bluuebunny/crossref_metadata_2025_split huggingface dataset:
Southern European Prospective Investigation Into Childhood Cancer and Nutrition (EPICkids): Study Design and Protocol
Authors: Perganti Foteini , Huybrechts Inge , Balduzzi Adriana Cristina , Barr Ronald , Biondi Andrea , Bladé Aina Llenas , Bravo Evangelina Muñoz , Damasco Erika , Katsagoni Christina N. , Kattamis Antonis , Lassaletta Alvaro , Lera Marta Llopis , Llort Anna , Blanco Lopez Jessica , Martinez Antonio Perez , Massimino Maura , La Madrid Andrés Morales , Moreno Lucas , Alonso Ana Muñoz , Nicolas Genevieve , Preziati Giorgia , Rizzari Sofia , Della Valle Serena , Marquez Vega Catalina , Walters Michelle , Kozlakidis Zisis , Ladas Elena J. 
Published: February 2025

AbstractThe survival rates for children with cancer have increased appreciably over the last few decades; however, childhood cancer survivors continue to suffer from long-lasting sequelae. Studies have demonstrated that the presence of malnutrition, over- and under-nutrition, at diagnosis or the duration of malnutrition during treatment is associated with increased toxicity, infection, and inferior survival. Dietary habits, along with behavioral and socioeconomic status, are known factors that lead to obesity or undernutrition and can affect the prognosis and quality of life of children with cancer. Unfortunately, the underlying mechanisms responsible for these observations are largely unknown. To address this gap in science, we established the EPICkidscohort study, an initiative of the International Initiative for Pediatrics and Nutrition at Columbia University Irving Medical Center and the International Agency for Research on Cancer of the World Health Organization. Over a 5-year period, children and adolescents with acute lymphoblastic leukemia and brain tumors receiving treatment in Spain, Italy, or Greece will be recruited. Clinical data and biospecimens (blood and stool) will be collected at designated timepoints in therapy. At the same time, several surveys will be administered to collect data on sociodemographics, physical activity, quality of life, food insecurity, and dietary habits. The primary aim of EPICkidsis to develop a large informative nutrition biobank and database to investigate the etiologic pathways that connect nutritional status and lifestyle factors with clinical outcomes in children and adolescents with cancer. Secondary aims are to create evidence-based guidelines for European children with cancer in this understudied region and to ultimately improve the quality of life of those children and adolescents.TheClinicalTrials.govID for EPICkidsstudy isNCT05375617.
A micro-costing of latent tuberculosis infection testing and treatment in adults in secondary care in England
Authors: Snoad Laura , Vesga Juan , Lipman Marc , Dedicoat Martin , Gupta Rishi K , Abubakar Ibrahim , Dart Susan , Gorsuch Thomas , Kunst Heinke , Mungall Sarah , Noonan Ryan , White Peter J 
Published: February 2025

ABSTRACTBackgroundLatent TB infection (LTBI) screening and treatment of population groups at high risk for TB is part of England’s Tuberculosis Action Plan, which has succeeded in increasing testing volumes. However, analysis of the cost-effectiveness is hampered by a lack of detailed information on health service costs.MethodsWe surveyed clinics with large volumes of activity, located in the London, West Midlands, South East & South West, and North West England TB Control Board areas. These represent three-quarters of England’s TB diagnoses. We mapped clinical pathways and determined costs of staff time, testing, and drugs.ResultsThe clinics use interferon gamma release assays (IGRAs) (Quantiferon-TB Gold Plus, T-SPOT.TB, or both) for LTBI testing, and the most common outcomes of the testing pathways are asymptomatic patients testing negative (costing £64.11 per patient, range: £49.08-£81.02) or positive (costing £142.86(£120.95-£174.68)). Symptomatic patients, testing positive or negative, have higher costs (£124.35(£101.29-£138.23)). The estimated cost per patient diagnosed with LTBI is £458.32(£362.49-£571.47). Treatment costs depend on the regimen and the amount of monitoring the patient requires, e.g. 3 months daily Isoniazid and Rifampicin costs £192.86(£140.43-£255.32) for most patients, and £238.62(£157.47-£346.03) for those requiring more monitoring. 6 months daily Isoniazid costs £407.71(£342.56-£474.25). 4 months daily Rifampicin costs £226.98(£190.16-£270.73). One clinic uses 3 months of weekly Isoniazid and Rifapentine for some patients, costing £559.05.DiscussionThese are the first detailed cost estimates of latent TB screening and treatment, and will enable improved assessment of cost-effectiveness, and allocation of resources.
Beyond contacts: the important role of the support region to distinguish stable and transient protein interfaces
Authors: Miclot Tom , Timr Stepan 
Published: February 2025

AbstractProtein-protein interactions (PPIs) are fundamental to virtually all cellular processes; however, elucidating the principles that govern protein association into complexes remains a significant challenge. In this study, we present a comparative analysis of stable and transient protein interfaces, offering a detailed perspective on the interactions that form them. Moving beyond the traditional focus on pairs of neighboring residues, we examine interacting pairs by identifying their distinct non-bonded interactions. Additionally, we account for the contextual dependence of these interactions by analyzing the regions of the interface where they occur. Our approach quantifies the diversity of pairs in each region, considering the type of interface. Furthermore, we introduce an innovative strategy to analyze pair co-occurrence, enabling a comparison of the inner local organization of stable and transient interfaces. Our findings reveal that stable and transient interfaces differ not in overall residue composition, but in the residue- and interaction-partitioning patterns across the variably hydrated regions of the interface. These results underscore the importance of considering the contextual environment in which pairs interact and identify the support region as a key determinant for distinguishing transient and stable protein complexes. The software package developed for this analysis is available as open source.
Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation
Authors: Zhang Luojia , Gordiyenko Yuliya , Morgan Tomos , Franco Catarina , Vidaković Ana Tufegdžić , Zhang Suyang 
Published: February 2025

AbstractDuring productive transcription elongation, the speed of RNA polymerase II (Pol II) is highly dynamic within individual genes and varies between different genes1,2. Unregulated rapid transcription elongation can lead to detrimental consequences such as transcription-replication collisions, altered alternative splicing patterns, and genome instability1–7. Therefore, elongating Pol II requires mechanisms to slow its progression, yet the molecular basis of transcription braking remains unclear. RECQL5 is a DNA helicase that functions as a general elongation factor by slowing down Pol II8–11. Here we report cryo-electron microscopy (cryo-EM) structures of human RECQL5 bound to multiple transcription elongation complexes. Combined with biochemical analysis, we identify an α-helix of RECQL5 responsible for Pol II binding and slowdown of transcription elongation. We further reveal that the transcription-coupled DNA repair (TCR) complex allows Pol II to overcome RECQL5-induced transcription braking through concerted actions of its translocase activity and competition with RECQL5 for engaging Pol II. Additionally, RECQL5 inhibits TCR-mediated Pol II ubiquitination to prevent activation of the DNA repair pathway. Our results suggest a model in which RECQL5 and the TCR complex coordinately regulate the transcription elongation rate to ensure transcription efficiency while maintaining genome stability. This work provides a framework for future studies on the regulatory role of elongation speed in gene expression.
Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance
Authors: Qi XiaoYan , Xiong Feng , Xiao Jiening , Muthukumarasamy Kalai Mangai , Altuntas Yasemin , Zhong Yuan , Abu-Taha Issam , Bruns Florian , Tekook Marcel , Kamler Markus , Villeneuve Louis , Nozza Anna , Sirois Martin , Karch Jason , Pasdois Philippe , Bers Donald M. , Dobrev Dobromir , Nattel Stanley 
Published: February 2025

ABSTRACTBACKGROUNDChanges in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model.METHODS AND RESULTSAtrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca2+-concentration ([Ca2+]Mito), reactive oxygen species (mtROS) production, membrane potential (ΔΨm), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca2+]Mitoand mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca2+-current (ICaL)-downregulation in canine and human AF ACMsin vitro. Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca2+-overload, mtROS-overproduction, structural damage and abnormalities in ΔΨmand respiration. Functionally, mitoquinone reduced AF-induced Ca2+-current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability.CONCLUSIONSMitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.
Hyaluronic acid hydrogels: Establishing a sustained delivery system for extracellular vesicles
Authors: Chabria Yashna , O’Dwyer Joanne , McDermott Emma , Owens Peter , Lowery Aoife J. , Duffy Garry P. , Dwyer Róisín M. 
Published: February 2025

AbstractExtracellular vesicles (EVs) are versatile transporters of genetic cargo with enormous potential in the therapeutic setting. Scalable production of EVs, and routes to overcome rapid clearance are required. Biocompatible hydrogels may support precise, localized delivery of EVs to target sites. This study aimed to establish sustained production of EVs in a scalable 3D dynamic bioreactor and to fabricate hydrogels using tyramine-modified hyaluronic acid (HA-TA) to study EV integration and release patterns.MDA-MB-231 cells transduced with lentiviral GFP fused with CD63, were cultured in a 20kD dynamic hollow fiber bioreactor and GFP-EVs harvested over five weeks. GFP-EVs were characterized by Nanoparticle Tracking Analysis(NTA), Western Blot(WB) and Transmission Electron Microscopy(TEM). Tyramine modified hyaluronic acid(HA-TA) hydrogels were formulated via enzymatic crosslinking using hydrogen peroxide and horseradish peroxidase, to investigate EV release patterns in static and dynamic conditions. Hydrogel swelling was recorded at 1-72 hrs and hydrogels were loaded with GFP-EVs to assess distribution and release by Scanning Electron Microscopy(SEM) and NTA respectively. GFP-EV uptake was assessed by confocal microscopy.Longitudinal GFP expression was demonstrated in transduced cells and released EVs throughout bioreactor culture. TEM and NTA demonstrated successful isolation of EVs of 30-200 nm in size with intact lipid bilayers (average 4×109EVs/harvest). Initial harvests exhibited subpopulations of larger EVs, which disappeared upon serum withdrawal. WB verified the presence of EV markers CD63, TSG101, and CD81. HA-TA hydrogels were successfully formed and swelling assays revealed the requirement for higher concentrations of HA-TA and crosslinkers for scaffold stability and continued swelling. GFP-EVs were successfully incorporated into the hydrogels with variable release patterns observed over time, depending on EV concentration and hydrogel formulation. EV clusters in hydrogels were visualized by SEM. Investigation of GFP-EV release patterns under static and dynamic conditions highlighted a significant increase in release under fluid flow conditions. Efficient transfer of released EVs to recipient cells was also demonstratedin vitro.The data demonstrate the potential for scalable production of engineered EVs in serum free conditions and subsequent incorporation into HA-TA hydrogels for sustained release. These biocompatible hydrogels hold promise for tuneable delivery of therapeutic EVs in a variety of disease settings.
Therapeutic Potential of PRMT1 as a Critical Survival Dependency Target in Multiple Myeloma
Authors: Hussain Tabish , Awasthi Sharad , Shahid Farid , Yi S. Stephen , Sahni Nidhi , Aldaz C Marcelo 
Published: February 2025

AbstractMultiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through post-translational modification. Dysregulation or overexpression of PRMT1 has been observed in various malignancies including MM and is linked to chemoresistance. Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines. This was accompanied by reduced levels of asymmetric dimethylation of arginine (ADMA) and increased arginine monomethylation (MMA) in MM cells. Cell cycle analysis revealed an accumulation of cells in the G0/G1 phase and a reduction in the S phase upon GSK3368715 treatment. Additionally, PRMT1 inhibition led to a significant downregulation of genes involved in cell proliferation, DNA replication, and DNA damage response (DDR), likely inducing genomic instability and impairing tumor growth. This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM.
Benchmarking gene embeddings from sequence, expression, network, and text models for functional prediction tasks
Authors: Zhong Jeffrey , Li Lechuan , Dannenfelser Ruth , Yao Vicky 
Published: February 2025

AbstractGene embeddings have emerged as transformative tools in computational biology, enabling the efficient translation of complex biological datasets into compact vector representations. This study presents a comprehensive benchmark by evaluating 38 classic and state-of-the-art gene embedding methods across a spectrum of functional prediction tasks. These embeddings, derived from data sources such as amino acid sequences, gene expression profiles, protein-protein interaction networks, and biomedical literature, are assessed for their performance in predicting individual gene attributes, paired gene interactions, and gene set relationships. Our analysis reveals that biomedical literature-based embeddings consistently excel in general predictive tasks, amino acid sequence embeddings outperform in functional and genetic interaction predictions, gene expression embeddings are particularly well-suited for disease-related tasks, and protein-protein interaction embeddings perform well in pairwise tasks. Importantly, we find that the type of training data has a greater influence on performance than the specific embedding construction method, with embedding dimensionality having only minimal impact. By elucidating the strengths and limitations of various gene embeddings, this work provides guidance for selecting and successfully leveraging gene embeddings for downstream biological prediction tasks. All associated code is available athttps://github.com/ylaboratory/gene-embedding-benchmarks.
Boosting Motor Cortex Plasticity through Respiratory Phase-Triggered Paired Associative Stimulation
Authors: Baker Stuart N , Zaaimi Boubker 
Published: February 2025

AbstractPaired Associative Stimulation (PAS) has shown promise in promoting motor cortex plasticity by using transcranial magnetic stimulation (TMS) paired with peripheral nerve stimulation. However, the effectiveness of PAS is often limited by its short-lived potentiation effects. Recent research indicates that respiratory rhythms can influence cortical excitability, suggesting a potential method to enhance PAS efficacy. This study investigated the impact of synchronizing PAS with respiratory phase transitions - specifically, the transition from inspiration to expiration (I-E) and expiration to inspiration (E-I) - on motor cortical plasticity. We conducted experiments with 18 healthy volunteers (13 females, 5 males) aged 21-45 years, assessing motor-evoked potentials (MEPs) elicited by TMS applied to the left motor cortex. Participants underwent PAS sessions where paired stimuli were delivered either at I-E or E-I transitions, or at random intervals. MEPs were recorded at baseline, immediately post-PAS, and at 10, 20, and 30 minutes post-stimulation. Results showed that PAS triggered at the I-E transition significantly increased MEP amplitudes, with significant differences in MEP amplitudes at 20 minutes post-PAS between the I-E and the other conditions. This highlights the benefit of timing PAS with the I-E transition for enhanced motor cortical plasticity. These findings underscore the potential of integrating respiratory rhythms into neuromodulation techniques to improve therapeutic outcomes. Synchronizing PAS with natural respiratory phases may enhance motor recovery strategies and offers a refined approach for therapeutic interventions. This approach could be particularly relevant for stroke rehabilitation, where enhancing motor cortical plasticity is crucial for recovery.Significance StatementThis study demonstrates that syncing brain stimulation with breathing patterns can enhance motor learning. By coordinating Paired Associative Stimulation (PAS)—a technique that stimulates sensory and motor inputs—with specific phases of the breathing cycle, we observed stronger responses in the motor cortex. This approach not only improves our understanding of brain adaptability but also offers a new way to fine-tune therapeutic techniques. For stroke patients, where regaining motor function is critical, integrating natural body rhythms into treatment could lead to more effective and personalized rehabilitation strategies.
Evaluating the Causal Impact of Immune Cells on Breast Cancer and the Mediating Role of Inflammatory Proteins through Mendelian Randomization
Authors: Guo Qianling , Yang Jiahao , Wen Ying , Zhuang Kai , Fahira Aamir , Yan Lin , Huang Zunnan 
Published: February 2025

AbstractBreast cancer (BC) is a leading cause of mortality among women globally. Emerging evidence suggests that the immune system is involved in BC pathogenesis, with distinct subtypes showing unique immune responses. Inflammation correlates closely with these immune responses. However, the causal role of immune cell characteristics across BC subtypes and the mediating influence of inflammatory proteins remains unclear. We used bi-directional two-sample Mendelian Randomization (MR) to evaluate causal relationships between 731 immune traits and BC risk, including its subtypes, followed by a two-step mediation analysis with 91 inflammatory proteins. The Inverse Variance Weighted (IVW) method served as the primary analysis, supported by sensitivity and reverse MR analyses. Sixteen immune traits showed significant causal associations with BC and its subtypes, with 108 relationships potentially mediated by inflammatory proteins. Traits such as CD25 on CD24+ CD27+, CD25 on IgD- CD38dim, and HLA DR++ monocyte %monocyte acted as protective factors, while CD40 on CD14-CD16+ monocytes posed risks. Notably, CD40L receptor levels mediated up to 73% of the relationship between IgD- CD27-%B cells and ER+BC. Sensitivity analyses indicated no horizontal pleiotropy or reverse causality. This study underscores immune cells’ potential role in BC risk and the mediating impact of inflammatory proteins across subtypes. Targeting specific inflammatory proteins may offer novel strategies for BC risk reduction, informing clinical decision-making and therapeutic development.