bluuebunny/crossref_metadata_2025_split huggingface dataset:
Candida albicans exhibits heterogeneous and adaptive cytoprotective responses to anti-fungal compounds
Authors: Dumeaux V , Massahi S , Bettauer V , Khurdia S , Costa ACBP , Omran RP , Simpson S , Xie JL , Whiteway M , Berman J , Hallett MT 
Published: July 2022

AbstractCandida albicans is an opportunistic human pathogen which represents a significant threat to human health and is associated with substantial socio-economic burden. Current antifungal treatments fail at least in part because C. albicans can initiate a strong drug tolerance response, allowing cells to grow at concentrations above their minimal inhibitory concentration. Our goal is to better characterize this cytoprotective tolerance program at the molecular single cell level. We present here a nano-liter droplet-based fungal single cell transcriptomics platform capable of profiling thousands of individual C. albicans SC5314 cells in an efficient manner. Profiles of untreated cells partition into three transcriptional clusters with each highlighting a cell cycle checkpoint coupled with specific metabolic and stress responses, as perhaps expected. After just two days post-treatment with fluconazole, surviving cells bifurcate into two distinct subpopulations: the so-called α response involving upregulation of protein translation, rRNA processing and mitochondrial cellular respiration, and the β response involving processes and stress responses that assist damaged cells. By extending our time series to six days and profiling with other antifungals and bioactive compounds, we provide evidence that surviving cells transition from the α to β responses mediated by the Ribosome Assembly Stress Response (RASTR).
MAVEN: Compound mechanism of action analysis and visualisation using transcriptomics and compound structure data in R/Shiny
Authors: Hosseini-Gerami Layla , Ballesteros Rosa Hernansaiz , Liu Anika , Broughton Howard , Collier David Andrew , Bender Andreas 
Published: July 2022

AbstractBackgroundUnderstanding the mechanism of action (MoA) of a compound is an often challenging but equally crucial aspect of drug discovery that can help improve both its efficacy and safety. Computational methods to aid MoA elucidation usually either aim to predict direct drug targets, or attempt to understand modulated downstream pathways or signalling proteins. Such methods usually require extensive coding experience and results are often optimised for further computational processing, making them difficult for wet-lab scientists to perform, interpret and draw hypotheses from.ResultsTo address this issue, we in this work present MAVEN (Mechanism of Action Visualisation and Enrichment), an R/Shiny app which allows for GUI-based prediction of drug targets based on chemical structure, combined with causal reasoning based on causal protein-protein interactions and transcriptomic perturbation signatures. The app computes a systems-level view of the mechanism of action of the input compound. This is visualised as a sub-network linking predicted or known targets to modulated transcription factors via inferred signalling proteins. The tool includes a selection of MsigDB gene set collections to perform pathway enrichment on the resulting network, and also allows for custom gene sets to be uploaded by the researcher. MAVEN is hence a user-friendly, flexible tool for researchers without extensive bioinformatics or cheminformatics knowledge to generate interpretable hypotheses of compound Mechanism of Action.ConclusionsMAVEN is available as a fully open-source tool at https://github.com/laylagerami/MAVEN with options to install in a Docker or Singularity container. Full documentation, including a tutorial on example data, is available at https://laylagerami.github.io/MAVEN.
Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue
Authors: Murthy Megha , Shireby Gemma , Miki Yasuo , Viré Emmanuelle , Lashley Tammaryn , Warner Thomas T. , Mill Jonathan , Bettencourt Conceição 
Published: July 2022

AbstractAimsEpigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter.MethodsWe analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical, in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes.ResultsEstimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical, r = [0.80-0.97], p<0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClockMulti significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClockCortica tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p=6.1×10-5) suggested that this cell-type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClockCortica (r>0.31, p<0.05), and similar trends with DNAmClockMulti. Although increased age acceleration was observed in MSA compared to controls, no significant differences were observed upon adjustment for possible confounders (e.g., cell-type proportions).ConclusionsOur findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.
Endogenous Retroviruses and TDP-43 Proteinopathy Form a Sustaining Feedback to Drive the Intercellular Spread of Neurodegeneration
Authors: Chang Yung-Heng , Dubnau Josh 
Published: July 2022

AbstractNeurodegenerative disorders are thought to initiate focally and then spread over time through neural circuits. A mechanism that has been proposed to explain this is the inter-cellular movement of misfolded “prion-like” proteins that then recruit normally folded proteins in recipient cells to also adopt pathological conformations. Such a mechanism has been proposed, for example, to explain the propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) during the progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases such as mad cow disease, which can be caused by ingestion or by injection into animal brains of misfolded PrP, ALS and FTD are not infectious and the injection of phosphorylated and aggregated TDP-43 protein into rodent brains is not sufficient to cause disease phenotypes unless those animals also express high levels of transgenic TDP-43 protein. This suggests a missing component of a positive feedback that is necessary to sustain disease progression. We provide evidence that endogenous retroviruses (ERVs) are that missing component. We demonstrate that ERV expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either the Drosophila ERV, gypsy (mdg4) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Importantly. We also demonstrate that viral ERV transmission causes propagation of such TDP-43 pathology to cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism underlies the toxicity of glial cells to neurons and other glia in a Drosophila in vivo model.
Freshwater connectivity transforms spatially integrated signals of biodiversity
Authors: Littlefair Joanne E. , Hleap José S. , Palace Vince , Rennie Michael D. , Paterson Michael J. , Cristescu Melania E. 
Published: July 2022

AbstractAquatic ecosystems offer a continuum of water flow from headwater streams to inland lakes and coastal marine systems. This spatial connectivity influences the structure, function and dynamics of aquatic communities, which are among the most threatened and degraded on earth. Environmental DNA achieves biodiversity surveys in these habitats in a high-throughput, spatially integrated way. Here, we determine the spatial resolution of eDNA in dendritic freshwater networks that are typical of aquatic habitats. Our intensive sampling campaign comprised over 430 eDNA samples across 21 connected lakes, allowing us to analyse detections at a variety of scales, from different habitats within a lake to entire lake networks. We found strong signals of within-lake variation in eDNA distribution reflective of typical habitat use by both fish and zooplankton. Most importantly, we also found that connecting channels between lakes resulted in an accumulation of downstream eDNA detections in lakes with a higher number of inflows, and as networks increased in length. These findings have profound implications for the interpretation of eDNA detections in aquatic ecosystems in global-scale biodiversity monitoring observations.
Genome-wide SNPs reveal the social structure and invasion pathways of the invasive tropical fire ant (Solenopsis geminata)
Authors: Lenancker P , Walsh T , Metcalfe S , Gotzek D , Hoffmann BD , Lach L , Tay WT , Elfekih S 
Published: July 2022

ABSTRACTElucidating invasion pathways of invasive species is often challenging because invasive populations frequently have low genetic diversity caused by genetic bottlenecks during introduction events. Genome-wide sequencing such as Restriction Site-Associated DNA Sequencing (RADseq) can overcome these challenges by generating thousands of genome-wide single nucleotide polymorphic (SNP) markers. The tropical fire ant,Solenopsis geminata, is a global invader with low genetic diversity in its introduced range, making RADseq one of the best available methods to investigate its population genetics. We used double digest RADseq to generate 3,834 SNPs to compare the genetic diversity ofS. geminatain its introduced range to its most likely source of introduction, determined the invasion pathways among populations at an unprecedented level of detail for this species, and determined the social structure ofS. geminataworkers collected in 13 locations worldwide. We found that introducedS. geminatawent through a strong genetic bottleneck. We also identified multiple secondary introduction events amongS. geminatapopulations, indicating that the bridgehead effect is an important driver in the global spread of this species. We found that all colonies in the introduced range were polygyne (i.e., with more than one queen) which may increase their invasion success and potential to cause adverse effects.
Host cell neddylation facilitates alphaherpesvirus entry in a virus-specific and cell-dependent manner
Authors: Lee Becky H. , Tebaldi Giulia , Pritchard Suzanne M. , Nicola Anthony V. 
Published: July 2022

ABSTRACTHerpes simplex virus 1 (HSV-1) commandeers the host cell proteasome at several steps of its replication cycle, including entry. Here we demonstrate that HSV-2, pseudorabies virus (PRV), and bovine herpesvirus 1 (BoHV-1) entry are blocked by bortezomib, a proteasome inhibitor that is a FDA-approved cancer drug. Proteasome-dependent entry of HSV-1 is thought to be ubiquitin-independent. To interrogate further the proteasomal mechanism of entry, we determined the involvement of the ubiquitin-like molecule NEDD8 and the neddylation cascade in alphaherpesvirus entry and infection. MLN4924 is a small-molecule inhibitor of neddylation that binds directly to the NEDD8-activating enzyme. Cell treatment with MLN4924 inhibited plaque formation and infectivity by HSV-1, PRV and BoHV-1 at non-cytotoxic concentrations. Thus, the neddylation pathway is broadly important for alphaherpesvirus infection. However, the neddylation inhibitor had little effect on entry of the veterinary viruses but had a significant inhibitory effect on entry of HSV-1 and HSV-2 into seven different cell types. Wash-out experiments indicated that MLN4924’s effect on viral entry was reversible. Time-of-addition assay suggested that the drug was acting on an early step in the entry process. siRNA knockdown of NEDD8 significantly inhibited HSV entry. In probing the neddylation-dependent step in entry, we found that MLN4924 dramatically blocked endocytic uptake of HSV from the plasma membrane by >90%. In contrast, the rate of HSV entry into cells that support direct fusion of HSV with the cell surface was unaffected by MLN4924. Interestingly, proteasome activity was less important for the endocytic internalization of HSV from the cell surface. The results suggest that the NEDD8 cascade is critical for the internalization step of HSV entry.IMPORTANCEAlphaherpesviruses are ubiquitous pathogens of humans and veterinary species that cause lifelong latent infections and significant morbidity and mortality. Host cell neddylation is important for cell homeostasis and for the infection of many viruses, including HSV-1, HSV-2, PRV, and BoHV-1. Inhibition of neddylation by a pharmacologic inhibitor or siRNA blocked HSV infection at the entry step. Specifically, the NEDD8 pathway was critically important for HSV-1 internalization from the cell surface by an endocytosis mechanism. The results expand our limited understanding of cellular processes that mediate HSV internalization. To our knowledge, this is the first demonstration of a function for the neddylation cascade in virus entry.
Comparison of Bayesian Networks, G-estimation and linear models to estimate causal treatment effects in aggregated N-of-1 trials with carry-over effects
Authors: Gärtner Thomas , Schneider Juliana , Arnrich Bert , Konigorski Stefan 
Published: July 2022

AbstractThe aggregation of a series of N-of-1 trials presents an innovative and efficient study design, as an alternative to traditional randomized clinical trials. Challenges for the statistical analysis arise when there is carry-over or complex dependencies of the treatment effect of interest.In this study, we evaluate and compare methods for the analysis of aggregated N-of-1 trials in different scenarios with carry-over and complex dependencies of treatment effects on covariates. For this, we simulate data of a series of N-of-1 trials for Chronic Nonspecific Low Back Pain based on assumed causal relationships parameterized by directed acyclic graphs. In addition to existing statistical methods such as regression models, Bayesian Networks, and G-estimation, we introduce a carry-over adjusted parametric model (COAPM).The results show that all evaluated existing models have a good performance when there is no carry-over and no treatment dependence. When there is carry-over, COAPM yields unbiased and more efficient estimates while all other methods show some bias in the estimation. When there is known treatment dependence, all approaches that are capable to model it yield unbiased estimates. Finally, the efficiency of all methods decreases slightly when there are missing values, and the bias in the estimates can also increase.This study presents a systematic evaluation of existing and novel approaches for the statistical analysis of a series of N-of-1 trials. We derive practical recommendations which methods may be best in which scenarios.
A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004)
Authors: Pilankar Aishwarya , Singhavi Hitesh , Raghuram Gorantla V. , Siddiqui Sophiya , Khare Naveen Kumar , Jadhav Vishalkumar , Tandel Harshali , Pal Kavita , Bhattacharjee Atanu , Chaturvedi Pankaj , Mittra Indraneel 
Published: July 2022

AbstractBackgroundOur earlier studies have shown that cell-free chromatin particles (cfChPs) that are released from dying cancer cells are readily internalised by bystander cells leading to activation of two hallmarks of cancer viz. genome instability and inflammation. These hallmarks could be down-regulated by deactivating cfChPs via medium of oxygen radicals generated upon admixing small quantities of the nutraceuticals resveratrol (R) and copper (Cu). In this exploratory study, we investigated whether oral administration of R and Cu (R-Cu) would down-regulate the hallmarks of cancer and immune checkpoints in advanced squamous cell carcinoma of oral cavity (OSCC).Patients and methodsThe study comprised of 25 patients divided into 5 equal groups. Five patients acted as controls; the remaining 20 were given R-Cu in four escalating doses. The lowest dose of R-Cu was 5.6mg and 560ng respectively, and the highest dose was 500mg and 5mg respectively. An initial biopsy was taken from patients at first presentation, and a second biopsy was taken 2 weeks later on the operating table. R-Cu was administered orally twice daily in the intervening period. Confocal microscopy was performed on tumour sections after fluorescent immuno-staining with anti-DNA and anti-histone antibodies to detect presence of cfChPs in the tumour micro-environment (TME). Immunofluorescence analysis was performed for 23 biomarkers representing the 10 Hallmarks of cancer, including 5 immune checkpoints, defined by Hanahan and Weinberg.ResultsConfocal microscopy detected copious presence of cfChPs in TME of OSCC, which were eradicated / deactivated following two-week treatment with R-Cu. Eradication of cfChPs from TME was associated with marked down-regulation of 21 / 23 biomarkers, including the five immune checkpoints. The lower two doses of R-Cu were more effective than the higher doses. No adverse effects attributable to R-Cu were observed.ConclusionThese results suggest that cfChPs released into TME from dying cancer cells are global instigators for cancer hallmarks and immune checkpoints in surviving cancer cells. The ability of R-Cu to deactivate cfChPs raises the prospect of a novel and non-toxic form of cancer treatment which sans killing of cancer cells, and instead induces healing by down-regulating cancer hallmarks and immune check-points.Clinical Trial Registrationhttp://ctri.nic.in/Clinicaltrials/login.php,(CTRI/2018/03/012459)
Air and surface sampling for monkeypox virus in UK hospitals
Authors: Gould Susan , Atkinson Barry , Onianwa Okechukwu , Spencer Antony , Furneaux Jenna , Grieves James , Taylor Caroline , Milligan Iain , Bennett Allan , Fletcher Tom , Dunning Jake ,   NHS England Airborne HCID Network
Published: July 2022

AbstractBackgroundAn unprecedented outbreak of monkeypox virus (MPXV) infections in non-endemic countries has been recognised since 12 May 2022. More than 6000 cases have been identified globally with more than 1500 in the UK by July 2022. Transmission of MPXV is believed to be predominantly through direct contact with lesions or infected body fluids, with possible involvement of fomites and large respiratory droplets. Importantly, a case of monkeypox in a UK healthcare worker in 2018 was suspected to be due to virus exposure while changing bedding.MethodsWe investigated environmental contamination with MPXV from infected patients admitted to isolation rooms in the UK, to inform infection prevention and control measures. Surface swabs of high-touch areas in isolation rooms, of healthcare worker personal protective equipment (PPE) in doffing areas, and from air samples collected before and during bedding change were analysed using MPXV qPCR to assess contamination levels. Virus isolation was performed to confirm presence of infectious virus in key positive samples.FindingsWe identified widespread surface contamination (66 positive out of 73 samples) in occupied patient rooms (MPXV DNA Ct values 24·7-38·6), on healthcare worker personal protective equipment after use, and in doffing areas (Ct 26·3-34·3). Five out of fifteen air samples taken were positive. Significantly, three of four air samples collected during a bed linen change in one patient’s room were positive (Ct 32·7-35·8). Replication-competent virus was identified in two of four samples selected for viral isolation, including from air samples collected during the bed linen change.InterpretationThese data demonstrate significant contamination in isolation facilities and potential for aerosolisation of MPXV during specific activities. PPE contamination was observed after clinical contact and changing of bed linen. Additionally, contamination of hard surfaces in doffing areas supports the importance of cleaning protocols, PPE use and doffing procedures.FundingNo funding source for this study
TREK-1 knock-down in human atrial fibroblasts leads to a myofibroblastic phenotype: a role in phenoconversion and over-view of mechano-sensitive channel mRNA expression in cardiac diseases
Authors: Darkow Elisa , Yusuf Dilmurat , Rajamani Sridharan , Backofen Rolf , Kohl Peter , Ravens Ursula , Peyronnet Rémi 
Published: July 2022

AbstractCardiac cell mechanical environment changes on a beat-by-beat basis and also in the course of various cardiac diseases. Cells sense and adapt to such mechanical cues via specialized mechano-sensors mediating adaptive signaling cascades. Here, we report TREK-1 mRNA expression and activity in human atrial fibroblasts and reveal a cross talk between TREK-1 and fibroblast phenoconversion. With the aim to reveal additional candidates underlying mechano-transduction relevant to cardiac diseases, we investigated mechano-sensitive ion channels (MSC) mRNA expression in diseased and non-diseased human hearts.Our results showed higher TREK-1 expression and activity in fibroblasts compared to myofibroblasts and we found that TREK-1 down-regulation leads a more myofibroblastic phenotype suggesting a role for this mechano-sensor in phenoconversion. In addition, TREK-1 is preferentially expressed in the left atrium compared to the right one and its expression is not significantly changed when fibroblasts from patients in sinus rhythm vs. sustained atrial fibrillation are compared. At the whole-heart level, numerous MSC were differentially expressed between atrial and ventricular or between non-diseased and diseased tissue samples.Thus, we identify atrial fibroblast-specific TREK-1 expression and activity and reveal a role of TREK-1 in atrial fibroblast pheno-conversion. We also provide a comprehensive overview of cardiac MSC mRNA expression in atrial and ventricular tissue from diseased and non-diseased patients, identifying potential novel candidates underlying mechanotransduction in cardiac diseases.
Mechanistic basis for targeting homologous recombination defective liver cancer via synthetic lethality
Authors: Zeng Ming , Tang Zizhi , Ren Laifeng , Wang Haibin , Wang Xiaojun , Zhu Wenyuan , Mao Xiaobing , Li Zeyang , Mo Xianming , Chen Jun , Han Junhong , Kong Daochun , Ji Jianguo , Carr Antony M. , Liu Cong 
Published: July 2022

AbstractMany cancers harbour homologous recombination defects (HRD). The identification of PARP inhibitors as synthetic lethal with HRD has led to new therapeutic strategies for HRD cancers. Here we report a subtype of HRD that is caused by the perturbation of a previously uncharacterised proteasome variant, CDW19S, in hepatitis virus B (HBV) positive hepatocellular carcinoma (HBVHCC). CDW19S contains the 19S complex decorated with a Cullin 4 ubiquitin ligase (CRL4WDR70) that is assembled at broken chromatin and regulates end processing nucleases. The HBV oncoprotein, HBx, prevents integration of the CRL4 backbone into CDW19S. We show that CDW19S directly ubiquitinates ADRM1Rpn13, targeting it for degradation, and that HBx interferes with this, leading to the imposition of a novel ADRM1Rpn13-dependent resection barrier that results in HRD and promotes carcinogenesis with concurrent TP53 loss. Using cellular and patient-derived xenograft models we demonstrate that HRD in HBVHCC can be exploited to restrict tumour progression. Our work clarifies the mechanism of a virally-induced HRD and suggests a new route for targeted HBVHCC therapy.