bluuebunny/crossref_metadata_2025_split huggingface dataset:
PET imaging studies to investigate functional expression of mGluR2 using [11C]mG2P001
Authors: Yuan Gengyang , Dhaynaut Maeva , Guehl Nicolas J. , Neelamegam Ramesh , Moon Sung-Hyun , Qu Xiying , Poutiainen Pekka , Afshar Sepideh , Fakhri Georges El , Brownell Anna-Liisa , Normandin Marc D. 
Published: July 2021

AbstractMetabotropic glutamate receptor 2 (mGluR2) has been extensively studied for the treatment of various neurological and psychiatric disorders. Understanding of the mGluR2 function is pivotal in supporting the drug discovery targeting mGluR2. Herein, the positive allosteric modulation of mGluR2 was investigated via the in vivo positron emission tomography (PET) imaging using 2-((4-(2-[11C]methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-imidazo[4,5-b]pyridine ([11C]mG2P001).Distinct from the orthosteric compounds, pretreatment with the unlabeled mG2P001, a potent mGluR2 positive allosteric modulator (PAM), resulted in a significant increase instead of decrease of the [11C]mG2P001 accumulation in rat brain detected by PET imaging. Subsequent in vitro studies with [3H]mG2P001 revealed the cooperative binding mechanism of mG2P001 with glutamate and its pharmacological effect that contributed to the enhanced binding of [3H]mG2P001 in transfected CHO cells expressing mGluR2. The in vivo PET imaging and quantitative analysis of [11C]mG2P001 in non-human primates (NHPs) further validated the characteristics of [11C]mG2P001 as an imaging ligand for mGluR2. Self-blocking studies in primates enhanced accumulation of [11C]mG2P001 dose- and delivery-dependently. Altogether, these studies show that [11C]mG2P001 is a sensitive biomarker for mGluR2 expression and the binding is affected by the tissue glutamate concentration.
Capturing hidden regulation based on noise change of gene expression level from single cell RNA-seq in yeast
Authors: Itoh Thoma , Makino Takashi 
Published: July 2021

AbstractRecent progress in high throughput single cell RNA-seq (scRNA-seq) has activated the development of data-driven inferring methods of gene regulatory networks. Most network estimations assume that perturbations produce downstream effects. However, the effects of gene perturbations are sometimes compensated by a gene with redundant functionality (functional compensation). In order to avoid functional compensation, previous studies constructed double gene deletions, but its vast nature of gene combinations was not suitable for comprehensive network estimation. We hypothesized that functional compensation may emerge as a noise change without mean change (noise-only change) due to varying physical properties and strong compensation effects. Here, we show compensated interactions, which are not detected by mean change, are captured by noise-only change quantified from scRNA-seq. We investigated whether noise-only change genes caused by a single deletion of STP1 and STP2, which have strong functional compensation, are enriched in redundantly regulated genes. As a result, noise-only change genes are enriched in their redundantly regulated genes. Furthermore, novel downstream genes detected from noise change are enriched in “transport”, which is related to known downstream genes. Herein, we suggest the noise difference comparison has the potential to be applied as a new strategy for network estimation that capture even compensated interaction.
Epigenetic regulation of frog innate immunity: Discovery of frog microRNAs associated with antiviral responses and ranavirus infection using a Xenopus laevis skin epithelial-like cell line
Authors: Todd Lauren A. , Bui-Marinos Maxwell P. , Katzenback Barbara A. 
Published: July 2021

AbstractEpigenetic regulators such as microRNAs are emerging as conserved regulators of innate antiviral immunity in vertebrates, yet their roles in amphibian antiviral responses remain uncharacterized. We profiled changes in microRNA expressions in the Xenopus laevis skin epithelial-like cell line Xela DS2 in response to poly(I:C) – an analogue of double-stranded viral RNA and inducer of type I interferons – or frog virus 3 (FV3), an immunoevasive virus associated with amphibian mortality events. We sequenced small RNA libraries generated from untreated, poly(I:C)-treated, and FV3-infected cells. We detected 136 known X. laevis microRNAs and discovered 133 novel X. laevis microRNAs. Sixty-five microRNAs were differentially expressed in response to poly(I:C), many of which were predicted to target regulators of antiviral pathways such as cGAS-STING, RIG-I/MDA-5, TLR signaling, and type I interferon signaling, as well as products of these pathways (NF-κB-induced and interferon-stimulated genes). In contrast, only 49 microRNAs were altered by FV3 infection, fewer of which were predicted to interact with antiviral pathways. Interestingly, poly(I:C) treatment or FV3 infection downregulated transcripts encoding factors of the host microRNA biogenesis pathway. Our study is the first to suggest that host microRNAs regulate innate antiviral immunity in frogs, and sheds light on microRNA-mediated mechanisms of immunoevasion by FV3.
Collateral damage: Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme
Authors: Lewis Morag A. , Ingham Neil J. , Chen Jing , Pearson Selina , Di Domenico Francesca , Rekhi Sohinder , Allen Rochelle , Drake Matthew , Willaert Annelore , Rook Victoria , Pass Johanna , Keane Thomas , Adams David , Tucker Abigail S. , White Jacqueline K. , Steel Karen P. 
Published: July 2021

AbstractMice carrying targeted mutations are important for investigating gene function and the role of genes in disease, but the process of culturing embryonic stem cells during the making of a targeted allele offers opportunities for spontaneous mutations to arise. Identifying spontaneous mutations relies on the detection of phenotypes segregating independently of targeted alleles, and many phenotypes are easy to miss if not specifically looked for. Here we present data from a large, targeted knockout programme in which mice were analysed through a phenotyping pipeline. Twenty-five lines out of 1311 displayed different deafness phenotypes that did not segregate with the targeted allele. We have identified 8 different mutations causing deafness in 16 of these 25 lines and characterised the resulting phenotypes. Our data show that spontaneous mutations with observable effects on phenotype are a common side effect of intensive breeding programmes, including those underlying targeted mutation programmes.
Genomic Modules and Intramodular Network Convergency of Susceptibility and Resilience in Multimodeled Stress in Male Mice
Authors: Marrocco Jordan , Caradonna Salvatore G. , Zhang Tie-Yuan , O’Toole Nicholas , Shen Mo-Jun , Khalil Huzefa , Einhorn Nathan R. , Wen Xianglan , Parent Carine , Lee Francis S. , Akil Huda , McEwen Bruce S. , Meaney Michael J. 
Published: July 2021

ABSTRACTThe multifactorial etiology of stress-related disorders is a challenge in developing synchronized medical standards for treatment and diagnosis. It is largely unknown whether there exists molecular convergence in preclinical models of stress generated using disparate construct validity. Using RNA-sequencing (RNA-seq), we investigated the genomic signatures in the ventral hippocampus, which mostly regulates affective behavior, in mouse models that recapitulate the hallmarks of anxiety and depression. Chronic oral corticosterone (CORT), a model that causes a blunted endocrine response to stress, induced anxiety- and depression-like behavior in wildtype mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor (BDNF) Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of mice, chronic social defeat stress led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, standard housing or enriched environment. A rank-rank-hypergeometric (RRHO) analysis of the RNA-seq data set across models demonstrated that in mice treated with CORT and susceptible mice raised in standard housing differentially expressed genes (DEGs) converged toward gene networks involved in similar biological functions. Weighted gene co-expression analysis generated 54 unique modules of interconnected gene hubs, two of which included a combination of all experimental groups and were significantly enriched in DEGs, whose function was consistent with that predicted in the RRHO GO analysis. This multimodel approach showed transcriptional synchrony between models of stress with hormonal, environmental or genetic construct validity shedding light on common genomic drivers that embody the multifaceted nature of stress-related disorders.
Pathogens, Virulence and Resistance Genes Surveillance with Metagenomics Can Pre-empt Dissemination and Escalation of Untreatable Infections: A Systematic Review and Meta-analyses
Authors: Sekyere John Osei , Faife Sara Lino 
Published: July 2021

AbstractBackgroundThe dissemination of pathogens carrying genetic elements such as antimicrobial resistance genes (ARGs), mobile-genetic elements (MGEs), virulome and methylome have a negative impact on food and environment safety, water quality and animal and human health. The applications of metagenomics to monitor and identify the prevalence/endemicity and emergence of these pathogenic agents from different sources were examined.MethodsArticles published in English language up to October 2020 were searched for on PubMed. Qualitative and quantitative data extracted from the included articles were translated into charts and maps. GraphPad Prism 9.0.2 was used to undertake statistical analysis using descriptive and column statistics, Chi-square, ANOVA, Wilcoxon’s signed-rank, and one-sample t-test.ResultsIn all, 143 articles from 39 countries from Europe, America, Asia, and Africa were quantitatively analysed. Metagenomes from sewage/wastewater, surface water samples (ocean, sea, river lake, stream and tap water), WWTP, effluents and sludge samples contained pathogenic bacteria (Aeromonas, Acinetobacter, Pseudomonas, Streptococcus, Bacteroides,Escherichia coli,Salmonella enterica,Klebsiella pneumoniaeandAcinetobacter baumannii), viruses (Adenovirus, Enterovirus, Hepatovirus, Mamastrovirus and Rotavirus) and parasites (Acanthamoeba, Giardia, Entamoeba, Blastocystis and Naegleria). Integrons, plasmids, transposons, insertion sequences, prophages and integrative and conjugative elements were identified. ARGs mediating resistance to important antibiotics, including β-lactams, aminoglycosides, fluoroquinolones, and tetracycline, and virulence factors such as secretion system, adherence, antiphagocytosis, capsule, invasion, iron uptake, hemolysin, and flagella.ConclusionClinically important pathogens, ARGs, and MGEs were identified in diverse clinical, environmental, and animal sources through metagenomics, which can be used to determine the prevalence and emergence of known and unknown pathogens and ARGs.Importance/significanceGlobal metagenomic analyses of drinking water, effluents, influents, un/-treated sewage, WWTPs, sludge, rivers, lakes, soil, sediments, biosolid, air and plants. showed the global distribution of diverse clinically important ARGs on mobile genetic elements, antimicrobial-resistant bacteria (ARB) and pathogens, metal resistance genes, and virulence genes in almost all environments. These depict the importance of shot-gun metagenomics as a surveillance tool for AMR and infectious disease control to safeguard water & food quality as well as public health from water- and food-borne outbreaks of pathogenic and ARB infections. More concerning was the identification of ARGs to last-resort antibiotics i.e., carbapenems, colistin, & tigecycline.
Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice
Authors: Belouzard Sandrine , Machelart Arnaud , Sencio Valentin , Vausselin Thibaut , Hoffmann Eik , Deboosere Nathalie , Rouillé Yves , Desmarets Lowiese , Séron Karin , Danneels Adeline , Robil Cyril , Belloy Loïc , Moreau Camille , Piveteau Catherine , Biela Alexandre , Vandeputte Alexandre , Heumel Séverine , Deruyter Lucie , Dumont Julie , Leroux Florence , Engelmann Ilka , Alidjinou Enagnon Kazali , Hober Didier , Brodin Priscille , Beghyn Terence , Trottein François , Déprez Benoît , Dubuisson Jean 
Published: July 2021

AbstractDrug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.SummaryAntivirals targeting SARS-CoV-2 are sorely needed. In this study, we screened a library of drug compounds and identified clofoctol as an antiviral against SARS-CoV-2. We further demonstrated that, in vivo, this compound reduces inflammatory gene expression and lowers pulmonary pathology.
TAILORED DC INDUCE PROTECTIVE HIV-1 SPECIFIC POLYFUNCTIONAL CD8+ T CELLS IN THE LYMPHOID TISSUE FROM HUMANIZED BLT MICE
Authors: Calvet-Mirabent Marta , Claiborne Daniel T. , Deruaz Maud , Tanno Serah , Serra Carla , Delgado-Arévalo Cristina , Sánchez-Cerrillo Ildefonso , de los Santos Ignacio , Sanz Jesús , García-Fraile Lucio , Sánchez-Madrid Francisco , Alfranca Arantzazu , Muñoz-Fernández María Ángeles , Allen Todd M. , Buzón Maria J. , Balazs Alejandro , Vrbanac Vladimir , Martín-Gayo Enrique 
Published: July 2021

AbstractEffective function of CD8+ T cells and enhanced innate activation of dendritic cells (DC) in response to HIV-1 is linked to protective antiviral immunity in controllers. Manipulation of DC targeting the master regulator TANK-binding Kinase 1 (TBK1) might be useful to acquire controller-like properties. Here, we evaluated the impact of TBK1-primed DC inducing protective CD8+ T cell responses in lymphoid tissue and peripheral blood and their association with reduced HIV-1 disease progression in vivo in the humanized bone marrow, liver and thymus (hBLT) mouse model. A higher proportion of hBLT-mice vaccinated with TBK1-primed DC exhibited less severe CD4+ T cell depletion following HIV-1 infection compared to control groups. This was associated with infiltration of CD8+ T cells in the white pulp from the spleen, reduced spread of infected p24+ cells to secondary lymphoid organs and with preserved abilities of CD8+ T cells from the spleen and blood of vaccinated animals to induce specific polyfunctional responses upon antigen stimulation. Therefore, TBK1-primed DC might be an useful tool for subsequent vaccine studies.Author summaryEmulating protective immunological characteristics from individuals capable of spontaneously controlling HIV-1 infection might be useful for the development of a protective vaccine. Enhanced function of dendritic cells (DC) in these HIV-1 controllers depends on the activation of TANK-binding Kinase 1 (TBK1) and might associate with protective T cells. Our study evaluated the ability of DCs trained through TBK1 activation inducing protective adaptive immune responses against HIV-1 and reducing disease progression in vivo, using a humanized mouse model. Our data indicate that mice vaccinated with tailored DC exhibit delayed disease progression, increased induction of protective CD8+ T lymphocyte subsets in the lymphoid tissue and blood upon antigen recognition. Therefore, trained-DC might be an useful tool for future HIV-1 vaccine designs.
The SARS-CoV-2 host cell membrane fusion protein TMPRSS2 is a tumor suppressor and its downregulation correlates with increased antitumor immunity and immunotherapy response in lung adenocarcinoma
Authors: Liu Zhixian , Zhang Zhilan , Feng Qiushi , Wang Xiaosheng 
Published: July 2021

AbstractBackgroundTMPRSS2 is a host cell membrane fusion protein for SARS-CoV-2 invading human host cells. It also has an association with cancer, particularly prostate cancer. However, its association with lung cancer remains insufficiently explored. Thus, an in-depth investigation into the association between TMPRSS2 and lung cancer is significant, considering that lung cancer is the leading cause of cancer death and that the lungs are the primary organ SARS-CoV-2 attacks.MethodsUsing five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, cancer-associated pathways, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we validated the findings from the bioinformatics analysis by performing in vitro experiments with the human LUAD cell line A549 and in vivo experiments with mouse tumor models. We also validated our findings in LUAD patients from Jiangsu Cancer Hospital, China.ResultsTMPRSS2 expression levels were negatively correlated with the enrichment levels of CD8+ T and NK cells and immune cytolytic activity in LUAD, which represent antitumor immune signatures. Meanwhile, TMPRSS2 expression levels were negatively correlated with the enrichment levels of CD4+ regulatory T cells and myeloid-derived suppressor cells and PD-L1 expression levels in LUAD, which represent antitumor immunosuppressive signatures. However, TMPRSS2 expression levels showed a significant positive correlation with the ratios of immune-stimulatory/immune-inhibitory signatures (CD8+ T cells/PD-L1) in LUAD. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory signatures than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with elevated activities of many oncogenic pathways in LUAD, including cell cycle, mismatch repair, p53, and extracellular matrix (ECM) signaling. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor advancement, and worse survival in LUAD. In vitro and in vivo experiments validated the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1.ConclusionsTMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a connection between lung cancer and pneumonia caused by SARS-CoV-2 infection.
Chemogenetic activation of midline thalamic nuclei fails to ameliorate memory deficits in two mouse models of Alzheimer’s disease
Authors: Kohli Shivali , Andrianova Lilya , Margetts-Smith Gabriella , Brady Erica S , Craig Michael T 
Published: July 2021

AbstractOne of the main features of Alzheimer’s disease is the progressive loss of memory, likely due to pathological changes within brain regions such as the hippocampus and entorhinal cortex. These structures are embedded within the extended memory circuit, an interconnected set of brain regions that are essential for episodic memory. The anterior thalamic nuclei (ATN) and thalamic nucleus reuniens (NRe) are both extensively and reciprocally connected with these important memory regions, so we sought to test the hypothesis that chemogenetically-enhancing neurotransmission through NRe and ATN would ameliorate memory deficits in two mechanistically-distinct mouse models of Alzheimer’s disease. Using the hAPP-J20 mouse model of amyloidopathy and the Tg4510 mouse model of tauopathy, we carried out stereotaxic injections of viral vectors to transduce hM3Dq (Gq)_mCherry into NRe or the anterio-dorsal/anterio-ventral nuclei of ATN, using mCherry as a control. At nine months (hAPP-J20) or six months (Tg4510) of age, mice underwent a behaviour battery of open field (OF), novel object recognition (NOR) and radial arm maze (RAM), with DREADD agonist 21 administered 30min prior to each behaviour test. Tissue was collected post-behaviour to confirm injection site and virus expression. Both Tg4510 and hAPP-J20 mice show marked hyperactivity in the OF, significant deficits in recognition memory, and a significant impairment in spatial reference and spatial working memory. Unexpectedly, chemogenetic activation of ATN or NRe did not significantly improve spatial memory impairments or reduce the observed hyperactivity, although NRe activation did modestly rescue recognition memory in J20 mice. This may be due to compensation elsewhere within the memory circuit, or that the pathological changes are too far advanced for behaviour reversal.
Acquisition of alveolar fate and differentiation competence by human fetal lung epithelial progenitor cells
Authors: Lim Kyungtae , Tang Walfred , Sun Dawei , He Peng , Teichmann Sarah A. , Marioni John C. , Meyer Kerstin B. , Rawlins Emma L. 
Published: July 2021

ABSTRACTVariation in lung alveolar development is strongly linked to disease susceptibility. However, the cellular and molecular mechanisms underlying alveolar development are difficult to study in humans. Using primary human fetal lungs we have characterized a tip progenitor cell population with alveolar fate potential. These data allowed us to benchmark a self-organising organoid system which captures key aspects of lung lineage commitment and can be efficiently differentiated to alveolar type 2 cell fate. Our data show that Wnt and FGF signalling, and the downstream transcription factors NKX2.1 and TFAP2C, promote human alveolar or airway fate respectively. Moreover, we have functionally validated cell-cell interactions in human lung alveolar patterning. We show that Wnt signalling from differentiating fibroblasts promotes alveolar type 2 cell identity, whereas myofibroblasts secrete the Wnt inhibitor, NOTUM, providing spatial patterning. Our organoid system recapitulates key aspects of human lung development allowing mechanistic experiments to determine the underpinning molecular regulation.
The histone chaperone FACT facilitates heterochromatin spreading through regulation of histone turnover and H3K9 methylation states
Authors: Murawska Magdalena , Greenstein R. A. , Schauer Tamas , Olsen Karl C.F. , Ng Henry , Ladurner Andreas G. , Al-Sady Bassem , Braun Sigurd 
Published: July 2021

AbstractHeterochromatin formation requires three distinct steps: nucleation, self-propagation (spreading) along the chromosome, and faithful maintenance after each replication cycle. Impeding any of those steps induces heterochromatin defects and improper gene expression. The essential histone chaperone FACT has been implicated in heterochromatin silencing, however, the mechanisms by which FACT engages in this process remain opaque. Here, we pin-pointed its function to the heterochromatin spreading process. FACT impairment reduces nucleation-distal H3K9me3 and HP1/Swi6 accumulation at subtelomeres and derepresses genes in the vicinity of heterochromatin boundaries. FACT promotes spreading by repressing heterochromatic histone turnover, which is crucial for the H3K9me2 to me3 transition that enables spreading. FACT mutant spreading defects are suppressed by removal of the H3K9 methylation antagonist Epe1 via nucleosome stabilization. Together, our study identifies FACT as a histone chaperone that specifically promotes heterochromatin spreading and lends support to the model that regulated histone turnover controls the propagation of epigenetic marks.