bluuebunny/crossref_metadata_2025_split huggingface dataset:
Humanized Bone Marrow-Liver-Thymus Mice for Studying HIV-1 Persistence in Liver and Lung CD4+ T and Myeloid Cell Subsets during Antiretroviral Therapy
Authors: Cattin Amélie , Pham Tram NQ , Dias Jonathan , Do Rosario Natalia Fonseca , Marchand Laurence Raymond , Volodina Olga , Guimond Jean-Victor , Patey Natalie , Li Yuanyi , Béland Kathie , Jenabian Mohammad-Ali , Estaquier Jérôme , Haddad Elie , Cohen Éric A. , Ancuta Petronela 
Published: February 2025

ABSTRACTBackgroundWhile the role of CD4+T-cells in HIV-1 reservoir persistence during antiretroviral therapy (ART) is well-established, studies on tissue-resident macrophages (MΦ) in people with HIV-1 (PWH) are restricted by difficulties in accessing deep tissue samples. Investigations in myeloid-only humanized mouse models demonstrated the contribution of MΦ to viral rebound upon ART interruption. Two distinct MΦ subsets exist in mice and humans: one of embryonic origin and self-renewal capacity generating long-lived tissue-resident MΦ (LL-TRM), and another one of short-lived MΦ (SL-MΦ), constantly replenished by bone marrow monocytes. The relative contribution of LL-TRMversusSL-MΦ to tissue HIV-1 reservoir persistence during ART remains understudied. Here, we used a humanized BM-liver-thymus (hu-BLT) mouse model to quantify integrative HIV-1 infection in liver/lung MΦversusCD4+T-cells before/after ART and document their expression of LL-TRM/SL-MΦ markers.ResultsLung/liver immune cells were extracted from ART-naive (ART-) and ART-treated (ART+) HIV-infected (HIV+) hu-BLT mice, as well as HIV-uninfected mice (HIV-). MΦ were identified as cells expressing the myeloid markers CD33/HLA-DR and/or CD68 and flow-cytometry sorted based on their differential expression of CD14 and/or CCR2. Matched CD3+CD4+T-cells were sorted in parallel and used as controls. HIV-DNA integration was measured by nested real-time PCR. In contrast to CD4+T-cells that carried the highest levels of proviral HIV-DNA before and after ART, integrative infection in liver/lung MΦ was detected before ART, but was drastically reduced in HIV+ART+ hu-BLT mice, regardless of CD14 or CCR2 expression on MΦ. Markers of LL-TRM (CD163/CX3CR1/Ki67/c-Kit) were expressed on a small fraction of liver but not lung MΦ, indicative of a deficient LL-TRM development in this hu-BLT model.ConclusionsTogether our results demonstrate that lung/liver MΦ in hu-BLT mice support integrative HIV-1 infectionin vivo, but their contribution to viral reservoir persistence during ART is minor when compared to CD4+T-cells. This is consistent with the deficient development of LL-TRM we observed in hu-BLT mice. However, HIV-1 permissive MΦ present in this model likely contribute to viral rebound upon ART interruption. Therefore, HIV-1 cure interventions that are tested in such preclinical models should consider targeting HIV-1 replication in both MΦ and CD4+T-cells.
Swirling motion of breast cancer cells radially aligns collagen fibers to enable collective invasion
Authors: Saraswathibhatla Aashrith , Rabbi Md Foysal , Varma Sushama , Srivastava Vasudha , Ilina Olga , Alyafei Naomi Hassan Kahtan , Hodgson Louis , Gartner Zev , Friedl Peter , West Robert , Kim Taeyoon , Chaudhuri Ovijit 
Published: February 2025

AbstractIn breast cancer (BC), radial alignment of collagen fibers at the tumor-matrix interface facilitates collective invasion of cancer cells into the surrounding stromal matrix, a critical step toward metastasis. Collagen remodeling is driven by proteases and cellular forces, mediated by matrix mechanical plasticity, or irreversible matrix deformation in response to force. However, the specific mechanisms causing collagen radial alignment remain unclear. Here, we study collective invasion of BC tumor spheroids in collagen-rich matrices. Increasing plasticity to BC-relevant ranges facilitates invasion, with increasing stiffness potentiating a transition from single cell to collective invasion. At enhanced plasticity, cells radially align collagen at the tumor-matrix interface prior to invasion. Surprisingly, cells migrate tangentially to the tumor-matrix interface in a swirling-like motion, perpendicular to the direction of alignment. Mechanistically, swirling generates local shear stresses, leading to distally propagating contractile radial stresses due to negative normal stress, an underappreciated property of collagen-rich matrices. These contractile stresses align collagen fibers radially, facilitating collective invasion. The basement membrane (BM), which separates epithelia from stroma in healthy tissues, acts as a mechanical insulator by preventing swirling cells from aligning collagen. Thus, after breaching the BM, swirling of BC cells at the tumor-stroma interface radially aligns collagen to facilitate invasion.
Editing strigolactone biosynthesis genes in tomato reveals novel phenotypic effects and highlightsD27as a key target for parasitic weed resistance
Authors: Nicoliaa A. , Cuccurullo A. , Tamada K. , Yoneyama K. , Rambla J.L. , Granell A. , Camerlengo F. , Festa G. , Francese G. , Contaldi F. , D’Alessandro A. , Rigano M.M. , Principio L. , D’Agostino N. , Cardi T. 
Published: February 2025

AbstractParasitic weed infestations pose an increasing threat to agriculture worldwide, especially in the Mediterranean region.Phelipanche ramosaandP. aegyptiaca(broomrapes) cause severe damage to field-grown tomato (Solanum lycopersicum L.). Strigolactones (SLs), apocarotenoid phytohormones, play a critical role in plant physiology and development, and are also the primary signals that trigger the germination of parasitic weed seeds. We generated CRISPR/Cas9 tomato knock-out lines for theSlD27gene, as well as three other key genes involved in SL biosynthesis (SlCCD7,SlCCD8,SlMAX1), all within the same genetic background. The edited lines exhibited a marked reduction in SL content in root exudates, along with impaired broomrape seed germination. A comprehensive analysis of morphological, reproductive, and fruit-related traits revealed gene-specific effects on plant phenotype, including vegetative traits, fruit set, fruit development, and volatilome. Specifically, the knock-out of twoCCDsand theMAX1had a specific impact not only on plant development but also on the production of volatile organic compounds during fruit ripening. In contrast, theSld27lines, produced for the first time in this study, displayed a phenotype similar to the control non-edited plants, suggesting that theD27gene holds promise as a breeding target for enhancing resistance to parasitic weeds in tomato.HighlightThe characterization of tomato CRISPR/Cas9-edited lines for the four core genes involved in strigolactone biosynthesis revealed gene-specific effects on plant phenotype, withD27emerging as a potential target for resistance to parasitic weeds.
The acidic N-terminus of HHARI and neddylation are essential for the activation and maintenance of RIG-I-mediated type I interferon response
Authors: Kontra Ioanna , Ward Harry , Vinluan Faith , Lau Rachel , Rajeeve Vinothini , Cutillas Pedro , Stieglitz Benjamin , Lewis Myles J. 
Published: February 2025

AbstractHuman homolog of Ariadne (HHARI) is a RING-between-RING ubiquitin E3 ligase which interacts with cullin-RING E3 ligase (CRL) complexes. HHARI has been implicated in the type-I interferon anti-viral response. However, how HHARI drives interferon signalling is not fully understood and the function of the unique, highly conserved acidic N-terminal domain of the protein is unknown. Here, we show that HHARI stimulates interferon-β secretion and autocrine type-I interferon signalling by directly targeting the viral RNA sensor RIG-I (Retinoic Acid-Inducible Gene I) in a neddylation-dependent manner. This suggests that neddylation inhibition could be used to treat interferonopathies and related diseases. Truncated HHARI containing only the N-terminal acidic/UBA-like domains retained the ability to induce interferon signalling in a neddylation-dependent mechanism. HHARI-mediated interferon-β secretion was enhanced by overexpression of cullins 1-5. The N-terminal acidic/UBA-like domain of HHARI is critical for RIG-I activation and interferon signalling, as removal of these domains inactivated the pro-interferon phenotype. We propose a mechanism by which the N-terminus of HHARI interacts with all neddylated cullins leading to endogenous HHARI activation. This suggests a model in which the N-terminus of HHARI ‘unlocks’ and activates neddylated cullins, which in turn are required for activation of HHARI itself. As cullins typically form modular cullin-RING ligase super-assemblies our findings imply that the HHARI N-terminus domain is a critical regulator of the versatile CRL system, which, through widespread protein ubiquitylation, controls many eukaryotic cell functions.
Transcriptional control of T cell tissue adaptation and effector function in infants and adults
Authors: Szabo Peter A. , Levitin Hanna M. , Connors Thomas J. , Chen David , Jin Jenny , Thapa Puspa , Guyer Rebecca , Caron Daniel P. , Gray Joshua I. , Matsumoto Rei , Kubota Masaru , Brusko Maigan , Brusko Todd M. , Farber Donna L. , Sims Peter A. 
Published: February 2025

ABSTRACTThe first years of life are essential for the development of memory T cells, which rapidly populate the body’s diverse tissue sites during infancy. However, the degree to which tissue memory T cell responses in early life reflect those during adulthood is unclear. Here, we use single cell RNA-sequencing of resting andex vivoactivated T cells from lymphoid and mucosal tissues of infant (aged 2-9 months) and adult (aged 40-65 years) human organ donors to dissect the transcriptional programming of memory T cells over age. Infant memory T cells demonstrate a unique stem-like transcriptional profile and tissue adaptation program, yet exhibit reduced activation capacity and effector function relative to adults. Using CRISPR-Cas9 knockdown, we define Helios (IKZF2) as a critical transcriptional regulator of the infant-specific tissue adaptation program and restricted effector state. Our findings reveal key transcriptional mechanisms that control tissue T cell fate and function in early life.
Deciphering DNA’s sequence-dependent structure and deformability with normalizing flows
Authors: Liebl Korbinian 
Published: February 2025

AbstractThe sequence-dependent structure and deformability of double-stranded DNA plays a key role in many cellular processes. Accurate description thereof has thus been a long-standing problem. Previous approaches to this problem assume a specific functional form for the elastic energy in terms of internal coordinates of the DNA double-helix. The conformational flexibility of DNA, however, is strongly impacted by several stereo-chemical effects that complicate the formulation of an accurate functional form. In this work, I propose an entirely new, AI-based method to decipher the sequence-dependent structure and deformability of double-stranded DNA. This method employs normalizing flows that capture multimodal and correlation effects between internal coordinates of the DNA double helix excellently, and hence allows one to accurately quantify deformation energies for any double-stranded DNA structure and sequence. Thus, it offers a wide range of future applications, and speaks in favor of AI-based elasticity-descriptions also for other molecules.
Cutaneous lupus features specialized stromal niches and altered retroelement expression
Authors: Gehlhausen Jeff R. , Kong Yong , Baker Emily , Ramachandran Sarika , Koumpouras Fotios , Ko Christine J. , Vesely Matthew , Little Alicia J. , Damsky William , King Brett , Iwasaki Akiko 
Published: February 2025

AbstractCutaneous Lupus is an inflammatory skin disease causing highly morbid inflamed skin and hair loss. In order to investigate the pathophysiology of cutaneous lupus, we performed single-cell RNA and spatial sequencing of lesional and non-lesional cutaneous lupus skin compared to healthy controls. Pathway enrichment analyses of lesional keratinocytes revealed elevated responses to type I interferon, type II interferon, tumor necrosis factor, and apoptotic signaling. Detailed clustering demonstrated unique fibroblasts specific to lupus skin with likely roles in inflammatory cell recruitment and fibrosis. We also evaluated the association of retroelement expression with type I interferons in the skin. We observed increased retroelement expression which correlated with interferon-stimulated genes across multiple cell types. Moreover, we saw elevated expression of genes involved in RIG-I and cGAS-STING pathways, which transduce elevated nucleic acid signals. Treatment of active cutaneous lupus with Anifrolumab reduced RIG-I and cGAS-STING pathways in addition to the most abundant retroelement family, L2b. Our studies better define type I interferon-mediated immunopathology in cutaneous lupus and identify an association between retroelement expression and interferon signatures in cutaneous lupus.
Fast and Scalable Parallel External-Memory Construction of Colored Compacted de Bruijn Graphs with Cuttlefish 3
Authors: Khan Jamshed , Dhulipala Laxman , Patro Rob 
Published: February 2025

AbstractThe rapid growth of genomic data over the past decade has made scalable and efficient sequence analysis algorithms, particularly for constructing de Bruijn graphs and their colored and compacted variants critical components of many bioinformatics pipelines. Colored compacted de Bruijn graphs condense repetitive sequence information, significantly reducing the data burden on downstream analyses like assembly, indexing, and pan-genomics. However, direct construction of these graphs is necessary as constructing the original uncompacted graph is essentially infeasible at large scale. In this paper, we introduce Cuttlefish3, a state-of-the-art parallel, external-memory algorithm for constructing (colored) compacted de Bruijn graphs. Cuttlefish3 introduces novel algorithmic improvements that provide its scalability and speed, including optimizations to significantly speed up local contractions within subgraphs, a parallel algorithm to join local solutions based on parallel list-ranking, and a sparsification method to vastly reduce the amount of data required to compute the colored graph. Leveraging these algorithmic strategies along with algorithm engineering optimizations in parallel and external-memory setting, Cuttlefish3 demonstrates state-of-the-art performance, surpassing existing approaches in speed and scalability across various genomic datasets in both colored and uncolored scenarios.
Integrating fossils samples with heterogeneous diversification rates: a combined Multi-Type Fossilized Birth-Death model
Authors: Barido-Sottani Joëlle , Morlon Hélène 
Published: February 2025

AbstractBirth-death models are widely used to describe the diversification process which leads to the observed species and phylogenies. When integrated into Bayesian phylogenetic inference, birth-death models allow the joint inference of the phylogeny and the diversification parameters from molecular information. Two major classes of extensions of the birth-death process are considered in this article. The first extends the phylogenetic tree to include fossil samples alongside extant species, allowing the inference to integrate information about the past diversity. The second extension models diversification rates which can vary between lineages, and is thus able to infer patterns of variation in speciation or extinction rates. In this work, we combine these two types of extension into a multi-type fossilized birth-death (MTFBD) process, which can perform the joint inference of a phylogeny including extinct and extant samples, and lineage-specific diversification and fossilization rates in a Bayesian framework. The MTFBD model is implemented as part of the phylogenetic inference framework BEAST2. Using simulated and empirical datasets, we demonstrate the performance and accuracy of the new model compared to a model with rate heterogeneity but using only extant samples, and compared to a model without rate variation including fossils. We demonstrate that including fossils improves the accuracy of the phylogeny and diversification rates, especially extinction rates, provided that the inference includes morphological information to accurately place the fossil samples. When this information is not available however, MTFBD estimates are strongly driven by the priors and are thus no better or even worse than estimates obtained only with extant samples. With informative fossil characters, the MTFBD model provides accurate phylogenies, and precisely characterizes how speciation, extinction and fossilization rates vary as diversification proceeds.
Leveraging Pretrained Large Language Model for Prognosis of Type 2 Diabetes Using Longitudinal Medical Records
Authors: Nguyen Phong B.H. , Hungele Andreas , Holl Reinhard W. , Menden Michael P. 
Published: February 2025

AbstractTimely prognosis of type 2 diabetes (T2D) complications is critical for effective interventions and reducing economic burden. AI-driven large language models (LLMs) offer potential for extracting clinical insights but face challenges due to the sparse, high-dimensional nature of longitudinal medical records. This study demonstrates the utility of LLMs in medical time series prediction by preprocessing data with a missing mask, adding an embedding layer to a pretrained LLM, and fine-tuning both components. The fine-tuned model outperformed baselines in predicting both HbA1c and LDL levels using the DPV registry dataset of 449,185 T2D patients, achieving Pearson’s correlations of 0.749 and 0.754, with a delta improvement of 0.253 and 0.259, respectively. The model also demonstrated robust long-term prediction for HbA1c over 554.3 days (95% CI: [547.0, 561.5]), with a 9% improvement in MSE over last-observation-based methods. Integrated gradient analysis identified significant clinical features and visits, revealing potential biomarkers for early intervention. Overall, the results showed the possibility to leverage the prediction power of LLM in T2D prognosis using sparse medical time series, assisting clinical prognosis and biomarker discovery, ultimately advancing precision medicine.
Unveiling Meropenem Resistance and Co-Resistance Patterns inKlebsiella pneumoniaeandAcinetobacter baumannii: A Global Genome Analysis Using ML/DL and Association Mining
Authors: Ramachandran Srimathy , Deepak K , Shrikumaran M , Mohamed Rasiq R , Ananya S , Aruna V , Derrick Daniel P , Sruthi B , Suma Mohan S 
Published: February 2025

ABSTRACTBackgroundThe increasing prevalence of meropenem-resistant gram-negative bacteria has significantly undermined its effectiveness and has increased treatment failure and mortality rates. The global availability of bacterial WGS data with antimicrobial resistance phenotypes enables large-scale genome analysis to explore resistance determinants. This study investigated the meropenem resistance mechanism in multidrug-resistant (MDR)Klebsiella pneumoniae(KP) andAcinetobacter baumannii(AB) isolates using advanced data analytics approaches.MethodsWe analysed 2,411 KP and 375 AB isolates with meropenem-resistant and susceptible phenotypes from the BV-BRC database. AMR genes and mutations were identified from the isolates using the CARD database as a reference. Significant AMR genes and missense mutations, determined through chi-square tests, were subsequently used to train ML and DL models. The best-performing SVM model was used for sequential feature selection to identify key features. Additionally, association mining was conducted separately on the selected features and the antibiotics data.ResultsNotable differences were observed in the proportions of genes contributing to the meropenem resistance mechanism categories between KP and AB, including carbapenemases (4% in KP, 23% in AB), antibiotic efflux (30%, 60%), target alteration (23%, 12%), and reduced permeability (18%, 3%). Mutation frequencies also vary, with antibiotic efflux (26%, 67%), target alteration (64%, 5%), and reduced permeability (7%, 15%). A total of 410 significant features in KP and 211 in AB were identified for model building. SVM-based feature selection pinpointed seven key features in KP and 10 in AB, resulting in 95% accuracy for both. Association mining revealedblaKPC-2,blaKPC-3,bleMBL, andaac(6’)-Ib9as key factors in KP, andblaOXA-23, Abau_gyrA_FLO|Ser81Leu, and Abau_OprD_IMP|Asn411Asp in AB associated with meropenem resistance. The observed prevalence of AAC genes and thegyrAmutation, along with insights from association mining, reveals the co-resistance of meropenem with aminoglycosides and fluoroquinolones, whileoprDmutations imply potential shared resistance across antibiotics.ConclusionThe analysis of AMR genes and mutations based on resistance mechanisms revealed distinct differences in meropenem resistance between KP and AB. The ML/DL models and association mining approaches identified key resistance features and cross-antibiotic resistance insights. These findings deepen our understanding of meropenem resistance, enabling more precise and effective antimicrobial interventions.
Associations of ADHD symptom severity, sleep/circadian factors, depression and quality of life: Secondary analyses of the Netherlands Sleep Registry study
Authors: Nair Siddhi , Deshpande Neha , Hill Catherine M. , Cortese Samuele , Van Someren Eus , Chellappa Sarah L. 
Published: February 2025

ABSTRACTStudy objectivesWe investigated whether sleep disruption and circadian preference mediate the associations of ADHD symptom severity with depression symptom severity and quality of life.Methods1364 participants (mean: 51.86 [SD= 0.37] years, 75% females) from a large-scale cross-sectional online survey (Netherlands Sleep Registry) completed a sociodemographic questionnaire, the Adult ADHD Rating Scale, Hospital Anxiety and Depression Scale (HADS), Satisfaction With Life Scale (SLS) and Cantril Ladder (CL) (quality of life measures), Insomnia Severity Index, Pittsburgh Sleep Quality Index, and Munich Chronotype Questionnaire.ResultsHigher ADHD symptom severity was significantly associated with depression severity (p= 0.03), lower quality of life (p< 0.001), insomnia severity (p< 0.001), lower sleep quality (p< 0.001), and later circadian preference (p= 0.01). No sleep or circadian factor significantly mediated the association of the severity of symptoms of ADHD and depression (allp> 0.1). Conversely, only insomnia severity significantly mediated the association of the severity of symptoms of ADHD and quality of life (SLS: standardized beta = -0.10, 95% CI = [-0.12, -0.04]; CL: standardized beta = .103, 95% CI = [0.04, 0.16]).ConclusionADHD symptom severity was associated with lower quality of life, primarily mediated by insomnia symptom severity. Future studies targeting insomnia complaints in this population may help mitigate their depression complaints and improve their quality of life.