bluuebunny/crossref_metadata_2025_split huggingface dataset:
R allele of ACTN3 R577X gene polymorphism is associated with Elite Indian Boxer Status
Authors: Grover Vijmendra Kumar , Verma Jai Prakash , Kumar Ashish , Sharma Nivedita , Tiwari Pramod Kumar 
Published: January 2025

AbstractGenetic variations are considered important for athletic performance. In this regard, polymorphisms in angiotensin I-converting enzyme (ACE) and α-actinin-3 genes are widely studied for their association with elite athlete status. The ACE gene regulates circulatory homeostasis, with the I variant of the ACE insertion/deletion (ACE I/D) gene polymorphism being associated with endurance performance, while the R allele of the R577X polymorphism of the ACTN3 gene, crucial for fast glycolytic muscle fibers, has been associated with speed and power performances. The present study investigated the association of these genetic variants with elite boxer (N=57) status and compared it with elite power/speed athletes (N=40), endurance athletes (N=44) and nonathletes (N=98) in the Indian population. The R allele frequency was found significantly higher in boxers than the nonathletes (p< 0.05). The allele and genotype frequencies of boxers, endurance and power/speed athletes did not differ significantly (p> 0.05). After analyzing overall athletic cohort on the basis of their level of performance, the frequency of RR genotype (24.1%) and R allele (47.7%) in national level athletes was found significantly higher than in nonathletes (8.7% and 34.2%, respectively), with the significant difference (p< 0.05) between national level endurance athletes and nonathletes only. The ACE I/D gene polymorphism was not found associated with any of the athletic cohorts (p> 0.05). Taken altogether, our study showed that the R allele of ACTN3 gene polymorphism is associated with elite boxer status as compared to the nonathletes.HighlightsBoxers had a higher ACTN3 gene R allele frequency than nonathletes; genotype did not differ.Boxers with RR genotype had more than 3x higher odds versus nonathletes (p= 0.02) in the X dominant model (RR vs RX+XX).ACTN3 gene allele and genotype frequencies differed between overall athletic cohort and nonathletes.ACE gene frequencies showed no difference or association across athletic cohorts.
Global Profiling of N-terminal Cysteine-Dependent Degradation Mechanisms
Authors: Bekturova Aizat , Makaros Yaara , Ben-David Shahar , Koren Itay 
Published: January 2025

AbstractHypoxia, a condition characterized by insufficient oxygen supply, challenges cellular homeostasis and energy production, driving the activation of adaptive responses to maintain survival under these stress-inducing conditions. One key strategy involves enzymatic oxidation of N-terminal cysteine residues coupled with proteolysis through the Cys-Arg/N-degron pathway. Despite the presence of hundreds of proteins with N-terminal cysteine in humans, only two have been identified as substrates of this pathway, and its substrate selectivity remains unclear. Moreover, the biological role of this pathway in the cellular response to hypoxia is not well defined. By employing a systematic proteomics approach, we discovered that nearly half of the cysteine-commencing proteome could be regulated by the Cys-Arg/N-degron pathway. Mutagenesis experiments revealed the specificty of Cys-Arg/N-degron pathway showing a preference for hydrophobic and positively charged residues following cysteine. Furthermore, we uncovered substrates that are regulated by this pathway during hypoxia, including IP6K1. The loss of IP6K1 impaired glucose uptake, glycolytic ATP production, and overall mitochondrial morphology and function. As a result, IP6K1-deficient cells exhibited disrupted metabolic adaptation under hypoxic conditions and decreased survival under stress. These findings underscore the importance of the Cys-Arg/N-degron pathway in regulating metabolic responses and highlight its potential importance in hypoxia-related disorders.
Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo
Authors: Voke Elizabeth , Arral Mariah , Squire Henry J. , Lin Teng-Jui , Coreas Roxana , Lui Alison , Iavarone Anthony T. , Pinals Rebecca L. , Whitehead Kathryn A. , Landry Markita 
Published: January 2025

AbstractLipid nanoparticles (LNPs) are the most clinically advanced nonviral RNA-delivery vehicles, though challenges remain in fully understanding how LNPs interact with biological systems.In vivo, proteins form an associated corona on LNPs that redefines their physicochemical properties and influences delivery outcomes. Despite its importance, the LNP protein corona is challenging to study owing to the technical difficulty of selectively recovering soft nanoparticles from biological samples. Herein, we developed a quantitative, label-free mass spectrometry-based proteomics approach to characterize the protein corona on LNPs. Critically, this protein corona isolation workflow avoids artifacts introduced by the presence of endogenous nanoparticles in human biofluids. We applied continuous density gradient ultracentrifugation for protein-LNP complex isolation, with mass spectrometry for protein identification normalized to protein composition in the biofluid alone. With this approach, we quantify proteins consistently enriched in the LNP corona including vitronectin, C-reactive protein, and alpha-2-macroglobulin. We explore the impact of these corona proteins on cell uptake and mRNA expression in HepG2 human liver cells, and find that, surprisingly, increased levels of cell uptake do not correlate with increased mRNA expression in part likely due to protein corona-induced lysosomal trafficking of LNPs. Our results underscore the need to consider the protein corona in the design of LNP-based therapeutics.Abstract Figure
Development of human skin equivalents with inducible ceramide depletion for in vitro modelling of lipid deficiency
Authors: Dina Durotimi O. , Maiellaro Miriam , Camera Emanuela , Connelly John T. 
Published: January 2025

AbstractThe lipid composition of the epidermis plays a critical role in the skin’s barrier function, and defects in lipid synthesis or assembly can cause a spectrum of skin diseases, ranging from dry skin to severe ichthyoses. The aim of this study was to develop an in vitro model of human skin with tuneable lipid deficiency. Human N/TERT keratinocytes were engineered to express doxycycline-inducible short hairpin RNAs targeting ceramide synthase 3 (CerS3), which is essential for synthesis of ultra long chain ceramides and skin barrier function. We show that 3D human skin equivalents (HSEs) with induced knockdown of CerS3 display normal stratification and terminal differentiation but have reduced Nile Red staining for polar lipids. Further analysis of the lipidome by mass spectrometry confirmed a significant reduction in specific classes of ceramides and ceramide chain length in the CerS3 depleted HSEs. We also show that CerS3 knockdown is reversible upon removal of doxycycline and can be used to study recovery and repair of epidermal lipids. Together, these findings provide an overall strategy for genetically tuning the lipid composition within human skin models and establish a new in vitro model of ceramide deficiency.
Generative modeling for RNA splicing predictions and design
Authors: Wu Di , Maus Natalie , Jha Anupama , Yang Kevin , Wales-McGrath Benjamin D. , Jewell San , Tangiyan Anna , Choi Peter , Gardner Jacob R. , Barash Yoseph 
Published: January 2025

AbstractAlternative splicing (AS) of pre-mRNA plays a crucial role in tissue-specific gene regulation, with disease implications due to splicing defects. Predicting and manipulating AS can therefore uncover new regulatory mechanisms and aid in therapeutics design. We introduce TrASPr+BOS, a generative AI model with Bayesian Optimization for predicting and designing RNA for tissue-specific splicing outcomes. TrASPr is a multi-transformer model that can handle different types of AS events and generalize to unseen cellular conditions. It then serves as an oracle, generating labeled data to train a Bayesian Optimization for Splicing (BOS) algorithm to design RNA for condition-specific splicing outcomes. We show TrASPr+BOS outperforms existing methods, enhancing tissue-specific AUPRC by up to 2.4 fold and capturing tissue-specific regulatory elements. We validate hundreds of predicted novel tissue-specific splicing variations and confirm new regulatory elements using dCas13. We envision TrASPr+BOS as a light yet accurate method researchers can probe or adopt for specific tasks.
Pre- and post-capillary exercise contributions to pulmonary hypertension in older adults
Authors: Karvasarski Elizabeth , Park Joy , Savaris Simone , Beale Anna , Wright Stephen P. , Bentley Robert F. , Granton John T. , Mak Susanna 
Published: January 2025

ABSTRACTBackgroundDiagnosing pulmonary arterial hypertension (PAH) versus pulmonary hypertension associated with left hear disease (PH-LHD) can be challenging in patients with risk factors for both conditions. When resting pulmonary artery wedge pressure (PAWP) is proximate to a threshold of 15mmHg, exercise has been recommended to differentiate pre- versus post-capillary contributions to PH. To improve our understanding of this practice recommendation, we studied relationships between resting PAWP and the balance of pre- and post-capillary contributions to exercise PH.MethodsPatients suspected of PAH (n=29, 72±2y, 52% F) with risk factors for LHD were prospectively recruited to undergo cycle ergometry at time of diagnostic right-heart catheterization. Hemodynamic data, including pressure-flow slopes and contributions of transpulmonary gradient (TPG) and PAWP to mPAP, were analyzed to evaluate pre- and post-capillary contributions, respectively, at rest and during exercise.ResultsPAWP ranged from 0 to 20 mmHg. Exercise pressure-flow slopes demonstrated 62% with post-capillary PH, and 31% with pre-capillary PH only. The relationship between resting PAWP and the pre- versus post-capillary contributions to exercise PH was not straightforward. Of patients with PAWP<12mmHg, 67% had post-capillary contributions to exercise PH. Conversely, 50% of patients with PAWP>15mmHg had pre-capillary contributions to exercise PH. Exercise-associated increases in pulmonary artery pressures were more strongly associated with pre-capillary contributions regardless of post-capillary contributions or the value of resting PAWP.ConclusionIn this population, post-capillary contributions to exercise PH were commonly disclosed over a range of resting PAWP, including <12mmHg. The severity of exercise PH was determined by the pre-capillary contributions.
A single-chain antibody-based AID2 system for conditional degradation of GFP-tagged and untagged proteins
Authors: Islam Moutushi , Negishi Takefumi , Kitamoto Naomi , Hatoyama Yuki , Gamo Kanae , Hayashi Ken-ichiro , Kanemaki Masato T. 
Published: January 2025

AbstractProtein knockdown using an improved auxin-inducible degron (AID2) technology has proven to be a powerful tool for studying protein function. The current approach requires the fusion of target proteins with a degron tag, a process typically achieved through CRISPR knock-in. However, knock-in remains challenging in non-model organisms and humans, limiting the broader applicability of AID2. To overcome this limitation, we developed a single-chain antibody AID2 (scAb-AID2) system. This approach employs an adaptor composed of a single-chain antibody fused with a degron, which recognises a target protein and induces rapid degradation in the presence of the inducer 5-Ph-IAA. We demonstrated that scAb-AID2, in combination with an anti-GFP nanobody, degraded GFP-fused proteins in human cells andC. elegans. Furthermore, we showed that endogenous p53 and H/K-RAS were conditionally degraded in cells expressing an adaptor encoding an anti-p53 nanobody and -RAS monobody, respectively, and led to aphidicolin sensitivity in cell culture and growth inhibition in mouse xenografts. This study paves the way for broader application of AID2-based target depletion in model and non-model organisms and for advancing therapeutic strategies.
An Evolutionary Conserved Multi-Stress Sensory Histidine Kinase NblS Associates With Photosystem II Proteins And Responds To Its Redox Status In The CyanobacteriumSynechococcus elongatusPCC 7942
Authors: Tsurumaki Tatsuhiro , Tanaka Kan 
Published: January 2025

AbstractResponding to stress caused by various environmental changes is essential for living organisms. In cyanobacteria that perform oxygenic photosynthesis, the highly conserved histidine kinase Hik33/NblS homologs respond to diverse stressors such as high light, low temperature, high salts, high osmolarity, and reactive oxygen species. However, how this unique protein kinase responds to such divergent stresses remains unknown. This study has focused on the underlying stress sensing mechanism of NblS inSynechococcus elongatusPCC 7942. First, the sensory response by NblS was analyzedin vivoby monitoring the NblS-regulatedhliAtranscript accumulation with treatment of various benzoquinone reagents known as photosystem II (PSII) electron acceptors. It was found that molecular responses induced by various stresses were diminished in the presence of 2,6-dichloro-1,4-benzoquinone, which accepts electrons specifically from the PSII-bound plastoquinone QB. Cell fractionation analysis indicated that NblS was localized in the thylakoid membrane, which was consistent with its predicted membrane-spanning structure. In the thylakoid membrane, NblS was found in approximately 400 kDa and 800 kDa unknown complexes in clear native PAGE (CN-PAGE). Immunoprecipitation analysis of the cross-linked thylakoid membrane revealed that NblS is associated with D2 and CP47 proteins but not with CP43 protein, and thus it was suggested that dimeric NblS is associated with RC47-like complex, an assembly intermediate complex of PSII, as [RC47like-NblS2] (370 kDa) or [RC47like-NblS2]2(740 kDa). We propose that the redox status of an RC47-bound plastoquinone molecule is a cue for the NblS response.
A Domain-Specific Language Model Approach for Identifying Immunogenic Epitopes from Publicly Available Data: EpitopeMiner
Authors: Tan Wei Kit , Tang Wei Lin , Chadha Agamjyot Singh , Niedu Roopa , Lee Wendy , Lim Jing Quan , Rajapakse Menaka Priyadharsani , Wilson Solomon , Duan Kaibo , Chong Raymond Wei Liang , Ong Choon Kiat , Lee Bernett , Rotzschke Olaf , Lau Mai Chan 
Published: January 2025

AbstractPersonalized cancer vaccines represent a transformative approach in immunotherapy, leveraging tumor-specific antigens, such as neoantigens, to stimulate durable and targeted immune responses. However, identifying immunogenic neoantigen epitopes through conventional approaches - relying on in silico predictions followed by experimental validation - remains a significant challenge due to limitations of computational tools and scattering of experiment data. To address these challenges, we introduce EpitopeMiner, a domain-specific large language model (LLM) enhanced with a Retrieval-Augmented Generation (RAG) framework, specifically designed to identify immunogenic epitopes predicted by existing computational tools. EpitopeMiner utilizes a custom database of MHC-I-associated epitope-related literature to provide domain-specific knowledge, enhancing the precision and relevance of LLM-generated responses. EpitopeMiner offers three key features: First, the ability to identify epitopes with similar sequences and potentially similar immunogenic effects, which is especially valuable for neoantigens that are patient-specific and rarely found in public datasets. Second, it supports multiple epitope searches with structured outputs, enhancing scalability. Third, it provides original text chunks and paper identifiers, significantly simplifying validation and further exploration of the retrieved knowledge. Applying EpitopeMiner to well-characterized MHC class I epitopes demonstrates its ability to consistently retrieve relevant papers, efficiently providing targeted insights on T-cell response and immunogenicity, outperforming a commercial AI-powered literature tool. Notably, when applied to lymphoma patient-derived neoantigens, EpitopeMiner successfully retrieves immune response information for a few similar epitopes, despite operating with a relatively smaller database compared to the benchmark tool. All in all, EpitopeMiner bridges the gap between computational prediction and experimental validation, providing a scalable solution for extracting knowledge from public data, fostering cross-study synergies, and accelerating the development of personalized cancer vaccines.
ERGA-BGE genome ofAndrosace saussureiDentant, Lavergne, F. C. Boucher & S. Ibanez, a recently described plant from the rooftops of Europe
Authors: Lavergne Sébastien , Rosa Alexy , Peng Chuan , Monteiro Rita , Böhne Astrid , Marcussen Thomas , Struck Torsten , Oomen Rebekah A. ,   Genoscope Sequencing Team, Moussy Alice , Cruaud Corinne , Labadie Karine , Téodori Emilie , Demirdjian Lola , Wincker Patrick , Oliveira Pedro H. , Aury Jean-Marc , Brown Tom 
Published: January 2025

AbstractThe reference genome ofAndrosace saussurei(Ericales: Primulaceae: Primuloideae) provides a valuable resource for understanding the mechanisms of plant adaptations to the most extreme environments where flowering plants can thrive and the speciation mechanisms of plants dwelling on high alpine sky islands. The entirety of the genome sequence was assembled into 20 contiguous chromosomal pseudomolecules. This chromosome-level assembly encompasses 413 Mb, composed of 253 contigs and 101 scaffolds, with contig and scaffold N50 values of 4.95 Mb and 21.2 Mb, respectively.
Does repeated administration of baclofen in free feeding rats reduce body weight by stimulating brown fat metabolism through activation of the sympathetic nervous system?
Authors: Ebenezer Ivor S 
Published: January 2025

AbstractThe results of previous research have suggested that chronic administration of the GABABreceptor agonist baclofen can lead to weight loss in rodents by potentially activating brown adipose tissue (BAT) to increase metabolism rate. Studies in anaesthetised rats have shown that baclofen injected directly into the ventromedial nucleus of the hypothalamus (VMH) stimulates BAT to increase thermogenesis. This effect was attenuated by pretreatment with the beta-adrenoceptor antagonist propranolol, suggesting that baclofen microinjected into the VMH stimulate the sympathetic outflow to BAT, consequently increasing metabolic rate. The present study was designed to test this hypothesis by investigating whether pretreatment with propranolol would attenuate the weight loss induced by repeated daily administration of baclofen in free feeding rats. In the first experiment, male Wistar rats were injected intraperitoneal (ip) once daily for 24 days with either saline followed by saline, saline followed by baclofen (4 mg / kg), propranolol (10 or 20 mg / kg) followed by saline, or propranolol (10 mg / kg) followed by baclofen (4 mg / kg), with 5 minutes separating each injection. Body weight was measured each day 24 h after drug administration. Baclofen treatment resulted in significant reductions in daily body weight compared to the saline group. Propranolol alone had no significant effect on body weight. Importantly, pretreatment with propranolol did not attenuate the weight loss induced by baclofen. A similar experimental protocol as described above was used in a second experiment except that the rats were pretreated with a 20 mg / kg dose of propranolol and body weight was measured for 6 days. The high dose of propranolol significantly decreased body weight compared with control data and potentiated the baclofen-induced reduction in body weight. These results suggest that the effects of baclofen of body weight in free feeding rats may not be dependant on the the activation of BAT through stimulation of the sympathetic nervous system (SNS). Further research is therefore necessary to understand how baclofen influences metabolism and weight loss.
Lipogenic Mothers Alter Offspring Gut Microbiome Development via Breastmilk-Mediated Microbial Transfer
Authors: Cao Jianhong , Umar Abdulrahim , Yu Zheng 
Published: January 2025

AbstractMammals provide breastmilk as the primary source of nutrition for their offspring, which plays a crucial role in the development of gut microbiota (GM) and the establishment of immunity. Therefore, maternal dietary conditions during lactation significantly influence GM development. This study investigates the impact of a maternal high-fat diet on GM development in their offspring. Tissue and fecal samples were collected from both pups and their mothers (dams) that were fed a high-fat and a controlled diet. Their amplicon sequencing variants were used to perform comprehensive bioinformatic analysis.Our findings revealed breastmilk’s protective effect, inhibiting the proliferation of pathogenic bacteria, and regulating gut homeostasis during lactation. However, lipogenic dams induce microbial dysbiosis in their pups leading to an increased relative abundance of gut pathogenic bacteria leading to a heightened risk of chronic diseases. In contrast, pups from dams on a controlled diet exhibited an improved relative abundance of beneficial bacteria, includingMuribaculaceae,Faecalibaculum, andBifidobacterium. However, GM transferred from lipogenic dams adversely affected pups’ GM development and stability, leading to several physical consequences.This research revealed valuable insights into the relationship between breastmilk and gut microbiota, as specific genera were highly expressed at the beginning of lactation. This highlights the importance of timely interventions for the development of offspring gut microbiota to enhance overall gut health.
Revisiting the cancer microbiome using PRISM
Authors: Ghaddar Bassel C. , Blaser Martin J. , De Subhajyoti 
Published: January 2025

AbstractRecent controversy around the cancer microbiome highlights the need for improved microbial analysis methods for human genomics data. We developed PRISM, a computational approach for precise microorganism identification and decontamination from low-biomass sequencing data. PRISM removes spurious signals and achieves excellent performance when benchmarked on a curated dataset of 62,006 known true- and false-positive taxa. We then use PRISM to detect microbes in 8 cancer types from the CPTAC and TCGA datasets. We identify rich microbiomes in gastrointestinal tract tumors in CPTAC and identify bacteria in a subset of pancreatic tumors that are associated with altered glycoproteomes, more extensive smoking histories, and higher tumor recurrence risk. We find relatively sparse microbes in other cancer types and in TCGA, which we demonstrate may reflect differing sequencing parameters. Overall, PRISM does not replace gold-standard controls, but it enables higher-confidence analyses and reveals tumor-associated microorganisms with potential molecular and clinical significance.