bluuebunny/crossref_metadata_2025_split huggingface dataset:
Annotation and assessment of functional variants in regulatory regions using epigenomic data in farm animals
Authors: Ma Ruixian , Kuang Renzhuo , Zhang Jingcheng , Sun Jiahao , Xu Yueyuan , Zhou Xinbo , Han Zheyu , Hu Mingyang , Wang Daoyuan , Fu Yuhua , Zhang Yong , Li Xinyun , Zhu Mengjin , Zhao Shuhong , Xiang Tao , Shi Mengwei , Zhao Yunxia 
Published: February 2024

AbstractBackgroundUnderstanding the functional impact of genetic variants is essential for advancing animal genomics and improving livestock breeding. Variants that disrupt transcription factor (TF) motifs provide a means to assess functional potential, but the lack of TF ChIP-seq data for farm animals presents a challenge.ResultsTo address this, we curated nearly 900 epigenomic datasets from 10 farm animal species and annotated eight regulatory regions to assess how variants affect TF motifs. Over 127 million candidate functional variants were classified into five functional confidence categories across the species. Variants with high confidence were enriched in eQTLs and trait-associated SNPs, showing greater potential to affect gene expression and phenotypes. Incorporating these functional variants into genomic prediction models improved the accuracy of Estimated Breeding Values (EBVs). Active variants also revealed trait-related tissues, and single-cell RNA sequencing (scRNA-seq) identified the cell types most associated with production traits. To facilitate research, we developed the Integrated Functional Mutation (IFmut) platform, enabling users to explore variant functions easily. Our study provides a flexible platform and resource for studying genomic variation in farm animals, setting a new standard for research and breeding strategies.ConclusionThe results indicated that evaluating functional potential by annotating and categorizing variants that interfere with transcription factor motifs can help elucidate changes in gene expression and phenotype. By focusing on high-confidence variants enriched in eQTL and trait-associated SNPs, it improves the accuracy of genomic predictions in research and breeding strategies.
A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding
Authors: Wang CY , Philpott M , O’Brien DP , Ndungu A , Malzahn J , Maritati M , Mehta N , Gamble V , Martinez-Burgo B , Bonham S , Fischer R , Garbutt K , Becker CM , Manek S , Harris AL , Sacher F , Obendorf M , Schmidt N , Mueller J , Zollner T , Zondervan KT , Kessler BM , Oppermann U , Cribbs AP 
Published: February 2024

ABSTRACTUterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. To correlate systematically genetic, transcriptional and proteomic phenotypes, our study involved an integrative analysis of fibroid, myometrium and endometrium tissues from 137 patients, utilising genome-wide SNP arrays, targeted sequencing, RNA sequencing and proteomics. Our findings reveal 39.7% of UFs possess MED12 mutations, alongside novel variants in genes such as COL4A5 and COL4A6. Multi-omics factor analysis of integrated protein and mRNA highlighted differential regulation related to extracellular matrix remodelling, proteolysis and homeostasis in fibroid versus myometrium tissues, and distinct gene sets associated with RNA splicing in the endometrium of patients with HMB, particularly in MED12-mutated fibroids. Our study proposes a model, which is supported byin vivoevidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. This integrative approach unravels complex molecular pathways in UF pathogenesis and HMB, offering novel insights for targeted therapeutic development.
TumFlow: An AI Model for Predicting New Anticancer Molecules
Authors: Rigoni Davide , Yaddehige Sachithra , Bianchi Nicoletta , Sperduti Alessandro , Moro Stefano , Taccioli Cristian 
Published: February 2024

AbstractMotivationMelanoma is a severe form of skin cancer increasing globally with about 324.000 cases in 2020, making it the fifth most common cancer in the United States. Conventional drug discovery methods face limitations due to the inherently time consuming and costly. However, the emergence of artificial intelligence (AI) has opened up new possibilities. AI models can effectively simulate and evaluate the properties of a vast number of potential drug candidates, substantially reducing the time and resources required by traditional drug discovery processes. In this context, the development of AI normalizing flow models, employing machine learning techniques to create new molecular structures, holds great promise for accelerating the discovery of effective anticancer therapies.ResultsThis manuscript introduces a novel AI model, namedTumFlow, aimed at generating new molecular entities with potential therapeutic value in cancer treatment. It has been trained on the comprehensive NCI-60 dataset, encompassing thousands of molecules tested across 60 tumour cell lines, with a specific emphasis on the melanoma SK-MEL-28 cell line. The model successfully generated new molecules with predicted improved efficacy in inhibiting tumour growth while being synthetically feasible. This represents a significant advancement over conventional generative models, which often produce molecules that are challenging or impossible to synthesize. Furthermore,TumFlowhas also been utilized to optimize molecules known for their efficacy in clinical melanoma treatments. This led to the creation of novel molecules with a predicted enhanced likelihood of effectiveness against melanoma, currently undocumented on PubChem.Availability and Implementationhttps://github.com/drigoni/TumFlow.Supplementary informationUploaded.
Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis inC. elegans
Authors: Mir Dilawar Ahmad , Cox Matthew , Horrocks Jordan , Ma Zhengxin , Rogers Aric 
Published: February 2024

AbstractDietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimer’s disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide (flp) genes and the neuroprotective growth factor progranulin geneprgn-1under dietary restriction inC. elegans. Here, we tested the effects offlp-5,flp-14,flp-15andpgrn-1on lifespan and proteostasis under both standard and dietary restriction conditions. We also tested and distinguished function based on their expression in either neuronal or non-neuronal tissue. Lowering the expression ofpgrn-1andflpgenes selectively in neural tissue showed no difference in survival under normal feeding conditions nor under DR in two out of three experiments performed. Reduced expression offlp-14in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of theeat-2gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown ofpgrn-1orflpgenes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown ofpgrn-1andflpgenes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targetingflp-14increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi ofpgrn-1decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show thatpgrn-1,flp-5,flp-14, andflp-15do not have major roles in diet-related changes in longevity or whole-body proteostasis. However, reduced expression of these genes in neurons increases motility early in life in a neural-specific model of proteotoxicity, whereas knockdown of non-neuronal expression mostly increases motility in mid-life under the same conditions.
Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood stagePlasmodium falciparum
Authors: Abd-Rahman Azrin N. , Kaschek Daniel , Kümmel Anne , Webster Rebecca , Potter Adam J. , Odedra Anand , Woolley Stephen D , Llewellyn Stacey , Webb Lachlan , Marquart Louise , Chalon Stephan , El Gaaloul Myriam , McCarthy James S. , Möhrle Jörg J. , Barber Bridget E. 
Published: February 2024

ABSTRACTBackgroundThe combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.MethodsTwenty-four healthy adults enrolled over three consecutive cohorts were inoculated withPlasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of 7 dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42±2. The General Pharmacodynamic Interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.ResultsFor a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28in the phase 2b trial of 67.0%, 65.5%, and 75.4% respectively.ConclusionsThese results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.Trial registrationThis study was registered onClinicalTrials.govon 31 May 2018 with registration numberNCT03542149.
AlphaCRV: A Pipeline for Identifying Accurate Binder Topologies in Mass-Modeling with AlphaFold
Authors: Guzmán-Vega Francisco J. , Arold Stefan T. 
Published: February 2024

AbstractThe speed and accuracy of deep learning-based structure prediction algorithms makes it now possible to perform in silico “pull-downs” to identify protein-protein interactions at a proteome-wide scale. However, existing scoring algorithms struggle to accurately identify correct interactions at such a large scale, resulting in an excessive number of false positives. Here, we introduce AlphaCRV, a Python package that helps identify correct interactors in a one-against-many AlphaFold screen by clustering, ranking, and visualizing conserved binding topologies, based on protein sequence and fold.
Does amplitude compression help or hinder attentional neural speech tracking?
Authors: Orf Martin , Hannemann Ronny , Obleser Jonas 
Published: February 2024

AbstractAmplitude compression is an indispensable feature of contemporary audio production and especially relevant in modern hearing aids. The cortical fate of amplitude-compressed speech signals is not well-studied, however, and may yield undesired side effects: We hypothesize that compressing the amplitude envelope of continuous speech reduces neural tracking. Yet, leveraging such a ‘compression side effect’ on unwanted, distracting sounds could potentially support attentive listening if effectively reducing their neural tracking. In this study, we examined 24 young normal-hearing (NH) individuals, 19 older hearing-impaired (HI) individuals, and 12 older normal-hearing individuals. Participants were instructed to focus on one of two competing talkers while ignoring the other. Envelope compression (1:8 ratio, loudness-matched) was applied to one or both streams containing short speech repeats. Electroencephalography (EEG) allowed us to quantify the cortical response function and degree of speech tracking. With compression applied to the attended target stream, HI participants showed reduced behavioural accuracy, and compressed speech yielded generally lowered metrics of neural tracking. Importantly, we found that compressing the ignored stream resulted in a stronger neural representation of the uncompressed target speech. Our results imply that intelligent compression algorithms, with variable compression ratios applied to separated sources, could help individuals with hearing loss suppress distraction in complex multi-talker environments.Significant statementAmplitude compression, integral in contemporary audio production and hearing aids, poses an underexplored cortical challenge. Compressing the amplitude envelope of continuous speech is hypothesized to diminish neural tracking. Yet, capitalizing on this ’compression side effect’ for distracting sounds might enhance attentive listening. Studying normal-hearing (NH), older hearing-impaired (HI), and older normal hearing individuals in dual-talker scenarios, we applied envelope compression to speech streams. Both NH and HI participants showed diminished neural tracking with compression on the speech streams. Despite weaker tracking of a compressed distractor, HI individuals exhibited stronger neural representation of the concurrent target. This suggests that adaptive compression algorithms, employing variable ratios for distinct sources, could aid individuals with hearing loss in suppressing distractions in complex multi-talker environments.
Interplay between cortical adhesion and membrane bending regulates microparticle formation
Authors: Mahapatra A. , Malingen S. A. , Rangamani P. 
Published: February 2024

AbstractThe formation of blebs and microparticle formation requires the bending of the plasma membrane away from the cytosol. There are multiple factors that control the formation of the microparticles including the loss of lipid asymmetry, primarily the exposure of phosphatidylserine on the outer leaflet, detachment of the membrane from the cortical cytoskeleton, and bleb expansion due to pressure. In this work, we develop a biophysical model that accounts for the interaction between these different factors. Our findings reveal that linker attachment is a key determinant of outward budding and lays out the mechanical aspects of outward budding of the plasma membrane.Significance StatementCells release many types of membrane-enclosed vesicles in response to stress, inflammation, or other injuries. Formation of these membrane-enclosed structures is critical for proper function of the coagulation cascade and apoptosis. In many cases, these microparticles are also a part of the long distance intercellular communication and are implicated in chemoresistance. A particular class of vesicles called ectosomes or microparticles are released by the outward budding of the plasma membrane, a process which requires detachment of the membrane from the cortex, exposure of negatively charged, curvature-inducing lipids such as phosphatidylserine from the inner leaflet to the outer leaflet, and pressure-driven expansion of the bleb. Here, we used membrane mechanics coupled with the kinetics of adhesive linker binding-unbinding to investigate how these different factors interact together. Using our models, we predict how linker properties plays an important role in the outward budding of the plasma membrane and identify conditions that can promote or inhibit such curvature generation. These findings have implications not just for conditions that require successful microparticle formation such as the procoagulation cascade but also for inhibiting microparticle formation in cases of chemoresistant drug efflux by tumor cells.
Expression interplay of calcium-binding genes and transcription factors during the osmotic phase provides insights on salt stress response mechanisms in bread wheat
Authors: Duarte-Delgado Diana , Vogt Inci , Dadshani Said , Léon Jens , Ballvora Agim 
Published: February 2024

AbstractBread wheat is an important crop for the human diet, but the increasing soil salinization is reducing the yield. The Ca2+signaling events at the early stages of the osmotic phase of salt stress are crucial for the acclimation response of the plants through the performance of calcium-sensing proteins, which activate or repress transcription factors (TFs) that affect the expression of downstream genes. Physiological, genetic mapping, and transcriptomics studies performed with the contrasting genotypes Syn86 (synthetic, salt-susceptible) and Zentos (elite cultivar, salt-tolerant) were integrated to gain a comprehensive understanding of the salt stress response. The MACE (Massive Analysis of cDNA 3’-Ends) based transcriptome analysis until 4 h after stress exposure revealed among the salt-responsive genes, the over-representation of genes coding calcium-binding proteins. The functional and structural diversity within this category was studied and linked with the expression levels during the osmotic phase in the contrasting genotypes. The non-EF-hand category from calcium-binding genes was found to be specific for the susceptibility response. On the other side, the tolerant genotype was characterized by a faster and higher up-regulation of EF-hand genes, such as RBOHD orthologs, and TF members. This study suggests that the interplay of calcium-binding genes, WRKY, and AP2/ERF TF families in signaling pathways at the start of the osmotic phase can affect the expression of downstream genes. The identification of SNPs in promoter sequences and 3’-UTR regions provides insights into the molecular mechanisms controlling the differential expression of these genes through differential transcription factor binding affinity or altered mRNA stability.Key messageThe fine-tuned expression of calcium-binding genes and transcription factors during the osmotic phase underlies the susceptibility and tolerance to salt stress responses of contrasting bread wheat genotypes.
Hereditary breast cancer next-generation sequencing (NGS) panel evaluation in the south region of Brazil: a novelBRCA2candidate pathogenic variant is reported
Authors: Duarte Cesar Augusto B. , Santos Carlos Alberto dos , de Oliveira Cristine Domingues D. , Spautz Cleverton César , Sumita Laura Masami , Nakatani Sueli Massumi 
Published: February 2024

AbstractIn this article, we delineate a loosely selected cohort comprising patients with a history of early-onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer-related gene variants in a population from a micro-region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. Comprehensive next-generation sequencing (NGS) multigene panel testing was conducted, involving the evaluation of twelve patients. Two pathogenic variants and one candidate pathogenic variant were identified:BRCA2:c.8878C>T, p.Gln2960Ter;CHEK2:c.1100delAG>A, p.Thr367Metfs*15 andBRCA2:c.3482dupG>GA, p.Asp1161Glufs*3, a novel variant, previously unpublished, is reported.Author SummaryBreast cancer stands as one of the most prevalent cancers globally, affecting both genders, although it is much more common in women. Predominantly sporadic, around 5% to 10% of cases are attributed to hereditary factors, linked to specific gene mutations passed down through generations. BeyondBRCA1andBRCA2, there is a growing understanding that breast cancer risk is influenced by a range of genes. In the pursuit of understanding and mitigating breast cancer risks, genetic testing plays a pivotal role. These tests draw upon extensive databases, repositories of genetic information, to decipher individual variations. However, the lack of population diversity representation in genetic research databases is a global concern, and Latin America is no exception, presenting challenges in ensuring inclusivity and relevance in genetic research and healthcare applications. Addressing this gap, our study focused on a population in the Metropolitan Region of Curitiba, Brazil, sought to uncover breast cancer-related genetic variants. Despite the modest cohort, the study identified two pathogenic and one novel candidate pathogenic variants. While a small contribution, this research endeavors to enrich the collective knowledge base surrounding breast cancer, illustrating the ongoing efforts to comprehend and address the complexities of this prevalent disease.
Association of Center-Level Operative Volume and Acute Outcomes following Robotic-Assisted Colectomy for Malignancy
Authors: Cho Nam Yong , Kim Shineui , Hadaya Joseph , Chervu Nikhil , Ebrahimian Shayan , Cruz Emma , Lee Hanjoo , Benharash Peyman 
Published: February 2024

AbstractBackgroundThe adoption of RAC remains limited due to high costs. There is a paucity of data regarding the impact of institutional robotic experience on costs in patients undergoing RAC for colorectal cancer.MethodsAll adult patients undergoing RAC for colorectal cancer were identified using the 2016-2020 Nationwide Readmissions Database. A multivariable regression to model major adverse events (MAE) was developed with the inclusion of institutional robotic surgery volume as restricted cubic splines. The volume corresponding to the inflection point of the spline was used to stratify hospitals into high-(HVH) or low-volume (LVH). We subsequently examined the association of HVH status with costs, length of stay (LOS), MAE, non-home discharge and 30-day unplanned readmission.ResultsAmong the 43,475 patients undergoing RAC, 63.8% were treated at HVH. Following risk adjustment, RAC at HVH was associated with reduced index hospitalization costs by $2,000 (95%CI $1,500-2,400) and LOS by 0.3 days (95%CI 0.2-0.5 days) as well as decreased odds of MAE (AOR 0.86, 95%CI 0.77-0.96). Both non-home discharge and 30-day unplanned readmission were not associated with hospital volume. In our cross-volume analysis, we found an increase in institutional RAC and overall robotic volumes to be associated with reduced odds of MAE.ConclusionThe present study demonstrated higher institutional robotic-assisted operation volume to be associated with reduced MAE and cost in patients undergoing RAC. The findings suggest the potential benefits of increasing expertise and implementing efficient practices in robotic-assisted surgery programs.