bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatocellular carcinoma hosts immature neurons and cholinergic tumors that correlate with adverse molecular features and outcomes
Authors: Hernandez Charlotte A. , Verzeroli Claire , Chicherova Ievgeniia , Farca-Luna Abud-José , Tonon Laurie , Bellaud Pascale , Turlin Bruno , Fautrel Alain , Macek-Jilkova Zuzana , Decaens Thomas , Rebouissou Sandra , Viari Alain , Zoulim Fabien , Parent Romain 
Published: June 2022

AbstractBackground & aimsThe unexplained interpatient variation in hepatocellular carcinoma (HCC) remains a major challenge. We aimed at addressing the under-explored association between the disease and the hepatic autonomic nervous system (ANS).Methods & ResultsWe in-depth characterized the innervation of French biobanks HCC samples by conventional biochemistry methods. We also applied bioinformatics approaches to the TCGA dataset in order to stratify samples according to neural features and molecular correlates. We highlighted the predominant parasympathetic polarity of HCC nerves, and demonstrated that a cirrhotic rat model of aggressive HCC hosts liver neurogenesis with cholinergic features. Using the TCGA dataset, we then defined an HCC neural signature, derived from adrenergic and cholinergic receptor levels, that allowed patient stratification into two classes. Cholinergic tumors correlated with TP53 mutations (p ≤ 0.05), shorter progression-free interval (PFI) and overall survival (OS), displayed more pathogenic molecular traits (e.g., AFP-rich, proliferative tumors, mitotic functions including DNA repair, EMT, Ras, and Akt/mTOR pathways), aggressive HCC signatures and B cell accumulation. Instead, adrenergic tumors, predominant in patients aged >60 and with mutated CTNNB1, were correlated with better OS and PFI (p < 0.05), and numerous immune pathways.ConclusionsOur results depict neural features of HCC and how the existing tumor classification may also be shaped by neural inputs. Altogether, we show that the parasympathetic branch of the ANS is implicated in the pathobiology of HCC, and advocate for the use of ANS-targeting drugs in HCC research, many of which are clinically safe and well characterized.
The differential metabolic signature of breast cancer cellular response to olaparib treatment
Authors: Berardi Domenica , Hunter Yasmin , van den Driest Lisa , Farrell Gillian , Rattray Nicholas J W , Rattray Zahra 
Published: June 2022

ABSTRACTMetabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely to fingerprint the impact of olaparib treatment in cellular metabolism. Here, we report the biomolecular response of breast cancer cell lines with DNA damage repair defects to olaparib exposure.Following evaluation of olaparib sensitivity in breast cancer cell lines, we immunoprobed DNA double strand break foci and evaluated changes in cellular metabolism at various olaparib treatment doses using untargeted mass spectrometry-based metabolomics analysis. Following identification of altered features, we performed pathway enrichment analysis to measure key metabolic changes occurring in response to olaparib treatment.We show a cell-line dependent response to olaparib exposure, and an increased susceptibility to DNA damage foci accumulation in triple-negative breast cancer cell lines. Metabolic changes in response to olaparib treatment were cell-line and dose-dependent, where we predominantly observed metabolic reprogramming of glutamine-derived amino acids and lipids metabolism.Our work demonstrates the effectiveness of combining molecular biology and metabolomics studies for the comprehensive characterisation of cell lines with different genetic profiles. Follow-on studies are needed to map the baseline metabolism of breast cancer cells and their unique response to drug treatment. Fused with genomic and transcriptomics data, such readout can be used to identify key oncometabolites and inform the rationale for the design of novel drugs or chemotherapy combinations.
Distinct neurotoxic TDP-43 fibril polymorphs can be generated by heterotypic interactions with α-synuclein
Authors: Dhakal Shailendra , Robang Alicia S. , Bhatt Nemil , Puangamali Nicha , Fung Leiana , Kayed Rakez , Paravastu Anant K. , Rangachari Vijayaraghavan 
Published: June 2022

ABSTRACTAmyloid aggregates of specific proteins form important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers of patients show co-morbidities and overlaps between multiple neurodegenerative diseases, presenting distinct phenotypes. Such overlaps are often accompanied by co-localizations of more than one amyloid protein, prompting the question of whether direct interactions between different amyloid proteins could generate heterotypic amyloids. To answer this question, we investigated the effect of α-synuclein (αS) on TDP-43 aggregation inspired by their co-existence in pathologies such as Lewy body dementia and limbic predominant age-related TDP-43 encephalopathy. We previously showed that αS and prion-like C-terminal domain (PrLD) of TDP-43 synergistically interact with one another to generate toxic heterotypic aggregates in vitro. Here, we extend these studies to investigate whether αS induces structurally and functionally distinct polymorphs of PrLD aggregates. Using αS –PrLD heterotypic aggregates generated in two different stoichiometric proportions, we show that αS can effect PrLD fibril forms. The fibril samples have distinctive residue-level structural signatures in NMR spectra, dye-binding capability, proteinase K (PK) stability, and SDS-sensitive thermal stability. By gold nanoparticle labeling and TEM, we show the presence of both αS and PrLD proteins within the same fibrils, and thus the existence of hetertypic hybrid fibrils. We also observe that αS and PrLD co-localize in the cytosol of SH-SY5Y neuroblastoma cells, and show that the heterotypic PrLD fibrils selectively induce synaptic dysfunction in primary cortical neurons. These findings establish the existence of heterotypic amyloid polymorphs and provide a molecular basis for the observed overlap between synucleinopathies and TDP-43 proteinopathies.
Data Processing Choices Can Affect Findings in Differential Methylation Analyses: An Investigation Using Data from the LIMIT RCT
Authors: Louise Jennie , Deussen Andrea R , Dodd Jodie M 
Published: June 2022

AbstractObjectiveA wide array of methods exist for processing and analysing DNA methylation data. We aimed to perform a systematic comparison of the behaviour of these methods, using cord blood DNAm from the LIMIT RCT, in relation to detecting hypothesised effects of interest (intervention and pre-pregnancy maternal BMI) as well as effects known to be spurious, and known to be present.MethodsDNAm data, from 645 cord blood samples analysed using Illumina 450K BeadChip arrays, were normalised using three different methods (with probe filtering undertaken pre- or post-normalisation). Batch effects were handled with a supervised algorithm, an unsupervised algorithm, or adjustment in the analysis model. Analysis was undertaken with and without adjustment for estimated cell type proportions. The effects estimated included intervention and BMI (effects of interest in the original study), infant sex and randomly assigned groups. Data processing and analysis methods were compared in relation to number and identity of differentially methylated probes, rankings of probes by p value and log-fold-change, and distributions of p values and log-fold-change estimates.ResultsThere were differences corresponding to each of the processing and analysis choices. Importantly, some combinations of data processing choices resulted in a substantial number of spurious ‘significant’ findings. We recommend greater emphasis on replication and greater use of sensitivity analyses.Clinical Trials RegistrationACTRN12607000161426
Porcine ANTXR1, Heparan Sulfate and Neu5Gc act as entry factors for Seneca Valley virus invasion
Authors: Tang Wenda , Wang Yanchao , Qi Xiaolan , Gu Fengxing , Li Kangli , Han Haitang , Du Xuguang , Zhu Zixiang , Wu Sen , Zhao Yaofeng , Zheng Haixue 
Published: June 2022

AbstractSeneca Valley virus (SVV) disease is a newly emerging infectious disease of pigs caused by SVV, which seriously endangers the pig industry. This study was set out to identify the essential host factors required for SVV entering porcine cells. Using a CRISPR/Cas9 library containing 93,859 sgRNAs that were designed to target approximately 22,707 porcine genes, we generated mutated porcine cell libraries, which were subjected to SVV challenge for enrichment of cells resistant to SVV infection. These resistant cells were subsequently analyzed to identify genes essential for SVV infection. We demonstrated that ANTXR1, a type I transmembrane protein encoded by ANTXR1, heparan sulfate (HS), glycosaminoglycans modified by acetylation and sulfation of HS2ST1, and Neu5Gc, a non-human sialic acid catalyzed by CMAH, were the essential host factors for SVV entry into porcine cells. These results will be helpful to elucidate the pathogenesis of SVV and the development of prevention and control measures.
Hnf1b renal expression directed by a distal enhancer responsive to Pax8
Authors: Goea L. , Buisson I. , Bello V. , Eschstruth A. , Paces-Fessy M. , Le Bouffant R. , Chesneau A. , Cereghini S. , Riou J.F. , Umbhauer M. 
Published: June 2022

AbstractXenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.
No effects of offline high frequency transcranial magnetic stimulation to posterior parietal cortex on the choice of which hand to use to perform a reaching task
Authors: Fitzpatrick Aoife M. , Dundon Neil M. , Valyear Kenneth F. 
Published: June 2022

AbstractThe current study used a high frequency TMS protocol known as continuous theta burst stimulation (cTBS) to test a model of hand choice that relies on competing interactions between the hemispheres of the posterior parietal cortex. Based on the assumption that cTBS reduces cortical excitability, the model predicts a significant decrease in the likelihood of selecting the hand contralateral to stimulation. An established behavioural paradigm was used to estimate hand choice in each individual, and these measures were compared across three stimulation conditions: cTBS to the left posterior parietal cortex, cTBS to the right posterior parietal cortex, or sham cTBS. Our results provide no supporting evidence for the interhemispheric competition model. We find no effects of cTBS on hand choice, independent of whether the left or right posterior parietal cortex was stimulated. Our results are nonetheless of value as a point of comparison against prior brain stimulation findings that, in contrast, provide evidence for a causal role for the posterior parietal cortex in hand choice.HighlightsHigh-frequency TMS applied to the left and right posterior parietal cortex, separately, did not produce reliable aftereffects on hand choice.Response times to initiate actions were significantly increased when reaching near the point in space where hand choice was equally probable.
Pan-cancer classification of single cells in the tumour microenvironment
Authors: Nofech-Mozes Ido , Soave David , Awadalla Philip , Abelson Sagi 
Published: June 2022

AbstractSingle-cell RNA sequencing reveals valuable insights into cellular heterogeneity within tumour microenvironments (TMEs), paving the way for a deep understanding of cellular mechanisms contributing to cancer. However, high heterogeneity among the same cancer types and low transcriptomic variation in immune cell subsets present challenges for accurate, high-resolution confirmation of cells’ identities. Here we present scATOMIC; a modular annotation tool for malignant and non-malignant cells. We trained scATOMIC on >250,000 cancer, immune, and stromal cells defining a pan-cancer reference across 19 common cancer types and employed a novel hierarchical approach, outperforming current classification methods. We extensively confirmed scATOMIC’s accuracy on 198 tumour biopsies and 54 blood samples encompassing >420,000 cancer and a variety of TME cells. Lastly, we demonstrate scATOMIC’s practical significance to accurately subset breast cancers into clinically relevant subtypes and predict tumours’ primary origin across metastatic cancers. Our approach represents a broadly applicable strategy to analyze multicellular cancer TMEs.
Candesartan treatment preserves learning and working memory in female TgF344-AD rats
Authors: Sinon Christopher G , Carter Kathleen , Ma Jing , Bagchi Pritha , Zhang Xiancong , Williams Peter-Jon C. , Dammer Eric B , Seyfried Nicholas T , García Paul S , Sutliff Roy L , Hajjar Ihab M 
Published: June 2022

AbstractBackgroundTargeting the renin angiotensin system, especially with angiotensin receptor II blockers (ARB), and related vascular dysfunction is a promising therapeutic intervention for cognitive impairment including Alzheimer’s Disease (AD). The underlying mechanisms of the effects of ARB is unclear. This study sought to examine if treatment with candesartan, an ARB, affects neurobehavioral manifestation and the underlying neuro- and vascular mechanisms in male and female TgF344-AD rats.MethodsCandesartan or vehicle was administered to TgF344-AD rats (n=127) daily from 12-months to 18-months of age. Behavioral assays (spontaneous alternation test, novel object recognition, water radial arm maze) and neuropathologic assessment were completed along with brain proteome and measures of contractility in 12- and 18-month rat brains.ResultsUntreated 18-month TgF344-AD showed impairments in learning and increased perseverative working memory errors on the water radial arm maze (WRAM). These behavioral changes were corrected with candesartan treatment in female rats only. Treatment with candesartan was also associated with improved vascular reactivity and reduced blood pressure in both wild type and TgF344-AD male and female rats. Although there was no effect on amyloid-β, treatment with candesartan reduced whole brain clusterin, an AD-risk associated protein, and GFAP in female TgF344-AD.ConclusionsOur results demonstrate that candesartan administered in the early stages of AD has a sexual dimorphic response in Tgf344-AD rat, where it reduced cognitive disturbances only in female TgF344-AD rat. These effects appear to be independent of changes in blood pressure and amyloid-β reduction and are likely mediated through mechanisms related to clusterin and GFAP pathways.
Immune gene expression in the mosquito vector Culex quinquefasciatus during an avian malaria infection
Authors: García-Longoria L , Ahrén D , Berthomieu A , Kalbskopf V , Rivero A , Hellgren O 
Published: June 2022

ABSTRACTPlasmodium relictum is the most widespread avian malaria parasite in the world. It is listed as one of the 100 most dangerous invasive species, having been responsible for the extinction of several endemic bird species, and the near-demise of several others. Here we present the first transcriptomic study examining the effect of P. relictum on the immune system of its vector (the mosquito Culex quinquefasciatus) at different times post-infection. We show that over 50% of immune genes identified as being part of the Toll pathway and 30-40% of the immune genes identified within the Imd pathway are overexpressed during the critical period spanning the parasite’s oocyst and sporozoite formation (8-12 days), revealing the crucial role played by both these pathways in this natural mosquito-Plasmodium combination. Comparison of infected mosquitoes with their uninfected counterparts also revealed some unexpected RNA expression patterns earlier and later in the infection: Significant differences in expression of several immune effectors were observed as early as 30 minutes after the ingestion of the infected blood meal. In addition, in the later stages of the infection (towards the end of the mosquito lifespan), we observed an unexpected increase in immune investment in uninfected, but not in infected, mosquitoes. In conclusion, our work extends the comparative transcriptomic analyses of malaria-infected mosquitoes beyond human and rodent parasites and provides insights into the degree of conservation of immune pathways and into the selective pressures exerted by Plasmodium parasites on their vectors.
Stable twin rDNA loci form a single nucleolus in brewer’s yeast
Authors: Lazar-Stefanita Luciana , Luo Jingchuan , Haase Max A. B. , Zhang Weimin , Boeke Jef D. 
Published: June 2022

AbstractThe nucleolus is the most prominent membraneless compartment within the nucleus1, 2 - dedicated to the metabolism of ribosomal RNA. Nucleoli are composed of hundreds of ribosomal DNA (rDNA) repeated genes that form large chromosomal clusters3–5, whose high recombination rates can cause nucleolar dysfunction and promote genome instability6–8 related to metabolic and genetic diseases9–13. Intriguingly, the evolving architecture of genomes appears to have favored two strategic rDNA locations in a broad range of species – where a single locus per chromosome is situated either near the centromere or the telomere14, 15. To delve into how organisms may benefit from these nuclear organizations, we used a fused-karyotype strain of Saccharomyces cerevisiae16 to megabase-engineer a chromosome with twin chromosome-collinear rDNA loci. We showed that the twin-rDNA yeast readily adapts exhibiting wild-type growth and maintaining rRNA homeostasis. Using imaging and chromosome conformation capture, we found that the twin loci merge into a single subnuclear compartment throughout the cell cycle. Unexpectedly, we found that rDNA locus size is dependent on its position relative to the centromere, whereby the locus that is centromere–distal undergoes size reduction at a higher frequency compared to the centromere-proximal counterpart. In sum, our work sheds light on the structural evolution of rDNA loci and provides new tools to study the rDNA dosage effect on cellular metabolism.
Modeling foot-and-mouth disease dissemination in Brazil and evaluating the effectiveness of control measures
Authors: Cardenas Nicolas C. , Lopes Francisco P. N. , Machado Alencar , Maran Vinicius , Trois Celio , Machado Felipe Amadori , Machado Gustavo 
Published: June 2022

AbstractFoot-and-mouth disease (FMD) is known to infect multiple food-animal species and to spread among ungulate populations. We introduce a multiscale compartmental stochastic model that incorporates population dynamics, births, deaths, and species-specific transmission dynamics. The model integrates disease dynamics at both the between-farm and the within-farm levels. We developed four scenarios to evaluate the effectiveness of countermeasures, including movement standstill, vaccination, and depopulation. The base scenario involved vaccinating the animals on 20 farms and depopulating four infected farms. The three alternative control scenarios included increasing vaccination and depopulation capacities and no vaccination. Our findings indicate that bovines were the most frequently infected species, followed by swine and small ruminants. After ten days of initial spread, the number of infected farms ranged from 1 to 123, with most simulations (90.12%) predicting fewer than 50 infected farms. Most of the secondary spread occurred within a range of 25 km. Early response to initiating the control action reduces the number of days spent working on control actions while intensifying daily depopulation and vaccination capacity; this may be worth considering in decision-making processes for future control of FMD. Emergency vaccination proved to be efficient in reducing the magnitude and duration of outbreaks, whereas increasing depopulation without the use of vaccination also proved to be effective in eliminating the outbreaks.
GAMBIT (Genomic Approximation Method for Bacterial Identification and Tracking): A methodology to rapidly leverage whole genome sequencing of bacterial isolates for clinical identification
Authors: Lumpe Jared , Gumbleton Lynette , Gorzalski Andrew , Libuit Kevin , Varghese Vici , Lloyd Tyler , Tadros Farid , Arsimendi Tyler , Wagner Eileen , Stephens Craig , Sevinsky Joel , Hess David , Pandori Mark 
Published: June 2022

AbstractWhole genome sequencing of clinical bacterial isolates has the potential to transform the fields of medicine and public health, with particular impact on molecular epidemiology, infection control and assessing the spread of antibiotic resistance. To realize this potential, bioinformatic software needs to be developed that meets the quality standards of a diagnostic test to allow the reporting of identification results. Our research group has developed a methodology (GAMBIT: Genomic Approximation Method for Bacterial Identification and Tracking) using k-mer based strategies for identification of bacteria based on whole genome sequence reads. GAMBIT incorporates this algorithm with a highly curated searchable database of genomes, which is a subset of the NCBI RefSeq assembly database. In this manuscript, we describe the validation of the scoring methodology, robustness to chosen parameters, establishment of confidence thresholds and the curation of the reference database. We discuss a validation set with GAMBIT deployed as a laboratory-developed test at the Alameda County Public Health Laboratory in Oakland, California. Three advancements were required to build upon existing k-mer based strategies to allow GAMBIT to possess the quality control parameters desired for its use as a diagnostic laboratory-developed test. Firstly, we innovated the data structure used to store the database of known bacterial genomes. This allowed us to store 48,224 bacterial genomes in a k-mer based database—a majority of the bacterial genomes in the NCBI RefSeq database at the time of development. Secondly, curation of the NCBI RefSeq database was required to remove ambiguous or potentially incorrectly labeled bacterial genomes to greatly increase confidence in positive matches. Lastly, we used this curated version of the NCBI RefSeq database and our scoring method to generate confidence thresholds for identification. Thus, the end-user does not rely simply on the closest match, but is informed whether that closest match exceeds a threshold for highly confident identification. This method greatly reduces or eliminates false identifications which are often detrimental in a clinical setting.