scholarly journals Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease

2021 ◽  
Author(s):  
Samuel C. Forster ◽  
Simon Clare ◽  
Benjamin S. Beresford-Jones ◽  
Katherine Harcourt ◽  
George Notley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Large Scale ◽  
Bacterial Species ◽  
The Novel ◽  
Host Immune Responses ◽  
Causes Of Disease ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Scale Experiment

The mammalian gut microbiota consists of hundreds of anaerobic bacterial species that shape intestinal homeostasis and influence host immune responses. Although the causal roles of specific human gut bacterial species in health and disease are emerging, the role of indigenous gut bacteria in driving immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 laboratory mice designed to identify and validate the causes of disease variability in the widely used dextran sulphate sodium (DSS) mouse model of inflammatory bowel disease. Using microbiome analysis, coupled with machine learning and targeted anaerobic culturing, we identified and isolated the novel gut pathobiont species Duncaniella muricolitica and Alistipes okayasuensis and fulfilled Koch’s postulates in mice to show that each pathobiont exerts dominant effects in the DSS model leading to variable treatment responses. We show these pathobiont species are common, but not ubiquitous, in mouse facilities around the world, raising experimental design opportunities for improved mouse models of human intestinal diseases.

scholarly journals Comparative genomics suggests a taxonomic revision of the Staphylococcus cohnii species complex

2021 ◽  
Author(s):  
Anna Lavecchia ◽  
Matteo Chiara ◽  
Caterina De Virgilio ◽  
Caterina Manzari ◽  
Carlo Pazzani ◽  
...  
Keyword(s):  
Comparative Genomics ◽  
Species Complex ◽  
Large Scale ◽  
Genomic Sequence ◽  
Bacterial Species ◽  
Taxonomic Revision ◽  
Distinct Species ◽  
The Novel ◽  
Staphylococcus Cohnii ◽  
Taxonomic Assignments

Abstract Staphylococcus cohnii (SC), a coagulase-negative bacterium, was first isolated in 1975 from human skin. Early phenotypic analyses led to the delineation of two subspecies (subsp.), Staphylococcus cohnii subsp. cohnii (SCC) and Staphylococcus cohnii subsp. urealyticus (SCU). SCC was considered to be specific to humans whereas SCU apparently demonstrated a wider host range, from lower primates to humans. The type strains ATCC 29974 and ATCC 49330 have been designated for SCC and SCU, respectively. Comparative analysis of 66 complete genome sequences—including a novel SC isolate—revealed unexpected patterns within the SC complex, both in terms of genomic sequence identity and gene content, highlighting the presence of 3 phylogenetically distinct groups. Based on our observations, and on the current guidelines for taxonomic classification for bacterial species, we propose a revision of the SC species complex. We suggest that SCC and SCU should be regarded as two distinct species: SC and SU (Staphylococcus urealyticus), and that two distinct subspecies, SCC and SCB (SC subsp. barensis, represented by the novel strain isolated in Bari) should be recognized within SC. Furthermore, since large scale comparative genomics studies recurrently suggest inconsistencies or conflicts in taxonomic assignments of bacterial species, we believe that the approach proposed here might be considered for more general application.

scholarly journals OCTN Cation Transporters in Health and Disease

2013 ◽  
Vol 18 (8) ◽  
pp. 851-867 ◽  
Author(s):  
Lorena Pochini ◽  
Mariafrancesca Scalise ◽  
Michele Galluccio ◽  
Cesare Indiveri
Keyword(s):  
Large Scale ◽  
Intact Cell ◽  
Organic Cation Transporter ◽  
Carnitine Deficiency ◽  
Transmembrane Segments ◽  
Pharmacological Targets ◽  
Carnitine Transport ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Molecular Bases

The three members of the organic cation transporter novel subfamily are known to be involved in interactions with xenobiotic compounds. These proteins are characterized by 12 transmembrane segments connected by nine short loops and two large hydrophilic loops. It has been recently pointed out that acetylcholine is a physiological substrate of OCTN1. Its transport could be involved in nonneuronal cholinergic functions. OCTN2 maintains the carnitine homeostasis, resulting from intestinal absorption, distribution to tissues, and renal excretion/reabsorption. OCTN3, identified only in mouse, mediates also carnitine transport. OCTN1 and OCTN2 are associated with several pathologies, such as inflammatory bowel disease, primary carnitine deficiency, diabetes, neurological disorders, and cancer, thus representing useful pharmacological targets. The function and interaction with drugs of OCTNs have been studied in intact cell systems and in proteoliposomes. The latter experimental model enables reduced interference from other transporters or enzyme pathways. Using proteoliposomes, the molecular bases of toxicity of some drugs have recently been revealed. Therefore, proteoliposomes represent a promising experimental tool suitable for large-scale molecular screening of interactions of OCTNs with chemicals regarding human health.

scholarly journals Development of a Multiplex Immunohistochemistry Workflow to Investigate the Immune Microenvironment in Mouse Models of Inflammatory Bowel Disease and Colon Cancer

2021 ◽  
Vol 22 (20) ◽  
pp. 11001
Author(s):  
Lokman Pang ◽  
Matthias Ernst ◽  
Jennifer Huynh
Keyword(s):  
Colon Cancer ◽  
Mouse Model ◽  
Mouse Models ◽  
Colon Adenocarcinoma ◽  
Tumour Microenvironment ◽  
Human Patient ◽  
Mouse Tissues ◽  
Formalin Fixed Paraffin Embedded ◽  
Ffpe Tissues ◽  
Inflammatory Bowel

Multiplex immunohistochemistry (mIHC) enables simultaneous staining of multiple immune markers on a single tissue section. Mounting studies have demonstrated the versatility of mIHC in evaluating immune infiltrates in different diseases and the tumour microenvironment (TME). However, the majority of published studies are limited to the analysis of human patient samples. Performing mIHC on formalin-fixed paraffin-embedded (FFPE) mouse tissues, particularly with sensitive antigens, remain challenging. The aim of our study was to develop a robust and reproducible protocol to uncover the immune landscape in mouse FFPE tissues. Effective antibody stripping while maintaining sensitivity to antigens and tissue adhesion to the glass slide is critical in developing an mIHC panel to allow successive rounds of staining. Thus, we identified a highly efficient stripping method that preserves signal intensity and antigenicity to allow multiple rounds of staining. We subsequently optimised an mIHC workflow with antibodies specific against CD4, CD8α, FOXP3 and B220 to identify distinct T and B cell populations on mouse FFPE tissues. Lastly, the application of this mIHC panel was validated in a mouse model of inflammatory bowel cancer, two allograft mouse models of spontaneous colon adenocarcinoma and a sporadic mouse model of colon cancer. Together, these demonstrate the utility of the aforementioned protocol in establishing the quantity and spatial localisation of immune cells in different pathological tissues.

scholarly journals GutCyc: a Multi-Study Collection of Human Gut Microbiome Metabolic Models

2016 ◽  
Author(s):  
Aria S. Hahn ◽  
Tomer Altman ◽  
Kishori M. Konwar ◽  
Niels W. Hanson ◽  
Dongjae Kim ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Large Scale ◽  
High Throughput Sequencing ◽  
Human Microbiome ◽  
Therapeutic Interventions ◽  
Human Gut ◽  
Human Gut Microbiome ◽  
Disease States ◽  
Health And Disease ◽  
Inflammatory Bowel

AbstractAdvances in high-throughput sequencing are reshaping how we perceive microbial communities inhabiting the human body, with implications for therapeutic interventions. Several large-scale datasets derived from hundreds of human microbiome samples sourced from multiple studies are now publicly available. However, idiosyncratic data processing methods between studies introduce systematic differences that confound comparative analyses. To overcome these challenges, we developed GUTCYC, a compendium of environmental pathway genome databases constructed from 418 assembled human microbiome datasets using METAPATHWAYS, enabling reproducible functional metagenomic annotation. We also generated metabolic network reconstructions for each metagenome using the PATHWAY TOOLS software, empowering researchers and clinicians interested in visualizing and interpreting metabolic pathways encoded by the human gut microbiome. For the first time, GUTCYC provides consistent annotations and metabolic pathway predictions, making possible comparative community analyses between health and disease states in inflammatory bowel disease, Crohn’s disease, and type 2 diabetes. GUTCYC data products are searchable online, or may be downloaded and explored locally using METAPATHWAYS and PATHWAY TOOLS.

scholarly journals A Mouse Model to Assess STAT3 and STAT5A/B Combined Inhibition in Health and Disease Conditions

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1226 ◽  
Author(s):  
Herwig P. Moll ◽  
Julian Mohrherr ◽  
Leander Blaas ◽  
Monica Musteanu ◽  
Patricia Stiedl ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Mouse Model ◽  
Mouse Models ◽  
Marked Reduction ◽  
Genetically Engineered ◽  
Tissue Specific ◽  
Genetically Engineered Mouse Models ◽  
Pharmacological Inhibition ◽  
Specific Manner ◽  
Health And Disease

Genetically-engineered mouse models (GEMMs) lacking diseased-associated gene(s) globally or in a tissue-specific manner represent an attractive tool with which to assess the efficacy and toxicity of targeted pharmacological inhibitors. Stat3 and Stat5a/b transcription factors have been implicated in several pathophysiological conditions, and pharmacological inhibition of both transcription factors has been proposed to treat certain diseases, such as malignancies. To model combined inhibition of Stat3 and Stat5a/b we have developed a GEMM harboring a flox Stat3-Stat5a/b allele (Stat5/3loxP/loxP mice) and generated mice lacking Stat3 and Stat5a/b in hepatocytes (Stat5/3Δhep/Δhep). Stat5/3Δhep/Δhep mice exhibited a marked reduction of STAT3, STAT5A and STAT5B proteins in the liver and developed steatosis, a phenotype that resembles mice lacking Stat5a/b in hepatocytes. In addition, embryonic deletion of Stat3 and Stat5a/b (Stat5/3Δ/Δ mice) resulted in lethality, similar to Stat3Δ/Δ mice. This data illustrates that Stat5/3loxP/loxP mice are functional and can be used as a valuable tool to model the combined inhibition of Stat3 and Stat5a/b in tumorigenesis and other diseases.

scholarly journals Functional and taxonomic comparison of mouse and human gut microbiotas using extensive culturing and metagenomics

2021 ◽  
Author(s):  
Benjamin S. Beresford-Jones ◽  
Samuel C. Forster ◽  
Mark D. Stares ◽  
George Notley ◽  
Elisa Viciani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Mouse Models ◽  
Biomedical Research ◽  
Human Disease ◽  
Bacterial Species ◽  
Biomedical Science ◽  
Human Gut ◽  
Functional Differences ◽  
Health And Disease ◽  
Human And Mouse

AbstractMouse models are essential for biomedical science and drug discovery, yet it is not known how the bacteria in the mouse microbiota – important determinants of phenotypes of health and disease –affect their relevance to human disease. To interrogate the taxonomic and functional differences between the human and mouse gut microbiotas, we developed the Mouse Microbial Genome Collection (MMGC), a compilation of 276 genomes from cultured isolates and 45,218 metagenome-assembled genomes (MAGs) from 1,960 publicly available mouse metagenomes. The MMGC reveals that while only 2.65% of bacterial species are shared between mouse and human, over 80% of annotatable functions are present in both microbiomes. Using drug metabolism and butyrate synthesis as examples, we illustrate that although the species harbouring these key functions can differ between hosts, the MMGC enables identification of functionally equivalent taxa in the mouse and human microbiotas. The MMGC thereby facilitates the informed use of mice in biomedical research by providing access to the conservation and taxonomic locations of bacterial functions of interest.

scholarly journals Sex-Related Motor Deficits in the Tau-P301L Mouse Model

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1160
Author(s):  
Luana Cristina Camargo ◽  
Dominik Honold ◽  
Robert Bauer ◽  
N. Jon Shah ◽  
Karl-Josef Langen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Behavioral Changes ◽  
Motor Deficits ◽  
The Novel ◽  
Behavioral Alterations ◽  
Object Recognition Test ◽  
Histological Changes ◽  
Female Mice

The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain.

scholarly journals Microbial contributions to oxalate metabolism in health and disease

2020 ◽  
Author(s):  
Menghan Liu ◽  
Joseph C. Devlin ◽  
Jiyuan Hu ◽  
Angelina Volkova ◽  
Thomas W. Battaglia ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Large Scale ◽  
Degradation Pathways ◽  
Omics Data ◽  
Oxalobacter Formigenes ◽  
Increased Risk ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Oxalate Metabolism

AbstractOver-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbiota can degrade oxalate and protect against its absorption. However, the particular microbes that actively degrade oxalate in vivo are ill-defined, which restricts our ability to disentangle the underlying taxonomic contributions. Here we leverage large-scale multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota in health harbors diverse ODP-encoding microbial species, but an oxalate autotroph-Oxalobacter formigenes- dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) are at significantly increased risk for disrupted oxalate homeostasis and calcium-oxalate nephrolithiasis. Here, by analyzing multi-omics data from the iHMP-IBD study, we demonstrate that the oxalate degradation function conferred by the intestinal microbiota is severely impaired in IBD patients. In parallel, the enteric oxalate levels of IBD patients are significantly elevated and associated with intestinal disease severity, which is consistent with the clinically known nephrolithiasis risk. The specific changes in ODP expression by several important taxa suggest that they play different roles in the IBD-induced nephrolithiasis risk.

scholarly journals Transcriptomic similarities and differences between mouse models and human Alzheimer's Disease

2021 ◽  
Author(s):  
Marco Ant&ocircnio De Bastiani ◽  
Bruna Bellaver ◽  
Giovanna Collar ◽  
Stefania Forner ◽  
Alessandra Cadete Martini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mouse Models ◽  
Autosomal Dominant ◽  
Interaction Analysis ◽  
The Novel ◽  
Preclinical Research ◽  
Similarities And Differences ◽  
Transcriptomic Level

Alzheimer's disease (AD) is a multifactorial pathology responsible for most cases of dementia worldwide. Only a small percentage of AD cases are due to autosomal dominant mutations, while the vast majority have a sporadic presentation. Yet, preclinical research studies relied for decades on animal models that overexpress human genes found in AD autosomal dominant patients. Thus, one could argue that these models do not recapitulate sporadic AD. To avoid human gene overexpression artifacts, knock-in (KI) models have been developed, such as the novel hAβ-KI mouse model, which are still in early phases of characterization. We hypothesize that comparisons at the transcriptomic level may elucidate critical similarities and differences between transgenic/KI models and AD patients. Thus, we aimed at comparing the hippocampal transcriptomic profiling of overexpression (5xFAD and APP/PS1) and KI (hAβ-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. We first evaluated differentially expressed genes (DEGs) and Gene Ontology biological processes (GOBP) overlapping cross-species. After, we explored a network-based strategy to identify master regulators (MR) and the similarities of such elements among models and AD subtypes. A multiple sclerosis (MS) dataset was included to test the molecular specificity of the mouse models to AD. Our analysis revealed that all three mouse models presented more DEGs, GOBP terms and enriched signaling pathways in common with LOAD than with EOAD subjects. Furthermore, semantic similarity of enriched GOBP terms showed mouse model-specific biological alterations, and protein-protein interaction analysis of DEGs identified clusters of genes exclusively shared between hAβ-KI mice and LOAD. Furthermore, we identified 17 transcription factor candidates potentially acting as MR of AD in all three models. Finally, though all mouse models showed transcriptomic similarities to LOAD, hAβ-KI mice presented a remarkable specificity to this AD subtype, which might support the use of the novel hAβ-KI mouse model to advance our understanding of sporadic LOAD.

Covalent Atomic Bridges Enable Unidirectional Enhancement of Electronic Transport in Aligned Carbon Nanotubes

2019 ◽  
Author(s):  
Mingguang Chen ◽  
Wangxiang Li ◽  
Anshuman Kumar ◽  
Guanghui Li ◽  
Mikhail Itkis ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Electrical Transport ◽  
Large Scale ◽  
The Novel ◽  
Electrical Measurements ◽  
Metal Atoms ◽  
Aligned Carbon Nanotubes ◽  
Transport Channels ◽  
Walled Carbon Nanotubes ◽  
Bulk Structures

<p>Interconnecting the surfaces of nanomaterials without compromising their outstanding mechanical, thermal, and electronic properties is critical in the design of advanced bulk structures that still preserve the novel properties of their nanoscale constituents. As such, bridging the p-conjugated carbon surfaces of single-walled carbon nanotubes (SWNTs) has special implications in next-generation electronics. This study presents a rational path towards improvement of the electrical transport in aligned semiconducting SWNT films by deposition of metal atoms. The formation of conducting Cr-mediated pathways between the parallel SWNTs increases the transverse (intertube) conductance, while having negligible effect on the parallel (intratube) transport. In contrast, doping with Li has a predominant effect on the intratube electrical transport of aligned SWNT films. Large-scale first-principles calculations of electrical transport on aligned SWNTs show good agreement with the experimental electrical measurements and provide insight into the changes that different metal atoms exert on the density of states near the Fermi level of the SWNTs and the formation of transport channels. </p>

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