bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Remodeling of the BRCA1 Interactome by a Unique Minimal Clinical Truncation Mutation
Authors: Chen Jingjing , Sardiu Mihaela E. , Rekowski Michaella J. , Nde Jules , Clark Zachary S. , Anant Shrikant , Washburn Michael P. , Jensen Roy A. 
Published: December 2024

AbstractBRCA1, a critical tumor suppressor gene, plays an essential role in maintaining genomic stability through its involvement in DNA double-strand break repair, particularly via homologous recombination. Loss or impairment of BRCA1 function disrupts this repair pathway, resulting in genomic instability and significantly increased susceptibility to breast and ovarian cancers. To elucidate the molecular mechanisms by which BRCA1 mutations contribute to tumorigenesis, we employed quantitative mass spectrometry-based proximity labeling and affinity purification to identify cancer-specific protein-protein interactions (PPIs). Our integrated omics and visualization analysis of interactors revealed that the BRCA1-Y1853ter mutant, through its interaction with BARD1, perturbs the interactome and impacts cellular processes within the cytoplasm and nucleoplasm. Structural data further corroborated these findings, showing enhanced binding between the mutant BRCA1 and specific interactors, suggesting an altered functional profile. Together, these observations raise the hypothesis that the BRCA1-Y1853ter mutant may exhibit gain-of-function characteristics, providing new insights into the molecular and cellular effects of mutations in the BRCA1 C-Terminal (BRCT) domain and their implications for the pathogenesis of breast and ovarian cancers.
Enriched Methylomes of Low-input and Fragmented DNA Using Fragment Ligation EXclusive Methylation Sequencing (FLEXseq)
Authors: Yu Jingru , Ahmann Lauren S. , Yao Yvette Y. , Gu Wei 
Published: December 2024

AbstractMethylome profiling is an emerging clinical tool for tumor classification and liquid biopsies. Here, we developed FLEXseq, a genome-wide methylation profiler that enriches and sequences the fragments of DNA flanking the CCGG motif. FLEXseq strongly correlates (Pearson’s r = 0.97) with whole genome bisulfite sequencing (WGBS) while enriching 18-fold. To demonstrate the broad applicability of FLEXseq, we verified its usage across cells, body fluids, and formalin-fixed paraffin-embedded (FFPE) tissues. DNA dilutions down to 250 pg decreased CpG coverage, but bias in methylation remained low (Pearson’s r ≥ 0.90) compared to a 10 ng input. FLEXseq offers a cost-efficient, base-pair resolution methylome with potential as a diagnostic tool for tissue and liquid biopsies.
Methods for safely sharing dual-use genetic data
Authors: Sawaya Sterling , Lo Chien-Chi , Li Po-E , Hovde Blake , Chain Patrick 
Published: December 2024

AbstractBackgroundSome genetic data has dual-use potential. Sharing pathogen data has shown tremendous value. For example therapeutic development and lineage tracking during the COVID pandemic. This data sharing is complicated by the fact that these data have the potential to be used for harm. The genome sequence of a pathogen can be used to enable malicious genetic engineering approaches or to recreate the pathogen from synthetic DNA. Standard data security methods can be applied to genetic data, but when data is shared between institutions, ensuring appropriate security can be difficult. Sensitive data that is shared internationally among a wide array of institutions can be especially difficult to control. Methods for securely storing and sharing genetic data with potential for dual-use are needed to mitigate this potential harm.ResultsHere we propose new methods that allow genetic data to be shared in a data format that prevents a nefarious actor from accessing sensitive aspects of the data. Our methods obfuscate raw sequence data by pooling reads from different samples. This approach can ensure that data is secure while stored and during electronic transfer. We demonstrate that by pooling raw sequence data from multiple samples of the same organism, the ability to fully reconstruct any individual sample is prevented. In the pooled data, most genomic information remains, but reads or mutations cannot be directly attributed to any individual sample. To further restrict access to information, regions of a genome can be removed from the reads.ConclusionOur methods obscure genomic information within raw sequence reads. This method can allow genetic data to be stored and shared while preventing a nefarious actor from being able to perfectly reconstruct an organism. Broad-scale sequence information remains, while fine scale details about specific samples are difficult or impossible to reconstruct.
EUROPEAN SUBTYPE TICK-BORNE ENCEPHALITIS VIRUS EMERGENCE IN SOUTH KOREA (2005 – 2014) CAN BE ASSOCIATED WITH HUMAN ACTIVITY
Authors: Kovalev S.Y. 
Published: December 2024

AbstractTick-borne encephalitis virus (TBEV) is the etiological agent of tick-borne encephalitis. TBEV is maintained in nature by the ixodid ticksIxodes ricinusandI. persulcatus, which are its hosts and main vectors. The classification distinguishes three TBEV subtypes: Far Eastern, European (TBEV-Eu) and Siberian. Each subtype is characterized by its own range, reflected in its name. Nevertheless, numerous findings of TBEV subtypes in non-endemic areas have been reported. This phenomenon may be the result of virus introduction due to natural causes such as bird and mammal migrations. Detection of TBEV-Eu in South Korea in 2005 and in Siberia in the second half of the 20th century are significantly different from other cases of virus introduction. This paper presents the results of a comprehensive study including phylogenetic analysis, clusteron approach, establishing specificity of viral population dynamics, etc. The age of viral populations and the probable time of their emergence in non-endemic regions were determined. Using the example of TBEV-Eu in South Korea, we conclude that there is negative population dynamics of the virus after its introduction. This conclusion, in conjunction with several other features, indicates that human activity played a pivotal role in the TBEV-Eu introduction into South Korea and Siberia.
POLYGENIC DETERMINANTS OF H5N1 ADAPTATION TO BOVINE CELLS
Authors: Turnbull Matthew L , Zakaria Mohammad Khalid , Upfold Nicole S , Bakshi Siddharth , Das Udeet Ranjan , Magill Callum , Mojsiejczuk Laura , Herder Vanessa , Dee Kieran , Liu Nancy , Folwarczna Monika , Ilia Georgios , Furnon Wilhelm , Schultz Verena , Chen Hanting , Devlin Ryan , McCowan Jack , Young Alex L , Po Wai-Wai , Smollett Katherine , Yaseen Muhammad Ahsan , da Silva Filipe Ana , Iqbal Munir , Roberts Ed , Hughes Joseph , Werling Dirk , Murcia Pablo R. , Palmarini Massimo 
Published: December 2024

ABSTRACTH5N1 avian influenza virus (lineage 2.3.4.4b, B3.13 genotype) has caused, unexpectedly, a large outbreak in dairy cattle in North America. It is critical to ascertain how this virus has specifically adapted to bovine cells and the molecular determinants of this process. Here, we focused on the contribution of the viral “internal” genomic segments of H5N1 B3.13 to bovine cells adaptation. We generated 45 reassortant viruses harbouring the haemagglutinin and neuraminidase from A/Puerto Rico/8/1934 and internal gene constellations from several influenza A viruses (IAV) or carrying segment swaps between distinct H5N1 strains. The recombinant B3.13 viruses displayed faster replication kinetics in bovine cells compared to other IAV. Importantly, multiple genomic segments of B3.13 viruses contribute to their faster replicative fitness. Further, recombinants with the B3.13 internal genes were less susceptible than ancestral 2.3.4.4b strain to the bovine IFN response. However, bovine (and human) MX1, a key restriction factor for avian IAV, restricted both ancestral 2.3.4.4b and B3.13 recombinant viruses. Interestingly, the latter escape restriction from human BTN3A3. Finally, recombinant B3.13 was virulent in mice unlike the ancestor 2.3.4.4b recombinant virus. Our results highlight the polygenic nature of influenza host range as multiple internal genes of B3.13 contribute to bovine adaptation.
The mechanisms by which miRNAs critically contribute to differential roles of Nrf1 and Nrf2 in modulating the epithelial-mesenchymal transformation of hepatocellular carcinoma
Authors: Chen Juan , Feng Jing , Zhu Yu-ping , Hu Shaofan , Zhang Yiguo 
Published: December 2024

ABSTRACTAccumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the abnormal expression of several microRNAs arising from lack of antioxidant transcription factor Nrf2 (encoded byNfe2l2) leads to cancer metastasis. However, much less known is about regulation of microRNAs by Nrf1 (encoded byNfe2l1), even though it acts as an essential determinon of cell homeostasis by governing the transcriptional expression of those driver genes contributing to the epithelial–mesenchymal transition (EMT) involved in its metastasis. In this study, distinctive EMT phenotypes were unveiled to result from specific knockout of Nrf1 and Nrf2 in HepG2 cells, as accompanied by differential migratory and invasive capabilities. TheNrf1α−/−-leading EMT results from a significantly decrease in the epithelialCDH1expression, plus another increased expression of the mesenchymalCDH2. Such distinct phenotypes ofNrf1α−/−fromNrf2−/−cell lines were also attributable to differential regulation of two key microRNAs, i.e.,miR3187-3PandmiR1247-5p. Further experiments unraveled that Nrf1 activates the expression ofmiR-3187-3p, directly targeting for the inhibition ofSNAI1, leading to CDH1 activation but CDH2 inhibition insomuch as to prevent the process of EMT. By contrast, Nrf2 inhibits the expression ofmiR1247-5p,relieving its inhibitory effect on MMP15 and MMP17 to promote the EMT. Collectively, these demonstrate that the EMT of liver cancer cells is likely prevented by Nrf1viathe miR3187-3P signaling to the SNAI1-CDH1/2 axis, but conversely promoted by Nrf2 through the miR1247-5p-MMP15/17 signaling axis.
Improving Automated Deep Phenotyping Through Large Language Models Using Retrieval Augmented Generation
Authors: Garcia Brandon T. , Westerfield Lauren , Yelemali Priya , Gogate Nikhita , Rivera-Munoz E. Andres , Du Haowei , Dawood Moez , Jolly Angad , Lupski James R. , Posey Jennifer E. 
Published: December 2024

AbstractBackgroundDiagnosing rare genetic disorders relies on precise phenotypic and genotypic analysis, with the Human Phenotype Ontology (HPO) providing a standardized language for capturing clinical phenotypes. Traditional HPO tools, such as Doc2HPO and ClinPhen, employ concept recognition to automate phenotype extraction but struggle with incomplete phenotype assignment, often requiring intensive manual review. While large language models (LLMs) hold promise for more context-driven phenotype extraction, they are prone to errors and “hallucinations,” making them less reliable without further refinement. We present RAG-HPO, a Python-based tool that leverages Retrieval-Augmented Generation (RAG) to elevate LLM accuracy in HPO term assignment, bypassing the limitations of baseline models while avoiding the time and resource intensive process of fine-tuning. RAG-HPO integrates a dynamic vector database, allowing real-time retrieval and contextual matching.MethodsThe high-dimensional vector database utilized by RAG-HPO includes >54,000 phenotypic phrases mapped to HPO IDs, derived from the HPO database and supplemented with additional validated phrases. The RAG-HPO workflow uses an LLM to first extract phenotypic phrases that are then matched via semantic similarity to entries within a vector database before providing best term matches back to the LLM as context for final HPO term assignment. A benchmarking dataset of 120 published case reports with 1,792 manually-assigned HPO terms was developed, and the performance of RAG-HPO measured against existing published tools Doc2HPO, ClinPhen, and FastHPOCR.ResultsIn evaluations, RAG-HPO, powered by Llama-3 70B and applied to a set of 120 case reports, achieved a mean precision of 0.84, recall of 0.78, and an F1 score of 0.80—significantly surpassing conventional tools (p<0.00001). False positive HPO term identification occurred for 15.8% (256/1,624) of terms, of which only 2.7% (7/256) represented hallucinations, and 33.6% (86/256) unrelated terms; the remainder of false positives (63.7%, 163/256) were relative terms of the target term.ConclusionsRAG-HPO is a user-friendly, adaptable tool designed for secure evaluation of clinical text and outperforms standard HPO-matching tools in precision, recall, and F1. Its enhanced precision and recall represent a substantial advancement in phenotypic analysis, accelerating the identification of genetic mechanisms underlying rare diseases and driving progress in genetic research and clinical genomics.
Extreme MetaboHealth scores in three cohort studies associate with plasma protein markers for inflammation and cholesterol transport
Authors: Bizzarri D. , van den Akker E.B. , Reinders M.J.T. , Pool R. , Beekman M. , Lakenberg N. , Drouin N. , Stecker K.E. , Heck A.J.R. , Knol E.F. , Vergeer J.M. , Ikram M.A. , Ghanbari M. , van Gool A.J. ,   BBMRI-NL, Boomsma D.I. , Slagboom P.E. 
Published: December 2024

ABSTRACTThe MetaboHealth score is a highly informative health indicator in ageing studies and yet contains only a small number of metabolites. Here we estimate the heritability of the score in 726 monozygotic (MZ) and 450 dizygotic (DZ) twin pairs, and test for association with plasma proteins by comparing extreme scoring individuals selected from two large population cohorts -the Leiden Longevity Study (LLS) and the Rotterdam Study (RS) and discordant monozygotic twin pairs from the Netherlands Twin Register (NTR).The heritability for the MetaboHealth score was estimated at 40%. In 50 high and 50 low scoring MetaboHealth groups from LLS and RS, we uncovered significant differences in plasma proteins, notably in 3 (out of 15) cytokines (GDF15, IL6, and MIG), and 106 proteins (out of 289) as determined by Mass Spectrometry based proteomics analysis. A high MetaboHealth score associated with an increased level for 42 serum proteins, predominantly linked to inflammation and immune response, including CRP and HPT. A low score associated with decreased levels of 71 proteins enriched in high-density lipoprotein (HDL) remodeling and cholesterol transport pathways, featuring proteins such as APOA1, APOA2, APOA4, and TETN.In MZ twins selected for maximal discordance within a pair we found 68 serum proteins associated with the MetaboHealth score indicating that a minor part of the associations observed in LLS and RS is likely explained by genetic influences. Taken together, our study sheds light on the intricate interplay between MetaboHealth, plasma proteins, cytokines, and genetic influences, paving the way for future investigations aimed at optimizing this mortality risk indicator.
Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria
Authors: Ahmadi Zeinab Alsadat , Cabrera-Orefice Alfredo , Zaninello Marta , Barth Esther , Rodenburg Richard , Rugarli Elena I. , Brodesser Susanne , Arnold Susanne , Brandt Ulrich 
Published: December 2024

AbstractInherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, the correlation between molecular causes and clinical presentations is poorly understood. To address this conundrum, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45Pretained 30-40% of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ·mol-1in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.
G-quadruplex topologies determine the functional outcome of guanine-rich bioactive oligonucleotides
Authors: Kharel Prakash , Bhatter Nupur , Zubair Safiyah , Lyons Shawn , Anderson Paul J. , Ivanov Pavel 
Published: December 2024

AbstractGuanine-rich nucleic acid sequences can exert sequence and/or structure specific activities to influence biological and pathobiological cellular processes. As such, it has been reported that different G-rich oligonucleotides (both DNA and RNA) can have cytotoxic as well as cytoprotective effects to the cells. However, the mechanisms of such a biological outcome are unclear. In this report, we report that G-rich DNA oligonucleotides (ODNs) that can form four stranded secondary structures called G-quadruplexes (G4s) can have topology-dependent biological outcome. Using different biochemical, biophysical, and cellular approaches, we demonstrate that only the parallel topology G4-forming ODNs can repress eukaryotic translation by directly interacting with eukaryotic translation initiation protein 1 (EIF4G1), while the antiparallel topology G4s do not have inhibitory effect on mRNA translation To the best of our knowledge, this is the first report to directly connect the G4 topological differences with differential functional biological impacts. Our study provides the foundation for the rational design of G-rich oligonucleotides for a desired therapeutic outcome.
The interplay between Zfh1 and Nau orchestrates the myogenic stage-dependent expression ofRbfox1and its targetStat92Evia amir-9a-mediated negative feedback loop inDrosophila melanogaster
Authors: Mukherjee Amartya , Nongthomba Upendra 
Published: December 2024

AbstractRNA-binding Fox protein 1 (Rbfox1) controls gene expression at various levels: as a transcription co-factor, a splicing factor, and a regulator of mRNA stability and translation. Rbfox1 and its vertebrate orthologues have critical functions during development.Rbfox1mRNA, during adult myogenesis inDrosophila,exhibits bimodal expression, suggestive of the presence of a negative feedback loop. However, there are no known negative regulators ofRbfox1expression for this context. In this study, we show that the microRNAmir-9afunctions as a repressor ofRbfox1expression. Furthermore, the expression ofmir-9ais regulated by the expression of the identity transcription factor Nau. Nau and its targetmir-9aare expressed at mid myogenesis stage, and serve to restrict the expression ofRbfox1, and its targetsStat92Eandzfh1, to the early and the late myogenesis stages, as their ectopic expression is detrimental to early myofibrillogenesis. Zfh1, in turn, repressesmir-9aexpression, completing the feedback loop. Therefore, our findings identify the mechanism by which the temporal expression of the developmental geneRbfox1and its targets are tightly regulated, essential for their functions during myogenesis.Summary statementUsingDrosophila, we show that a microRNA-mediated negative feedback loop controls the expression of genes critical for skeletal muscle development.
Strong decay widths and mass spectra of the
1D
,
2P
and
2S
singly bottom baryons
Authors: García-Tecocoatzi H. , Giachino A. , Ramirez-Morales A. , Rivero-Acosta Ailier , Santopinto E. , Vaquera-Araujo Carlos Alberto 
Published: December 2024

We calculate the 1D, 2P, and 2S mass spectra of the singly bottom baryons and their strong decay widths. The calculations are performed within a harmonic oscillator quark model that incorporates the spin, spin-orbit, isospin, and flavor interactions. To obtain the model parameters, we conducted a fit using only 13 of the 22 experimentally observed states. Our predictions align well with the observed states, showing a root-mean-square deviation of 9.6 MeV. We calculate the three-quark strong decay widths within the P03 model, which has only one free parameter, the pair creation strength γ0; this is the first time that the Λbη, Σbρ, Σb*ρ, Λbη′, Λbω, ΞbK, Ξb′K, Ξb*K, ΞbK*, Ξb′K*, and Ξb*K* channels have been considered in the calculation of the strong decay widths of the excited Λb states; the Σbη, ΞbK, Σbρ, Σb*ρ, Λbρ, Σb*η, Σbη′, Σb*η′, Ξb′K,Ξb*K, ΞbK*, Ξb′K*, Ξb*K*, Σbω, Σb*ω, Σ8Bs, ΔB, N(1520)B, N(1535)B, N(1680)B, and N(1720)B channels in the calculation of the strong decay widths of the excited Σb states; the ΛbK*, Ξbρ, Ξb′ρ, Ξb*ρ, ΣbK*, Σb*K*, Ξbη′, Ξb′η′, Ξb*η′, Ξbω, Ξb′ω, Ξb*ω, Ξbϕ, Ξb′ϕ, Ξb*ϕ, Ξ8Bs, Σ8B*, and Σ10B channels in the calculation of the strong decay widths of the excited Ξb and Ξb′ states; the ΞbK*, Ξb′K*, Ξb*K*, Ωbη, Ωb*η, Ωbϕ, Ωb*ϕ, Ωbη′, Ωb*η′, Ξ8B, and Ξ10B channels in the calculation of the strong decay widths of the Ωb states. Moreover, in Appendix D, we give the flavor couplings that can be useful for other articles. In Appendix E, our partial decay widths are reported for each open flavor channel; these may be useful to the LHCb, ATLAS, and CMS experimentalists in order to plan in which particular channels to look for missing bottom baryons. The experimental masses and widths of the discovered Λb(6146)0 and Λb(6152)0 states are consistent with our mass and width predictions for the Dλ excitations with quantum numbers JP=32+ and JP=52+, respectively. Moreover, the masses and widths of the new Ξb(6327)0 and Ξb(6333)0 states agree with our calculations for the Dλ excitations with quantum numbers JP=32+ and JP=52+, respectively. Finally, we calculate the electromagnetic decay widths from P-wave states to ground states. We give the exact analytical expressions of the spin-flip and orbit-flip transition amplitudes, both of which are functions of the photon-transferred momentum. The electromagnetic decays are dominant when the strong decays are suppressed. A relevant case is the Ωb− missing spin excitation, with JP=32+, which cannot decay strongly, but has a nonvanishing predicted electromagnetic decay width in the Ωb−γ channel. Therefore, we suggest the Ωb−γ electromagnetic decay channel as a golden channel in which to search for this state. In all of our calculations, we report the uncertainties related to the experimental and model errors by means of the Monte Carlo bootstrap method.

Published by the American Physical Society
2024