bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Lung Cancer Screening: A Comparative Study of CNN and Radiomics Models with Pulmonary Nodule Biologic Characterization
Authors: Gupta Mukund , Fandy Edbert Victor , Ghindani Krrish 
Published: July 2024

AbstractLung cancer has become an increasingly prevalent disease, with an estimated 125,070 deaths in the United States alone in 2024 (5). To improve patient outcomes and assist doctors in differentiating between benign and malignant pulmonary nodules, this paper developed a Convolutional Neural Network (CNN) model for early binary detection of pulmonary nodules and assessed its effectiveness compared to other approaches. The CNN model showed an accuracy of 98.47%, while the radiomics-based SVM-LASSO model and the Lung-RADS system showed accuracies of 84.6% and 72.2% respectively. This demonstrates that the CNN model is significantly more effective for the early binary detection of pulmonary nodules than both the radiomics-based model and the Lung-RADS system. The paper also discusses the applications of Deep Learning in healthcare, concluding that although AI proves to be an effective method for early lung cancer detection, more research is needed to carefully assess the role and impact of AI in healthcare.
The single-berry metabolomic clock paradigm reveals new stages and metabolic switches during grapevine berry development
Authors: Tavernier Flora , Savoi Stefania , Torregrosa Laurent , Hugueney Philippe , Baltenweck Raymonde , Segura Vincent , Romieu Charles 
Published: July 2024

SummaryAsynchronous development of berries causes metabolic chimerism in usual samples. We thus revisited the developmental changes in the metabolome of theVitis viniferasingle berries from anthesis to over-ripening.A dataset of 9,256 ions obtained by non-targeted ultra-performance liquid chromatography coupled to high-resolution mass spectrometry was submitted to an analysis workflow combining classification and dimension reduction tools, to reveal the dynamics of metabolite composition without phenologicala priori.This approach led to a metabolome-based definition of developmental stages, as well as the clustering of metabolites into 12 specific kinetic patterns. The single berry intrinsic metabolomic clock alleviates constitutive asynchronicity biases in the usual combination of phenological scales and observer clock. Such increase in temporal resolution enabled the identification of metabolite clusters annunciative of the onset of ripening since the herbaceous plateau. In particular, these clusters included transient lipidic changes and the start of ABA accumulation. We also highlighted a cluster of stilbenes that accumulate after sugar loading stops, during fruit shriveling.This non-targeted approach enables a more precise and unbiased characterization of grapevine berry development through the metabolomic clock paradigm. The discovery of new metabolic milestones of berry development paves the way towards an unbiased assessment of berry physiological stages.
CDK4/6 inhibitors promote PARP1 degradation and act synergistically with PARP inhibitors in non-small cell lung cancer
Authors: Roggero Carlos M , Ghosh Anwesha B , Devineni Anvita , Ma Shihong , Blatt Eliot , Raj Ganesh V. , Yin Yi 
Published: July 2024

AbstractDespite the widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), the clinical trials with CDK4/6 inhibitors (CDK4/6is) as a monotherapy have shown poor antitumor activity. However, our preclinical studies have revealed a significant potential for CDK4/6is to collaborate by influencing DNA damage repair pathways during radiotherapy. Given the considerable upregulation of PARP1 expression in NSCLC, we analyzed the efficacy of combined PARP and CDK4/6 inhibition in NSCLC models. Our findings demonstrate that CDK4/6is synergize with PARP inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy is associated with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. We showed that CDK4/6is mechanically promote PARP1 protein degradation, leading to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is required for this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. These findings reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the requirement of PARP trapping to render synergy between CDK4/6i and PARPi. Our research suggests that combining CDK4/6i with PARPi could be a promising therapeutic strategy for patients with RB-proficient NSCLC, potentially opening up new and more effective avenues for treatment.
The Virtual Parkinsonian Patient
Authors: Angiolelli Marianna , Depannemaecker Damien , Agouram Hasnae , Ŕegis Jean , Carron Romain , Woodman Marmaduke , Chiodo Letizia , Triebkorn Paul , Ziaeemehr Abolfazl , Hashemi Meysam , Eusebio Alexandre , Jirsa Viktor , Sorrentino Pierpaolo 
Published: July 2024

AbstractThis study investigates the influence of the pharmacological nigrostriatal dopaminergic stimula-tion on the entire brain by analyzing EEG and deep electrodes, placed near the subthalamic nuclei, from 10 Parkinsonian patients, before (OFF) and after (ON) L-Dopa administration. We charac-terize large-scale brain dynamics as the spatio-temporal spreading of aperiodic bursts. We then simulate the effects of L-Dopa utilizing a novel neural-mass model that includes the local dopamine concentration. Whole-brain dynamics are simulated for different dopaminergic tones, generating predictions for the expected dynamics, to be compared with empirical EEG and deep electrode data. To this end, we invert the model and infer the most likely dopaminergic tone from empirical data, correctly identifying a higher Dopaminergic tone in the ON-state, and a lower dopaminergic tone in the OFF-state, for each patient. In conclusion, we successfully infer the dopaminergic tone by integrating anatomical and functional knowledge into physiological predictions, using solid ground truth to validate our findings.
A genome-wide association study in 10,000 individuals links plasma N-glycome to liver disease and anti-inflammatory proteins
Authors: Sharapov Sodbo , Timoshchuk Anna , Zaytseva Olga , Maslov Denis , Soplenkova Anna , Elgaeva Elizaveta E. , Tiys Evgeny S. , Mangino Massimo , Wittenbecher Clemens , Karssen Lennart , Timofeeva Maria , Nostaeva Arina , Vuckovic Frano , Trbojević-Akmačić Irena , Štambuk Tamara , Feoktistova Sofya , Potapova Nadezhda A. , Voroshilova Viktoria , Williams Frances , Primorac Dragan , Zundert Jan Van , Georges Michel , Suhre Karsten , Allegri Massimo , Chaturvedi Nishi , Dunlop Malcolm , Schulze Matthias B. , Spector Tim , Tsepilov Yakov A. , Lauc Gordan , Aulchenko Yurii S. 
Published: July 2024

AbstractMore than a half of plasma proteins are N-glycosylated. Most of them are synthesized, glycosylated, and secreted to the bloodstream by liver and lymphoid tissues. While associations with N-glycosylation are implicated in the rising number of liver, cardiometabolic, and immune diseases, little is known about the genetic regulation of this process. Here, we performed the largest genome-wide association study of N-glycosylation of the blood plasma proteome in 10,000 individuals. We doubled the number of genetic loci known to be associated with blood N-glycosylation by identifying 16 novel loci and prioritizing 13 novel genes contributing to N-glycosylation. Among these were theGCKR,TRIB1,HP, SERPINA1andCFHgenes. These genes are predominantly expressed in the liver and show a previously unknown genetic link between plasma protein N-glycosylation, metabolic and liver diseases, and inflammatory response. By integrating glycomics, proteomics, transcriptomics, and genomics, we provide a resource that facilitates deeper exploration of disease pathogenesis and supports the discovery of glycan-based biomarkers.
What child and adolescent psychiatry in France for the second quarter of the 21stcentury? An AI-assisted qualitative action research study
Authors: Falissard Bruno , Espi Pauline , Rouquette Alexandra 
Published: July 2024

AbstractFrench Child and Adolescent Psychiatry (CAP) faces significant issues, primarily due to an overwhelming increase in demand and insufficient capacity. In response, the French Society for Child and Adolescent Psychiatry and Allied Professions (SFPEADA) initiated an action research project in June 2023 aimed at reimagining the future of CAP in France for the second quarter of the 21st century. Employing a holistic qualitative methodology that merges bottom-up and top-down approaches, the project progressed through four phases: interviews with informed individuals, consultations with trade unions or associations, synthesis of findings using thematic analysis and AI technologies, and public dissemination via a symposium at the ministry of health. The project identified 5 main themes: “CAP and Society”, “Knowledge Integration”, ”Healthcare Delivery”, “Caregivers”, ”System Organization”. This initiative underscores the importance of a collaborative, multidisciplinary approach to address the important needs of child and adolescent mental health in France, advocating for significant systemic changes to enhance CAP’s efficacy and accessibility.
HyperCas12a enables highly-multiplexed epigenome editing screens
Authors: Melore Schuyler M. , Hamilton Marisa C. , Reddy Timothy E. 
Published: July 2024

AbstractInteractions between multiple genes or cis-regulatory elements (CREs) underlie a wide range of biological processes in both health and disease. High-throughput screens using dCas9 fused to epigenome editing domains have allowed researchers to assess the impact of activation or repression of both coding and non-coding genomic regions on a phenotype of interest, but assessment of genetic interactions between those elements has been limited to pairs. Here, we combine a hyper-efficient version ofLachnospiraceae bacteriumdCas12a (dHyperLbCas12a) with RNA Polymerase II expression of long CRISPR RNA (crRNA) arrays to enable efficient highly-multiplexed epigenome editing. We demonstrate that this system is compatible with several activation and repression domains, including the P300 histone acetyltransferase domain and SIN3A interacting domain (SID). We also show that the dCas12a platform can perform simultaneous activation and repression using a single crRNA array via co-expression of multiple dCas12a orthologues. Lastly, demonstrate that the dCas12a system is highly effective for high-throughput screens. We use dHyperLbCas12a-KRAB and a ∼19,000-member barcoded library of crRNA arrays containing six crRNAs each to dissect the independent and combinatorial contributions of CREs to the dose-dependent control of gene expression at a glucocorticoid-responsive locus. The tools and methods introduced here create new possibilities for highly multiplexed control of gene expression in a wide variety of biological systems.
Genome-resolved year-round dynamics reveal a broad range of giant virus microdiversity
Authors: Fang Yue , Meng Lingjie , Xia Jun , Gotoh Yasushiro , Hayashi Tetsuya , Nagasaki Keizo , Endo Hisashi , Okazaki Yusuke , Ogata Hiroyuki 
Published: July 2024

AbstractGiant viruses are crucial for marine ecosystem dynamics because they regulate microeukaryotic community structure, accelerate carbon and nutrient cycles, and drive the evolution of their hosts through co-evolutionary processes. Previously reported long-term observations revealed that these viruses display fluctuations in abundance. However, the underlying genetic mechanisms driving such dynamics in these viruses remain largely unknown. In this study, we investigated population and intra-population dynamics of giant viruses using time-series metagenomes from eutrophic coastal seawater samples collected over 20 months. A newly developed near-automatic computational pipeline generated 1,065 high-quality metagenome-assembled genomes covering six major giant virus lineages. These genomic data revealed year-round recovery of the viral community at the study site and distinct dynamics of different viral populations classified as persistent (n = 9), seasonal (n = 389), sporadic (n = 318), or others. Notably, year-round recovery patterns were observed at the intra-population genetic diversity level for viruses classified as persistent or seasonal. Our results further indicated that the viral genome dynamics were associated with intra-population diversity; specifically, giant viruses with broader niche breadth tended to exhibit greater levels of microdiversity. We argue that greater microdiversity in viruses likely enhances adaptability and thus survival under the virus–host arms race during prolonged interactions with their hosts.
BRAT1 - a new therapeutic target for glioblastoma
Authors: Haydo Alicia , Schmidt Jennifer , Crider Alisha , Kögler Tim , Ertl Johanna , Hehlgans Stephanie , Hoffmann Marina E. , Rathore Rajeshwari , Güllülü Ömer , Wang Yecheng , Zhang Xiangke , Herold-Mende Christel , Pampaloni Francesco , Tegeder Irmgard , Dikic Ivan , Dai Mingji , Rödel Franz , Kögel Donat , Linder Benedikt 
Published: July 2024

AbstractGlioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of protein breast cancer type 1 susceptibility protein (BRCA1)-associated Ataxia telangiectasia mutated (ATM)-activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated byin vitroandin vivostudies demonstrating impaired tumor growth and invasion. Proteomic analyses further emphasize the role of BRAT1’s cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in anex vivoslice culture model, particularly when combined with irradiation, resulting a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments.
Asbestos Mineral Fibre Exposure Significantly Affects Volatile Organic Compound Profiles of Mesothelial Cell Lines In Vitro
Authors: Bonsall Sam , Issitt Theo , Peake Nick , Herigstad Mari , Webber Jason , Haywood-Small Sarah 
Published: July 2024

AbstractMalignant mesothelioma (MM) is a rare cancer caused by exposure to asbestos, this condition continues to represent a significant diagnostic and therapeutic challenge. Due to the long disease latency, non-invasive diagnostic modalities such as breath analysis may enhance MM early detection by identifying the disease specific pattern of volatile organic compounds (VOCs) in exhaled breath. In this study, solid phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) was used to extract VOCs from the headspace of two mesothelioma cell lines: MSTO-211H (biphasic mesothelioma) and NCI-H28 (epithelioid mesothelioma) in addition to MET-5a (non-malignant mesothelial cell line), following exposure to asbestos mineral fibers (actinolite, amosite, crocidolite and chrysotile) and a non-asbestos fiber control (wollastonite). Multivariate statistical analysis was applied to identify VOC-based biomarkers associated with asbestos exposure within the cell lines. Data confirms that exposure to mineral fibers (including the non-asbestos fiber control) induces significant alterations in the levels of as many as 24 VOCs in each cell line. This is the first study to investigate the impact of asbestos mineral fiber exposure on the VOC profile of MM cell lines. This may be relevant to studies involving mesothelioma patients, as these VOCs could also serve as indicators of asbestos exposure in individuals who have been exposed to asbestos.
Metagenomic insights into the development of microbial communities of straw and leaf composts
Authors: Kimeklis Anastasiia K. , Gladkov Grigory V. , Orlova Olga V. , Lisina Tatiana O. , Afonin Alexey M. , Aksenova Tatiana S. , Kichko Arina A. , Lapidus Alla L. , Abakumov Evgeny V. , Andronov Evgeny E. 
Published: July 2024

AbstractThe objects of this study are microbial communities formed on two types of contrasting lignocellulosic biomass. To study them, a long-term experiment was set up and conducted on the decomposition of oat straw and leaf litter using soil as a microbial inoculum. Combined analyses of enzymatic activity and NGS data for 16S rRNA gene amplicon and full metagenome sequencing was applied to study taxonomic, CAZy (Carbohydrate-Active enzymes), and PULs (Polysaccharide Utilization Loci) composition of microbial communities at different stages of decomposition between substrates. using a combination of 16S rRNA gene amplicon and long-read nanopore sequencing. In straw degradation, the microbial community demonstrated higher amylase, protease, catalase, and cellulase activities, while peroxidase, invertase, and polyphenol oxidase were more active in leaf litter. Consistent with this, the metagenome analysis showed that the microbiome of straw compost was enriched in genes for metabolic pathways of simpler compounds. At the same time, there were more genes for aromatic compound degradation pathways in leaf litter compost. We identified 9 MAGs (Metagenome-assembled genomes) as the most promising prokaryotic decomposers due to their abnormally high quantity of PULs for their genome sizes, which were confirmed by 16S rRNA gene amplicon sequencing to constitute the bulk of the community at all stages of degradation. MAGs classified as Bacteroidota (Chitinophaga,Ohtaekwangia), and Actinomycetota (Streptomyces) were found in both substrates, while those from Bacillota (Pristimantibacillus) were specific for leaf litter. The most frequent PULs were specialized on xylans and pectins, but not cellulose, suggesting that PUL databases may be lacking PULs for complex substrates.ImportanceOur study explores the microbial communities from natural ecosystems, like soil and lignocellulosic waste, capable of decomposing lignocellulosic substrates. We used a comprehensive approach with chemical analyses of the substrates, amplicon and full-metagenome sequencing data. We have shown that such communities may be a source of identifying the highly effective decomposing species with novel PULs.
CLEC18A interacts with sulfated GAGs and controls clear cell renal cell carcinoma progression
Authors: Jonsson Gustav , Hofmann Maura , Mereiter Stefan , Hartley-Tassell Lauren , Sakic Irma , Oliveira Tiago , Hoffmann David , Novatchkova Maria , Schleiffer Alexander , Penninger Josef M. 
Published: July 2024

AbstractC-type lectins are a large family of proteins with essential functions in both health and disease. In cancer, some C-type lectins have been found to both promote and inhibit tumor growth, but many of the C-type lectins still remain uncharacterised in a tumor context. Therefore, there is growing interst in further elucidating the mechanisms with which C-type lectins control tumor growth. Here, we report a key role of the CLEC18 family of C-type lectins in the progression of clear cell renal cell carcinoma (ccRCC). The CLEC18 family is conserved across the entire Chordata phylum with recent gene duplication events in humans. We found that CLEC18A is exclusively expressed in the proximal tubule of the kidney and the medial habenula of the brain. We further identified sulfated glycosaminoglycans (GAGs) of proteoglycans as the main CLEC18A ligand, making them unique among C-type lectins. In ccRCC patients, high expression of theCLEC18family lectins in the tumor are associated with improved survival. In mouse models of ccRCC, deletion of the mouse orthologClec18aresulted in enhanced tumor growth. Our results establishes CLEC18A as a novel and critical regulators of ccRCC tumor growth and highlights the potential benefit of modulatingCLEC18expression in the renal tumor microenvironment.
Combining computational modeling and experimental library screening to affinity-mature VEEV-neutralizing antibody F5
Authors: Sumner Christopher A. , Schwedler Jennifer L. , McCoy Katherine M. , Holland Jack , Duva Valery , Gelperin Daniel , Busygina Valeria , Stefan Maxwell A. , Martinez Daniella V. , Juarros Miranda A. , Phillips Ashlee M. , Weilhammer Dina R. , Grigoryan Gevorg , Kent Michael S. , Harmon Brooke N. 
Published: July 2024

ABSTRACTEngineered monoclonal antibodies (mAbs) have proven to be highly effective therapeutics in recent viral outbreaks due to their specificity and ability to provide immediate protection, regardless of immune status. However, despite technical advancements in the field, an ability to rapidly adapt or increase antibody affinity and by extension, therapeutic efficacy, has yet to be fully realized. We endeavored to stand-up such a pipeline using molecular modeling combined with experimental library screening to increase the affinity of a given antibody, F5, to recombinant E1E2 antigen from Venezuelan Equine Encephalitis Virus (VEEV) subtype IAB (TC-83). F5 is a monoclonal antibody with potent neutralizing activity against VEEV that was isolated from human bone marrow donors. F5 is known to bind to spikes on the surface of VEEV made up of a trimer of heterodimers of the glycoproteins E1 and E2. In this work we modeled the interaction of F5 with the E1E2 trimer of VEEV (TC-83) and generated predictions for mutations to improve binding using a Rosetta-based approach and dTERMen, an informatics approach. Modeling the structure of the complex was complicated by the fact that a high-resolution structure of F5 is not available and the H3 loop of F5 exceeds the length for which current modeling approaches can determine a unique structure. To overcome these challenges nine F5 structures with varying H3 loop conformations were generated using RosettaAntibody, PIGS (Prediction of ImmunoGlobulin Structure), and SWISS-Model and these base antibody structures were evaluated in docking trials to recombinant VEEV E1E2 based on relative binding affinity for several subtypes. The structure that gave the best agreement with the experimental trend in relative binding affinity was used for mutation analysis. A subset of the predicted mutations from both methods were incorporated into a phage display library of scFvs (single-chain variable fragments) and screened for binding affinity to the recombinant E1E2 antigen. Results from this screen were used to identify favorable mutations which were then incorporated into twelve human-IgG1 variants. All twelve variants showed increased binding relative to the parental F5 human-IgG1. The best case showed > 60x increased binding to recombinant E1E2 relative to the parental antibody, notably showing a drastic improvement of the Kd or “off rate” compared to the parental F5 IgG. These results demonstrate the ability of our methods to rapidly increase affinity and could be leveraged for increasing Ab binding breadth to additional viral variants.