bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic restoration of differentiation competency via reversal of epiblast regionalisation
Authors: Sutcliffe Magdalena A. , Wingett Steven W. , Morris Charles A.J. , Wong Eugenia , Schoenfelder Stefan , Lancaster Madeline A. 
Published: December 2024

AbstractAlthough the epiblast in the embryo has the capacity to generate all tissues of the body, itsin vitrocounterparts often exhibit differentiation biases, posing significant challenges for both basic research and translational applications involving pluripotent stem cells (PSCs). The origins of these biases remain incompletely understood. In this study, we identify PSC differentiation biases as arising from fluctuations in repressive and activating histone posttranslational modifications, leading to the acquisition of a caudal epiblast-like phenotype.We present a novel approach to overcome this bias using a chemical chromatin restoration (CHR) treatment. This method restores transcriptional programs, chromatin accessibility, histone modification profiles, and differentiation potential, effectively recapitulating the competent anterior epiblast-like state. Furthermore, we propose that a high bivalency state is a defining feature of the anterior human epiblast. We suggest that fluctuations in histone modification marks drive epiblast regionalization, ultimately shaping cellular responses to differentiation cues.
Virological and antigenic characteristics of SARS-CoV-2 variants LF.7.2.1, NP.1, and LP.8.1
Authors: Liu Jingyi , Yu Yuanling , Yang Sijie , Jian Fanchong , Song Weiliang , Yu Lingling , Shao Fei , Cao Yunlong 
Published: December 2024

AbstractXEC and KP.3.1.1 have surpassed KP.3 to become the globally dominant lineages due to their unique NTD mutations. However, several emerging JN.1 sublineages, such as LF.7.2.1, MC.10.1, NP.1, and, especially, LP.8.1, have demonstrated superior growth advantages compared to XEC. It is critical to access the virological and antigenic characteristics of these emerging SARS-CoV-2 variants. Here, we found that LF.7.2.1 is significantly more immune invasive than XEC, primarily due to the A475V mutation, which enabled the evasion of Class 1 neutralizing antibodies. However, LF.7.2.1’s weak ACE2 binding affinity substantially impaired its fitness. Likewise, MC.10.1 and NP.1 exhibited strong antibody immune evasion due to the A435S mutation, but their limited ACE2 engagement efficiency restricted their growth advantage, suggesting that A435S may regulate the Spike conformation, similar to the NTD glycosylation mutations found in KP.3.1.1 and XEC. Most importantly, we found that LP.8.1 showed comparable humoral immune evasion to XEC but demonstrated much increased ACE2 engagement efficiency, supporting its rapid growth. These findings highlight the trade-off between immune evasion and ACE2 engagement efficiency in SARS-CoV-2 evolution, and underscore the importance of monitoring LP.8.1 and its descend lineages.
Sequence-based coevolutionary prediction of species-specific interactomes
Authors: Fernandez-Martin Miguel , Pontes Camila , Ruiz-Serra Victoria , Valencia Alfonso 
Published: December 2024

AbstractEvolutionarily conserved protein-protein interactions (PPIs) reveal fundamental biological processes. However, predicting protein function solely from these interactions provides an incomplete picture of biological systems. Computational methods for predicting PPIs often struggle due to limited functional annotations in databases, making it difficult to fully understand unique biological systems.. This study introduces ContextMirror2.0 (CM2.0), a coevolution-based method designed to address these limitations. Coevolutionary approaches, unlike supervised machine learning methods, do not rely on labelled datasets, proving valuable in addressing the scarcity of data for species-specific PPIs. While around 40% of CM2.0’s top-1000 predicted PPIs forE. coli, S. enterica, andS. aureusare present in experimental PPI databases, a comparative analysis of predicted functional communities revealed highly conserved interaction patterns and species-specific interactions. CM2.0 leverages coevolutionary information to explore protein interaction dynamics and understand the functional consequences of species-specific variations. This information can inform further studies on the emergence of novel functions, adaptation to specific environments, and the development of targeted therapies.
SLC35A2 loss of function variants affect glycomic signatures, neuronal fate, and network dynamics
Authors: Lai Dulcie , Sosicka Paulina , Williams Damian J , Bowyer MaryAnn E , Ressler Andrew K , Kohrt Sarah E , Muron Savannah J , Crino Peter B , Freeze Hudson H , Boland Michael J , Heinzen Erin L 
Published: December 2024

AbstractSLC35A2encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline geneticSLC35A2variants have been identified in congenital disorders of glycosylation and somaticSLC35A2variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain elusive.In this study, we use an isogenic human induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss of function variants inSLC35A2through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics, and single cell electrophysiology.We show that loss of function variants inSLC35A2result in disrupted glycomic signatures and precocious neurodevelopment, yielding hypoactive, asynchronous neural networks. This aberrant network activity is attributed to an inhibitory/excitatory imbalance as characterization of neural composition revealed preferential differentiation ofSLC35A2loss of function variants towards the GABAergic fate. Additionally, electrophysiological recordings of synaptic activity reveal a shift in excitatory/inhibitory balance towards increased inhibitory drive, indicating changes occurring specifically at the pre-synaptic terminal.Our study is the first to provide mechanistic insight regarding the early development and functional connectivity ofSLC35A2loss of function variant harboring human neurons, providing important groundwork for future exploration of potential therapeutic interventions.
Cellular cartography reveals mouse prostate organization and determinants of castration resistance
Authors: Cho Hanbyul , Zhang Yuping , Tien Jean C. , Mannan Rahul , Luo Jie , Narayanan Sathiya Pandi , Mahapatra Somnath , Hu Jing , Shelley Greg , Cruz Gabriel , Shahine Miriam , Wang Lisha , Su Fengyun , Wang Rui , Cao Xuhong , Dhanasekaran Saravana Mohan , Keller Evan T. , Pitchiaya Sethuramasundaram , Chinnaiyan Arul M. 
Published: December 2024

AbstractInadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single-cell RNA sequencing, single-cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta-analysis of human prostates and prostate cancer, we identified cellular orthologs and key determinants of ADT response and resistance. Our findings reveal that mouse prostates harbor lobe-specific luminal epithelial cell types distinguished by unique gene regulatory modules and anatomically defined androgen-responsive transcriptional programs, indicative of divergent developmental origins. Androgen-insensitive, stem-like epithelial populations - resembling human club and hillock cells - are notably enriched in the urethra and ventral prostate but are rare in other lobes. Within the ventral prostate, we also uncovered two additional androgen-responsive luminal epithelial cell types, marked by Pbsn or Spink1 expression, which align with human luminal subsets and may define the origin of distinct prostate cancer subtypes. Castration profoundly reshaped luminal epithelial transcriptomes, with castration-resistant luminal epithelial cells activating stress-responsive and stemness programs. These transcriptional signatures are enriched in tumor cells from ADT-treated and castration-resistant prostate cancer patients, underscoring their likely role in driving treatment resistance. Collectively, our comprehensive cellular atlas of the mouse prostate illuminates the importance of lobe-specific contexts for prostate cancer modeling and reveals potential therapeutic targets to counter castration resistance.Significance StatementAndrogen deprivation therapy is a mainstay in prostate cancer treatment, yet many patients eventually develop castration-resistant disease—a lethal progression driven by poorly understood cellular mechanisms. Our study provides a comprehensive cellular map of the prostate, identifying key determinants of normal organization and castration-induced remodeling. By pinpointing the cell types and molecular programs that confer ADT responsiveness or resistance, our findings offer new directions for prostate cancer modeling and pave the way toward novel therapeutic strategies aimed at enhancing ADT efficacy and preventing the emergence of castration-resistant prostate cancer.
Direct and indirect effects of spliceosome disruption compromise gene regulation by Nonsense-Mediated mRNA Decay
Authors: Embree Caleb M. , Stephanou Andreas , Singh Guramrit 
Published: December 2024

ABSTRACTPre-mRNA splicing, carried out in the nucleus by a large ribonucleoprotein machine known as the spliceosome, is functionally and physically coupled to the mRNA surveillance pathway in the cytoplasm called nonsense mediated mRNA decay (NMD). The NMD pathway monitors for premature translation termination signals, which can result from alternative splicing, by relying on the exon junction complex (EJC) deposited on exon-exon junctions by the spliceosome. Recently, multiple genetic screens in human cell lines have identified numerous spliceosome components as putative NMD factors. Using publicly available RNA-seq datasets from K562 and HepG2 cells depleted of 18 different spliceosome components, we find that natural NMD targeted mRNA isoforms are upregulated when members of the catalytic spliceosome are reduced. While some of this increase could be due to widespread pleiotropic effects of spliceosome dysfunction (e.g., reduced expression of NMD factors due to mis-splicing of their mRNAs), we identify that AQR, SF3B1, SF3B4 and CDC40 may have a more direct role in NMD. We also test the hypothesis that increased production of novel NMD substrates may overwhelm the pathway to find a direct correlation between the amount of novel NMD substrates detected and the degree of NMD inhibition observed. Finally, similar transcriptome alterations and NMD substrate upregulation are also observed in cells treated with spliceosome inhibitors and in cells derived from retinitis pigmentosa patients with mutations inPRPF8andPRPF31. Overall, our results show that regardless of the cause, spliceosome disruption upregulates a broad set of NMD targets, which could contribute to cellular dysfunction in spliceosomopathies.AUTHOR SUMMARYDuring gene expression, a complex cellular machine known as spliceosome removes extraneous non-coding sequences from precursor RNAs to produce messenger RNA (mRNA) with a contiguous code for protein sequence. To guard against splicing errors that may interrupt protein coding sequence, splicing is linked to a mRNA surveillance pathway known as nonsense mediated mRNA decay (NMD). In this work, we follow up on recent findings from multiple genetic screens that several spliceosome components are necessary for efficient NMD. Our analysis of transcriptomes of lymphoblast K562 cells depleted of 18 spliceosome factors show that NMD based regulation is compromised in cells lacking catalytic spliceosome proteins. Four of these spliceosome proteins may have a direct effect on NMD even though spliceosome disruption in general also causes other changes in gene expression that indirectly affect NMD. Our results suggest that defective NMD based regulation contributes to cellular dysfunction in spliceosomopathies, a collection of human genetic disorders caused by mutations in spliceosome factors.
The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia
Authors: Arneson-Wissink Paige C. , Pelz Katherine , Worley Beth , Mendez Heike , Pham Peter , McCarthy Grace , Chitsazan Alex , Brody Jonathan R. , Grossberg Aaron J. 
Published: December 2024

ABSTRACTBackgroundCachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC), and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice.MethodsAdult C57BL/6J mice received orthotopic PDAC cell (KrasG12D; p53R172H/+; Pdx1-cre) (OT-PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24h, or fasted 24h and refed 24h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analyzed body mass, gross fat pad mass, and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytesin vitro, and gonadal fat pads (gWAT)ex vivo.Results3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) liberated less triglyceride into the culture media than control-treated adipocytes (−28.1%) and had lower expression of lipolysis and lipogenesis genes than control cells. PDAC gWAT culturedex vivodisplayed decreased lipolysis compared to sham gWAT (−54.7%). PDAC and sham mice lost equivalent fat mass after a 24h fast, however, PDAC mice could not restore inguinal fat pads (iWAT) (−40.5%) or gWAT (−31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (n=126) were associated with adipogenesis (adj p=0.05), and expression of adipogenesis master regulatorsPpargandCebpawere reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%) and genes regulating adipogenesis (Pparγ,Cebpa,Retn,Adipoq,Fasn).ConclusionsOur work highlights deficient adipose anabolism as a driver of wasting in 3T3-L1 adipocytes treated with PDAC conditioned media and OT-PDAC mice. The small molecule KH3, which disrupts HuR binding, was sufficient to restore adipogenic and lipogenic gene expression and prevent adipose wasting. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.
Community Engagement in Dengue Interventions in Conflict-affected Aden, Yemen: An Implementation Research Using CFIR Framework 2.0.
Authors: Dhaiban Mustafa Mohammed , Basaleem Huda , Purohit Neetu 
Published: December 2024

AbstractDengue fever is described by the World Health Organization (WHO) as “the most important mosquito-borne viral disease in the world.” In Yemen, dengue cases have consistently increased, with Aden Governorate reporting 12% of total cases and over 45% of dengue-related deaths, making it a leading public health challenge. Conflict has exacerbated health system weaknesses, limiting resources and energy for prevention efforts. Community engagement (CE) emerges as a critical approach to address these challenges.This study aimedto identify barriers and facilitators to CE in dengue interventions within conflict-affected contexts and recommend evidence-based strategies for improved implementation. A cross-sectional qualitative study was conducted between February and July 2024 in Aden Governorate, involving 15 in-depth interviews (IDIs) and four focus group discussions (FGDs) with key stakeholders.Findingsrevealed that while stakeholders perceived CE interventions positively, challenges included systemic issues such as lack of community trust, resource shortages, and health system politicization. Conflict intensified these barriers, reflected in security concerns, inadequate training, and fragmented institutional work. Financial constraints also limited implementers’ capacities. Facilitators included moral incentives, personal recognition, and community support from business owners. However, the dominance of policymakers and influencers due to systemic weaknesses negatively impacted the implementation process, particularly in participant selection and coordination strategies.In conclusion,addressing systemic fragmentation, enhancing political support, and defining clear coordination plans are critical to adapting CE interventions effectively in conflictAuthor SummaryDengue fever is considered a major health problem for many low-and middle-income countries, leading to high numbers of mortality and morbidity rates with a significant economic burden. Our study highlights the intersection of public health challenges and conflict dynamics, providing unique insights into how community engagement strategies for vector-borne diseases can be adapted to conflict settings. Using the implementation research tool CFIR Framework 2.0, we identified critical barriers, including systemic fragmentation, lack of trust, resource shortages, and weak coordination mechanisms. Conversely, facilitators such as moral incentives, personal recognition, and community-driven support offer actionable strategies for improving implementation outcomes.
Multi-omic Biomarkers Distinguish Rheumatoid Arthritis in Discordant Monozygotic Twins
Authors: Blank Rebecca B. , Bu Kevin , Chen Weixi , Cunningham Ian , Sokolove Jeremy , Lahey Lauren , Heguy Adriana , Medina Rhina , Ubeda Carles , Nayak Renuka R. , Hu Jiyuan , Cantor Adam , Lee Jakleen , Clemente Jose C. , Scher Jose U. 
Published: December 2024

AbstractBackgroundAlthough genetic factors have been identified in the pathogenesis of rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is low, suggesting that other features contribute to disease development. Further, the relative contribution of such non-genetic elements in identical twins have not been characterized. Here, we aimed to measure differentiating host and microbial biomarkers of RA by studying MZ twins discordant for disease using a multi-omics approach.MethodsEight pairs of MZ twins discordant for RA (n=16) were enrolled. Gut microbiome was assessed using shotgun metagenomic sequencing. Autoantibodies, cytokines, and other plasma proteins were measured in both plasma and feces. Levels of short and medium-chain fatty acids from serum and feces were quantified using gas chromatography mass spectrometry (GC-MS).ResultsWhile overall microbiome diversity and composition did not significantly differ between twins, we observed a decrease inBlautia faecisin affected twins. Affected twins had higher concentrations of both fecal and plasma citrullinated and non-citrullinated autoantibodies, as well as significantly lower concentrations of fecal butyrate and propionate.ConclusionMulti-omics biomarkers differentiate MZ twins discordant for RA.Blautia faecis, which is associated with reduced inflammatory cytokine expression, was decreased in RA twins. Similarly, short-chain fatty acids, known to have immune modulatory effects, were decreased in affected twins, suggesting further bi-directional interactions between inflammation at the gut barrier and disease state. If confirmed in other cohorts, exhaustive multi-omics approaches may improve our understanding of RA pathogenesis and potentially contribute to novel diagnostics and co-adjuvant therapies.
Factors Associated with Anxiety and Depression among Reproductive-aged Women in Bangladesh: Insights from the 2022 DHS
Authors: Sheoti Isna Haque , Shezuti Sanzana Saira , Alam Md. Zakiul 
Published: December 2024

AbstractIntroductionMental health disorder causes significant disturbance to every aspect of an individual’s life. Almost one in every eight people in the world lives with a mental disorder. In this study, we aimed to measure the prevalence and determinants of anxiety and depression among reproductive-aged women in Bangladesh.MethodologyWe utilized data from Bangladesh demographic and health survey-2022. Anxiety and depression were measured by the Generalized Anxiety Disorder 7 Scale (GAD-7) and the Patient Health Questionnaire (PHQ-9). We used the chi-square test in bivariate analysis and log-binomial logistic regression to explore the factors associated with anxiety and depression.FindingsAround 20% and 5% had symptoms of anxiety and depression, respectively. Compared to women aged 15-19, anxiety was significantly higher among women ages 20-49, and women aged 45-49 (PR= 1.73, p=0.004) had a substantially higher depression. Women living in Rangpur had the highest prevalence of both anxiety and depression. Women from the poorest households and having a bank account had a significantly higher prevalence of anxiety and depression than others. Muslims had higher anxiety (PR=1.40, p<0.001) and depression (PR= 1.48, p=<0.001). Women with positive attitudes towards wife-beating had higher anxiety (PR=1.28 p<0.001) and depression (PR= 1.47, p=<0.001). Women with no education had significantly higher anxiety levels (PR=1.37, p<0.001), whereas those who had access to mass media had a higher depression (PR=1.20, p=0.016).ConclusionWomen of reproductive age face multiple crucial life events that can have an impact on their mental health. In this situation, strategic policy actions need to be provided at both family, community, and provider levels to safeguard the mental health of women in the country. Additionally, specific actions and programs need to drive for women aged 40 or above, women of lower socioeconomic class, women of Rangpur, and women suffering from domestic violence.
Influence of trace Sc on microstructure and corrosion behavior of Mg-0.5Zn alloys
Authors: Han Tingzhuang , Wang Qingxia , Zhang Cheng , Peng Peng , Long Shuai , Yang Qingshan , Dai Qingwei 
Published: December 2024

Purpose
This paper aims to explore the impact of Sc element on the microstructure and corrosion properties of Mg-0.5Zn alloy.

Design/methodology/approach
Three kinds of Mg-0.5Zn-xSc (x = 0.1, 0.3 and 0.5 Wt.%) alloys were obtained, and the microstructure and corrosion properties were both analyzed.

Findings
As the Sc concentration increases, the corrosion resistance of the alloys initially improves and subsequently deteriorates. The trace addition of Sc can effectively reduce the grain size of Mg-Zn-Sc alloys and enhance the density of the corrosion products film. Consequently, an appropriate amount of Sc can reduce the corrosion rate of Mg-0.5Zn alloy.

Originality/value
However, the addition of Sc also introduces the second phase particles in the alloy, leading to galvanic corrosion, which adversely affects the corrosion resistance of Mg-0.5Zn alloy. Therefore, the amount of Sc added should be carefully controlled.