

The 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

Helminths 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 abstract

Applications 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.
Species distribution modeling for conservation science: new predictor layers, reproducible code, and an evaluation of California protected areas
Authors: MacDonald Zachary G. , Beninde Joscha , Matsunaga Kentaro , Zhou Bo , Gillespie Thomas W , Shaffer H. Bradley
Published: January 2025

Aim Our study provides foundational resources for future SDMing: methods for generating fine-scale, equal-area predictor datasets and best-practice SDM guidelines. We also provide reproducible code to streamline their implementation. Location Southwestern North America Methods Using over 215,000 research-grade iNaturalist occurrence records for 127 species of conservation concern or scientific interest in California and surrounding area, we quantified and compared SDM performance between two predictor datasets that differ in their source of bioclimatic data, spatial resolution, and coordinate reference system: one generated using ClimateNA software (resolution = 300 x 300 m; NAD83/California Albers) and the other using existing WorldClim data (varying resolution = ~669-797 x 926 m; WGS84). We also compared two modeling algorithms (MaxEnt vs Random Forests), and two background point selection strategies (random points vs weighted points accounting for sampling effort). As an example application, we used SDM predictions to evaluate the conservation value of different protected area types within California. Results ClimateNA outperformed WorldClim for 94% of species, Random Forests outperformed MaxEnt for 87%, and random background points outperformed weighted background points for 100%. All differences were statistically significant. Together, the ClimateNA dataset, Random Forests, and random background points achieved highest performance for 86% of species. Using this best-performing set of models, we found that regional parks, county parks, state beaches, and open spaces in California were highest in multi-species suitability, while larger protected areas, such as national parks and national forests, generally exhibited surprisingly low suitability. Substantial spatial biases intrinsic to SDMing with unprojected predictor datasets (e.g., WGS84) are described, along with clear solutions using equal-area predictor datasets. Main conclusions Considerable disparity was observed among the performance of common SDM methods. This study highlights the importance of fine-scale, equal-area predictor datasets and best-practice guidelines, and demonstrates how SDMs can provide critical insights into protected area planning.
Population history across timescales in an urban archipelago
Authors: Howell Emma K. , Nolfo-Clements Lauren E. , Payseur Bret A.
Published: January 2025

Contemporary 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 Statement

Detailed 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.
Vaccination with mRNA-encoded membrane-bound HIV Envelope trimer induces neutralizing antibodies in animal models
Authors: Ramezani-Rad Parham , Cottrell Christopher A. , Marina-Zárate Ester , Liguori Alessia , Landais Elise , Torres Jonathan L. , Myers Amber , Lee Jeong Hyun , Baboo Sabyasachi , Flynn Claudia , McKenney Katherine , Salcedo Eugenia , Zhou Xiaoya , Kalyuzhniy Oleksandr , Georgeson Erik , Phelps Nicole , Lu Danny , Eskandarzadeh Saman , Menis Sergey , Kubitz Michael , Groschel Bettina , Alavi Nushin , Jackson Abigail M. , Lee Wen-Hsin , Tran Andy S. , Ben-Akiva Elana , Michaels Katarzyna Kaczmarek , Diedrich Jolene K. , Enemuo Chiamaka A. , Lewis Vanessa , Pradhan Arpan , Kasturi Sudhir Pai , Schiffner Torben , Steichen Jon M. , Carnathan Diane G. , Himansu Sunny , Yates John R. , Paulson James C. , Ozorowski Gabriel , Irvine Darrell J. , Silvestri Guido , Sok Devin , Ward Andrew B. , Crotty Shane , Schief William R.
Published: January 2025

A protective vaccine against HIV will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope glycoprotein (Env) trimer. Nearly all vaccine strategies to induce bnAbs require the use of relatively complex immunization regimens involving a series of different immunogens, most of which are Env trimers. Producing protein-based clinical material to evaluate such relatively complex regimens in humans presents major challenges in cost and time. Furthermore, immunization with HIV trimers as soluble proteins induces strong non-neutralizing responses to the trimer base, which is normally occluded on the virion. These base responses could potentially detract from the induction of nAbs and the eventual induction of bnAbs. mRNA vaccine platforms offer potential advantages over protein delivery for HIV vaccine development, including increased production speed, reduced cost, and the ability to deliver membrane-bound trimers that might facilitate improved immuno-focusing to non-base epitopes. We report the design of mRNA-delivered soluble and membrane-bound forms of a stabilized native-like Env trimer (BG505 MD39.3), initial immunogenicity evaluation in rabbits that triggered clinical evaluation, and more comprehensive evaluation of B cell, T cell, and antibody responses in non-human primates. mRNA-encoded membrane-bound Env immunization elicited reduced off-target base-directed Env responses and stronger neutralizing antibody responses, compared with mRNA-encoded soluble Env. Overall, mRNA delivery of membrane-bound Env appears promising for enhancing B cell responses to subdominant epitopes and facilitating rapid translation to clinical testing, which should assist HIV vaccine development.

One Sentence Summary

HIV envelope trimer mRNA enables membrane-bound expression and represents a functional immunogen in pre-clinical mammalian models.
Plastoquinone redox status influences carboxysome integrity via a RpaA- and ROS-dependent regulatory network
Authors: Santos-Merino María , Nikkanen Lauri , Kokarakis Emmanuel J. , Allahverdiyeva Yagut , Ducat Daniel C.
Published: January 2025

Carboxysomes are bacterial microcompartments that encapsulate Rubisco and are a core component of the cyanobacterial carbon concentration mechanism (CCM). While carboxysome number, size and spatial organization are observed to vary in different environmental conditions (CO2, light, temperature, light quality), molecular mechanisms underlying this potentially adaptive process remain elusive. Herein, we observed that mutants of the circadian rhythm/metabolism factor, Regulator of Phycobilisome Associated A (RpaA), exhibit a striking breakdown of carboxysomes under certain environmental conditions. We find that growth conditions leading to overreduction of the plastoquinone (PQ) pool (mixotrophic growth, high irradiance, or chemical inhibition of electron transfer from PQ to the cytochromeb6fcomplex) are accompanied by elevated generation of reactive oxygen species (ROS), and correlate with carboxysome breakdown. Carboxysome breakdown is reversed by environmental conditions or chemical inhibitors that prevent PQ overreduction and accompanying ROS generation. Taken together, our data supports a novel link between the redox status of the PQ pool and carboxysome status and/or integrity. Our results have implications for fundamental understanding of cyanobacterial energy balancing pathways and may indicate new research directions for understanding how the carboxysome is remodeled in response to changing environments.
Caudata macrogenetics: Species range size predicts intraspecific genetic variation in global salamanders
Authors: Amador Luis , Wiley Daniele L.F. , Arroyo-Torres Irvin , McDaniels Chris X. , Rosario-Sanchez Esteban O. , Farmer Hannah , Bradley Hannah , Erdmann James , Pelletier Tara A , Barrow Lisa N
Published: January 2025

Aim: Genetic diversity contains information about adaptive potential and historical demography. Intraspecific genetic variation is shaped by species natural history traits and by characteristics of geography and climate within their ranges. Salamanders (Order Caudata) are amphibians of ecological and conservation interest because of their global distribution, trait diversity, and roles within ecological communities. Here, we studied genetic variation within global salamanders to investigate the most important predictors of genetic structure and genetic diversity in this group. Location: Global. Time Period: Present. Major Taxa Studied: Salamanders. Methods: We repurposed mitochondrial DNA sequences, natural history traits, and geographic and environmental data from open-access databases for 214 salamander species. We calculated nucleotide diversity (pi) and tested for isolation by distance (IBD) and isolation by environment (IBE) within each species. We analyzed these three response variables with random forest analyses and phylogenetic comparative methods using 27 predictors expected to be associated with genetic variation (e.g., number of offspring, total range size). Results: We recovered 8,175 Cytb sequences with their associated geographic coordinates, of which 7,007 sequences were manually curated by us. Species range size was an important predictor of genetic variation (pi, IBD, and IBE). We found higher diversity in regions including the Neotropics and central-eastern Europe. The absence of strong phylogenetic signal in pi, IBD, and IBE suggests that genetic variation is shaped by local ecological and geographical factors rather than by shared ancestry. Main Conclusions: Our finding that range size was an important predictor of genetic variation aligns with theoretical expectations that species with larger ranges tend to harbor more genetic diversity. Our results underscore the importance of integrating spatial data (i.e., geographic coordinates associated with DNA sequences) into macrogenetic studies, providing valuable information for future studies and conservation strategies targeting regions with high or low genetic diversity. Keywords: Amphibians, isolation-by-distance, isolation-by-environment, mitochondrial DNA, nucleotide diversity.
Spatial Heterogeneity and Subtypes of Functional Connectivity Development in Youth
Authors: Li Hongming , Cui Zaixu , Cieslak Matthew , Salo Taylor , Moore Tyler M. , Gur Raquel E. , Gur Ruben C. , Shinohara Russell T. , Oathes Desmond J. , Davatzikos Christos , Satterthwaite Theodore D. , Fan Yong
Published: January 2025

The brain functional connectome development is fundamental to neurocognitive growth in youth. While brain age prediction has been widely used to assess connectome development at the individual level, traditional approaches providing a global index overlook the spatial variability and inter-individual heterogeneity of functional connectivity (FC) development across the cortex. In this study, we introduced a regional brain development index to assess spatially fine-grained FC development. We examined the spatial variability of FC development and stratified individuals into subtypes with distinct patterns of spatial heterogeneity in region-wise FC development across the cortex through clustering. An evaluation conducted on a sample of youths aged 8-23 years using fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC) revealed three distinct FC development subtypes. Individuals with advanced FC development aligned with the hierarchical brain organization along the sensorimotor-association (S-A) axis demonstrated superior cognitive performance compared to those with other patterns. These patterns were replicated in the Human Connectome Project Development (HCP-D) cohort, confirming their robustness. Further analysis revealed associations between FC development and gene expression, with enriched genes linked to neural differentiation, synaptogenesis, and myelination. These findings suggest that spatial heterogeneity in FC development reflects underlying cortical microstructure and hierarchical cortical organization, underscoring its critical role in understanding neurocognitive maturation and individual variability during youth.
SU(N)
symmetry with ultracold alkali dimers: Weak dependence of scattering properties on hyperfine state
Authors: Mukherjee Bijit , Hutson Jeremy M.
Published: January 2025

We investigate the prospect of using ultracold alkali diatomic molecules to implement many-body quantum systems with SU(N) symmetry. Experimentally accessible molecules offer large N for both bosonic and fermionic systems, with both attractive and repulsive interactions. We carry out coupled-channel scattering calculations on pairs of NaK, NaRb, and NaCs molecules that are shielded from destructive collisions with static electric fields. We develop new methods to handle the very large basis sets required to include nuclear spins. We show that all the molecules studied have the properties required for SU(N) symmetry: the collisions are principally elastic, and the scattering lengths depend only weakly on the spin states of the molecules. The rates of spin-changing inelastic collisions are very low. We develop and test a semiclassical model of the spin dependence and find that it performs well.

Published by the American Physical Society
2025
Has AlphaFold3 achieved success for RNA?
Authors: Bernard Clément , Postic Guillaume , Ghannay Sahar , Tahi Fariza
Published: January 2025

Predicting the 3D structure of RNA is a significant challenge despite ongoing advancements in the field. Although AlphaFold has successfully addressed this problem for proteins, RNA structure prediction raises difficulties due to the fundamental differences between proteins and RNA, which hinder its direct adaptation. The latest release of AlphaFold, AlphaFold3, has broadened its scope to include multiple different molecules such as DNA, ligands and RNA. While the AlphaFold3 article discussed the results for the last CASP-RNA data set, the scope of its performance and the limitations for RNA are unclear. In this article, we provide a comprehensive analysis of the performance of AlphaFold3 in the prediction of 3D structures of RNA. Through an extensive benchmark over five different test sets, we discuss the performance and limitations of AlphaFold3. We also compare its performance with ten existing state-of-the-art ab initio, template-based and deep-learning approaches. Our results are freely available on the EvryRNA platform at https://evryrna.ibisc.univ-evry.fr/evryrna/alphafold3/.
The role of entrepreneurial alertness and temporal focus in fostering sustainable entrepreneurship in young family firms
Authors: Futre Bruno , Crespo Nuno Fernandes
Published: January 2025

Purpose

This study examines the relationship between entrepreneurial alertness, long-term and short-term focus and sustainable entrepreneurship in the context of young family firms. Additionally, we investigate how family management and long-term/short-term focus moderate the relationship between entrepreneurial alertness and sustainable entrepreneurship. Our findings contribute to a deeper understanding of the factors influencing sustainable entrepreneurship in family firms.

Design/methodology/approach

This quantitative study investigated 707 young family firms in Portugal. Structural equation modeling (SEM) was employed to analyze the data and test the proposed hypotheses.

Findings

The results indicate a positive relationship between young family firms’ entrepreneurial alertness and sustainable entrepreneurship. Also relevant is that long-term focus is positively related to sustainable entrepreneurship, while short-term focus shows a negative relationship, challenging the temporal ambidexterity of new ventures. Conversely, two moderating effects were found: family management weakens and short-term focus strengthens the relationship between entrepreneurial alertness and sustainable entrepreneurship.

Originality/value

As far as we know, this study is the first one to explore the link between the entrepreneurial alertness of young family firms and sustainable entrepreneurship. It is also the first study to explore the contradictory impacts of both long-term focus and short-term focus on sustainable entrepreneurship.
Bridging role conflict and active lurking: the role of transformational leadership in B2B online communities
Authors: Nguyen Mai , Septianto Felix , Das Gopal , Malik Ashish
Published: January 2025

Purpose

In the turbulence of a business-to-business (B2B) environment, employees often face role conflict as the result of changes in task allocations due to work requirements. This research uses organizational role theory to investigate the impact of role conflict on active lurking in B2B online communities. Active lurking, defined as the behavior of seeking information and acquiring knowledge without contributing, contrasts with posters who actively share knowledge. By focusing on these dynamics, this study aims to deepen the understanding of knowledge management (KM) practices and behaviors within B2B contexts.

Design/methodology/approach

This research conducts two experimental studies with a behavioral outcome to examine the impact of role conflict on active lurking and the mediating role of knowledge self-efficacy in this regard.

Findings

The results also indicate the moderating role of transformational leadership, such that when transformational leadership is low, role conflict decreases knowledge self-efficacy and active lurking. In contrast, this effect is attenuated in a high transformational leadership environment. The findings contribute to the KM literature by demonstrating how role conflict influences knowledge-sharing behaviors in B2B contexts and by capturing active lurking using a behavioral measure.

Practical implications

The implications of this study offer strategies to address role conflict and mitigate its negative impact. By integrating the concepts of posters and lurkers into the research framework, this paper offers a fresh perspective on organizational role conflict and KM. It provides insights into lurkers and active lurking behavior in B2B online communities, thereby extending the KM literature.

Originality/value

The findings of this research are novel as they first show the moderating role of transformational leadership, wherein when transformational leadership is low, role conflict decreases knowledge self-efficacy and active lurking and second it extends the literature on online knowledge sharing in a B2B context by capturing the role of active lurking through a behavioral measure.
Unlocking the power of AI in education: students’ intentions and AI tool use driving learning success in an emerging economy
Authors: Saha Priya , Hossain Md. Shakhawat , Roy Nirmal Chandra , Masud Abdullah Al , Amin Ruhul
Published: January 2025

Purpose

This study aims to evaluate students’ intention and actual use (AU) of artificial intelligence (AI) tools’ to discover how the power of AI influences learning and academic success.

Design/methodology/approach

This paper used the unified theory of acceptance and use of technology (UTAUT) to develop a structural equation model (SEM) and used convenience sampling to measure 304 students’ five-point Likert scale responses. The model was tested with AMOS-24 and SPSS-25, and the study found that AI boosted students’ learning experiences and explain importance of AI skills and knowledge.

Findings

Performance expectancy (PE), effort expectancy (EE), social influence and facilitating condition directly and indirectly affect AU via intent to use (IU), while subjective norms determining the use of AI tools’ and have no substantial influence. Attitude (ATT) moderates PE and EE, although the data show that ATT has no substantial effect on EE.

Originality/value

These insights may help student to understand how AI tools’ benefit them and what factors affect their utilization. When correctly designed and executed, UTAUT provides an appropriate integrated theoretical framework for robust statistical analysis like SEM.
A novel heuristic programming-based intelligent controller for autonomous farming
Authors: Mukherjee Subhradip
Published: January 2025

Purpose

This paper aims to develop one heuristic programming approach-based intelligent controller with unique necessary conditions for autonomous farming in a crop field, which improves path navigation and fewer damages to the vegetable crops in given environments. The proposed controller has also used the object detection and pesticide spraying technique with a ground robotic vehicle (GRv).

Design/methodology/approach

The controller contains a unique cost function, which approximates the cost of the easiest solution for the entire operation. Every time the main loop of the controller iterates, it detects the best-estimated solution from the given values. One path planning strategy is implemented in a crop field with the GRv in the simulated and experimental environment. The GRv moves to different planned positions of the crop field by avoiding obstacles and also optimizes the travelled path.

Findings

The proposed controller is also compared with the existing approaches to validate its efficacy. In comparison to the modified DAYANI and the advanced sine-cosine algorithm-advanced ant colony optimization strategy, the heuristic programming approach-based intelligent controller has convincingly improved the length of the navigational path by 4.53% and 3.7%, respectively.

Originality/value

In real time, the highest speed achieved by the GRv in the crop field is approximately 1.5 km/h. The proposed controller performs successfully in the given environments.
Deep reinforcement learning-based variable impedance control for grinding workpieces with complex geometry
Authors: Li Yanghong , Wang Yahao , Li Zhen , Yingxiang Lv , Chai Jin , Dong Erbao
Published: January 2025

Purpose

This paper aims to design a deep reinforcement learning (DRL)-based variable impedance control policy that supports stability analysis for robot force tracking in complex geometric environments.

Design/methodology/approach

The DRL-based variable impedance controller explores and pre-learns the optimal policy for impedance parameter tuning in simulation scenarios with randomly generated workpieces. The trained results are then used as feedforward inputs to improve the force-tracking performance of the robot during contact. Based on Lyapunov’s theory, the stability of the proposed control policy is analysed to illustrate the interpretability of the results.

Findings

Simulations and experiments are performed on different types of complex environments. The results show that the proposed method is not only theoretically feasible but also has better force-tracking effects in practice.

Originality/value

Compared with most other DRL-based control policies, the proposed method possesses stability and interpretability, effectively avoids the overfitting phenomenon and thus has better simulation-to-real deployment results.