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1.
Jean&#x;Christophe Lachance Dominick Matteau Joëlle Brodeur Colton J Lloyd Nathan Mih Zachary A King Thomas F Knight Adam M Feist Jonathan M Monk Bernhard O Palsson Pierre&#x;tienne Jacques Sbastien Rodrigue 《Molecular systems biology》2021,17(7)
Mesoplasma florum, a fast‐growing near‐minimal organism, is a compelling model to explore rational genome designs. Using sequence and structural homology, the set of metabolic functions its genome encodes was identified, allowing the reconstruction of a metabolic network representing ˜ 30% of its protein‐coding genes. Growth medium simplification enabled substrate uptake and product secretion rate quantification which, along with experimental biomass composition, were integrated as species‐specific constraints to produce the functional iJL208 genome‐scale model (GEM) of metabolism. Genome‐wide expression and essentiality datasets as well as growth data on various carbohydrates were used to validate and refine iJL208. Discrepancies between model predictions and observations were mechanistically explained using protein structures and network analysis. iJL208 was also used to propose an in silico reduced genome. Comparing this prediction to the minimal cell JCVI‐syn3.0 and its parent JCVI‐syn1.0 revealed key features of a minimal gene set. iJL208 is a stepping‐stone toward model‐driven whole‐genome engineering. 相似文献
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Emma J Chory Dana W Gretton Erika A DeBenedictis Kevin M Esvelt 《Molecular systems biology》2021,17(3)
Our understanding of complex living systems is limited by our capacity to perform experiments in high throughput. While robotic systems have automated many traditional hand‐pipetting protocols, software limitations have precluded more advanced maneuvers required to manipulate, maintain, and monitor hundreds of experiments in parallel. Here, we present Pyhamilton, an open‐source Python platform that can execute complex pipetting patterns required for custom high‐throughput experiments such as the simulation of metapopulation dynamics. With an integrated plate reader, we maintain nearly 500 remotely monitored bacterial cultures in log‐phase growth for days without user intervention by taking regular density measurements to adjust the robotic method in real‐time. Using these capabilities, we systematically optimize bioreactor protein production by monitoring the fluorescent protein expression and growth rates of a hundred different continuous culture conditions in triplicate to comprehensively sample the carbon, nitrogen, and phosphorus fitness landscape. Our results demonstrate that flexible software can empower existing hardware to enable new types and scales of experiments, empowering areas from biomanufacturing to fundamental biology. 相似文献
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Laleh Salarilak Zahra Pirdel Hossein Dinmohammadi Hassan Rokni&#x;Zadeh Renaud Lavend'homme Mehran Karimi Marc Jacquemin Tina Shahani 《Journal of cellular and molecular medicine》2023,27(1):30
The splenic endothelial Weibel‐palade bodies are one of the most important candidate organelles to release von Willebrand factor upon stimulation with desmopressin. However, the presence of functional desmopressin‐specific receptor has not yet been demonstrated on endothelial cells. Experimental evidences are in favour of an indirect pro‐haemostatic effect of desmopressin, but the exact mediator and its cellular origin are largely elusive. Here, we report partially hampered desmopressin response in a splenectomised severe haemophilia A/Beta Thalassemia patient without any genetic variant relevant to his incomplete desmopressin response. To further investigate the role of the spleen in this phenomenon, the release of VWF from desmopressin‐treated human splenic endothelial cells was assessed in vitro. As a result, desmopressin induced the release of VWF from endothelial cells when the cells were co‐cultured with non‐classical (CD14dim/CD16++), but not other subtypes of monocytes or PBMCs. This in vitro study which resembles close proximity of endothelial cells of sinusoids to monocyte reservoir reside in parenchyma of subcapsular red pulp of the spleen sheds a light upon the role of this highly vascularized VWF‐producing organ in driving indirect effect of desmopressin. 相似文献
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Andreas&#x;David Brunner Marvin Thielert Catherine Vasilopoulou Constantin Ammar Fabian Coscia Andreas Mund Ole B Hoerning Nicolai Bache Amalia Apalategui Markus Lubeck Sabrina Richter David S Fischer Oliver Raether Melvin A Park Florian Meier Fabian J Theis Matthias Mann 《Molecular systems biology》2022,18(3)
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Mujdat Zeybel Ozlem Altay Muhammad Arif Xiangyu Li Hong Yang Claudia Fredolini Murat Akyildiz Burcin Saglam Mehmet Gokhan Gonenli Dilek Ural Woonghee Kim Jochen M Schwenk Cheng Zhang Saeed Shoaie Jens Nielsen Mathias Uhln Jan Born Adil Mardinoglu 《Molecular systems biology》2021,17(10)
Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo‐controlled 10‐week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients. 相似文献
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Marion Vittecoq Lionel Brazier Eric Elguero Ignacio G. Bravo Nicolas Renaud Alejandro Manzano&#x;Marín Franck Prugnolle Sylvain Godreuil Thomas Blanchon Franois Roux Patrick Durand Franois Renaud Frdric Thomas 《Ecology and evolution》2022,12(6)
Wild animal species living in anthropogenic areas are commonly carriers of antimicrobial‐resistant bacteria (AMRB), but their role in the epidemiology of these bacteria is unclear. Several studies on AMRB in wildlife have been cross‐sectional in design and sampled individual animals at only one point in time. To further understand the role of wildlife in maintaining and potentially transmitting these bacteria to humans and livestock, longitudinal studies are needed in which samples are collected from individual animals over multiple time periods. In Europe, free‐ranging yellow‐legged gulls (Larus michahellis) commonly live in industrialized areas, forage in landfills, and have been found to carry AMRB in their feces. Using bacterial metagenomics and antimicrobial resistance characterization, we investigated the spatial and temporal patterns of AMRB in a nesting colony of yellow‐legged gulls from an industrialized area in southern France. We collected 54 cloacal swabs from 31 yellow‐legged gull chicks in 20 nests on three dates in 2016. We found that AMRB in chicks increased over time and was not spatially structured within the gull colony. This study highlights the complex occurrence of AMRB in a free‐ranging wildlife species and contributes to our understanding of the public health risks and implications associated with ARMB‐carrying gulls living in anthropogenic areas. 相似文献
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Ellen A. Bell Jo Cable Claudio Oliveira David S. Richardson Levi Yant Martin I. Taylor 《Ecology and evolution》2020,10(24):13949
Whole‐genome duplication (WGD) events occur in all kingdoms and have been hypothesized to promote adaptability. WGDs identified in the early history of vertebrates, teleosts, and angiosperms have been linked to the large‐scale diversification of these lineages. However, the mechanics and full outcomes of WGD regarding potential evolutionary impacts remain a topic of debate. The Corydoradinae are a diverse subfamily of Neotropical catfishes with over 170 species described and a history of WGDs. They are divided into nine mtDNA lineages, with species coexisting in sympatric—and often mimetic—communities containing representatives of two or more of the nine lineages. Given their similar life histories, coexisting species of Corydoras might be exposed to similar parasite loads and because of their different histories of WGD and genome size they provide a powerful system for investigating the impacts of WGD on immune diversity and function in an animal system. Here, we compared parasite counts and the diversity of the immune‐related toll‐like receptors (TLR) in two coexisting species of Corydoras catfish (C. maculifer and C. araguaiaensis), one diploid and one putative tetraploid. In the putative tetraploid C. araguaiaensis, we found significantly lower numbers of parasites and significantly higher diversity (measured by both synonymous and nonsynonymous SNP counts) in two TLR genes than in the diploid C. maculifer. These results provide insight into how WGD may impact evolution, in this case by providing greater immunogenetic diversity. 相似文献
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Katharina Imkeller Giulia Ambrosi Nancy Klemm Ainara Claveras Cabezudo Luisa Henkel Wolfgang Huber Michael Boutros 《Molecular systems biology》2022,18(8)
Wnt pathways are important for the modulation of tissue homeostasis, and their deregulation is linked to cancer development. Canonical Wnt signaling is hyperactivated in many human colorectal cancers due to genetic alterations of the negative Wnt regulator APC. However, the expression levels of Wnt‐dependent targets vary between tumors, and the mechanisms of carcinogenesis concomitant with this Wnt signaling dosage have not been understood. In this study, we integrate whole‐genome CRISPR/Cas9 screens with large‐scale multi‐omic data to delineate functional subtypes of cancer. We engineer APC loss‐of‐function mutations and thereby hyperactivate Wnt signaling in cells with low endogenous Wnt activity and find that the resulting engineered cells have an unfavorable metabolic equilibrium compared with cells which naturally acquired Wnt hyperactivation. We show that the dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and the mitochondrial phenotype of a given cell type in a context‐dependent manner. These findings illustrate the impact of context‐dependent genetic interactions on cellular phenotypes of a central cancer driver mutation and expand our understanding of quantitative modulation of oncogenic signaling in tumorigenesis. 相似文献
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Population translocations occur for a variety of reasons, from displacement due to climate change to human‐induced transfers. Such actions have adverse effects on genetic variation and understanding their microevolutionary consequences requires monitoring. Here, we return to an experimental release of brown trout (Salmo trutta) in order to monitor the genomic effects of population translocations. In 1979, fish from each of two genetically (F ST = 0.16) and ecologically separate populations were simultaneously released, at one point in time, to a lake system previously void of brown trout. Here, whole‐genome sequencing of pooled DNA (Pool‐seq) is used to characterize diversity within and divergence between the introduced populations and fish inhabiting two lakes downstream of the release sites, sampled 30 years later (c. 5 generations). Present results suggest that while extensive hybridization has occurred, the two introduced populations are unequally represented in the lakes downstream of the release sites. One population, which is ecologically resident in its original habitat, mainly contributes to the lake closest to the release site. The other population, migratory in its natal habitat, is genetically more represented in the lake further downstream. Genomic regions putatively under directional selection in the new habitat are identified, where allele frequencies in both established populations are more similar to the introduced population stemming from a resident population than the migratory one. Results suggest that the microevolutionary consequences of population translocations, for example, hybridization and adaptation, can be rapid and that Pool‐seq can be used as an initial tool to monitor genome‐wide effects. 相似文献
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Improving microbial fitness in the mammalian gut by in vivo temporal functional metagenomics 
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下载免费PDF全文 Stephanie J Yaung Luxue Deng Ning Li Jonathan L Braff George M Church Lynn Bry Harris H Wang Georg K Gerber 《Molecular systems biology》2015,11(3)
Elucidating functions of commensal microbial genes in the mammalian gut is challenging because many commensals are recalcitrant to laboratory cultivation and genetic manipulation. We present Temporal FUnctional Metagenomics sequencing (TFUMseq), a platform to functionally mine bacterial genomes for genes that contribute to fitness of commensal bacteria in vivo. Our approach uses metagenomic DNA to construct large‐scale heterologous expression libraries that are tracked over time in vivo by deep sequencing and computational methods. To demonstrate our approach, we built a TFUMseq plasmid library using the gut commensal Bacteroides thetaiotaomicron (Bt) and introduced Escherichia coli carrying this library into germfree mice. Population dynamics of library clones revealed Bt genes conferring significant fitness advantages in E. coli over time, including carbohydrate utilization genes, with a Bt galactokinase central to early colonization, and subsequent dominance by a Bt glycoside hydrolase enabling sucrose metabolism coupled with co‐evolution of the plasmid library and E. coli genome driving increased galactose utilization. Our findings highlight the utility of functional metagenomics for engineering commensal bacteria with improved properties, including expanded colonization capabilities in vivo. 相似文献
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Kevin Neil Nancy Allard Patricia Roy Frdric Grenier Alfredo Menendez Vincent Burrus Sbastien Rodrigue 《Molecular systems biology》2021,17(10)
Antibiotic resistance threatens our ability to treat infectious diseases, spurring interest in alternative antimicrobial technologies. The use of bacterial conjugation to deliver CRISPR‐cas systems programmed to precisely eliminate antibiotic‐resistant bacteria represents a promising approach but requires high in situ DNA transfer rates. We have optimized the transfer efficiency of conjugative plasmid TP114 using accelerated laboratory evolution. We hence generated a potent conjugative delivery vehicle for CRISPR‐cas9 that can eliminate > 99.9% of targeted antibiotic‐resistant Escherichia coli in the mouse gut microbiota using a single dose. We then applied this system to a Citrobacter rodentium infection model, achieving full clearance within four consecutive days of treatment. 相似文献
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William S. Pearman Sarah J. Wells Olin K. Silander Nikki E. Freed James Dale 《Ecology and evolution》2020,10(24):13624
Population genetic structure in the marine environment can be influenced by life‐history traits such as developmental mode (biphasic, with distinct adult and larval morphology, and direct development, in which larvae resemble adults) or habitat specificity, as well as geography and selection. Developmental mode is thought to significantly influence dispersal, with direct developers expected to have much lower dispersal potential. However, this prediction can be complicated by the presence of geophysical barriers to dispersal. In this study, we use a panel of 8,020 SNPs to investigate population structure and biogeography over multiple spatial scales for a direct‐developing species, the New Zealand endemic marine isopod Isocladus armatus. Because our sampling range is intersected by two well‐known biogeographic barriers (the East Cape and the Cook Strait), our study provides an opportunity to understand how such barriers influence dispersal in direct developers. On a small spatial scale (20 km), gene flow between locations is extremely high, suggestive of an island model of migration. However, over larger spatial scales (600 km), populations exhibit a clear pattern of isolation‐by‐distance. Our results indicate that I. armatus exhibits significant migration across the hypothesized barriers and suggest that large‐scale ocean currents associated with these locations do not present a barrier to dispersal. Interestingly, we find evidence of a north‐south population genetic break occurring between Māhia and Wellington. While no known geophysical barrier is apparent in this area, it coincides with the location of a proposed border between bioregions. Analysis of loci under selection revealed that both isolation‐by‐distance and adaption may be contributing to the degree of population structure we have observed here. We conclude that developmental life history largely predicts dispersal in the intertidal isopod I. armatus. However, localized biogeographic processes can disrupt this expectation, and this may explain the potential meta‐population detected in the Auckland region. 相似文献
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Hongzhong Lu Feiran Li Le Yuan Ivn Domenzain Rosemary Yu Hao Wang Gang Li Yu Chen Boyang Ji Eduard J Kerkhoven Jens Nielsen 《Molecular systems biology》2021,17(10)
Yeasts are known to have versatile metabolic traits, while how these metabolic traits have evolved has not been elucidated systematically. We performed integrative evolution analysis to investigate how genomic evolution determines trait generation by reconstructing genome‐scale metabolic models (GEMs) for 332 yeasts. These GEMs could comprehensively characterize trait diversity and predict enzyme functionality, thereby signifying that sequence‐level evolution has shaped reaction networks towards new metabolic functions. Strikingly, using GEMs, we can mechanistically map different evolutionary events, e.g. horizontal gene transfer and gene duplication, onto relevant subpathways to explain metabolic plasticity. This demonstrates that gene family expansion and enzyme promiscuity are prominent mechanisms for metabolic trait gains, while GEM simulations reveal that additional factors, such as gene loss from distant pathways, contribute to trait losses. Furthermore, our analysis could pinpoint to specific genes and pathways that have been under positive selection and relevant for the formulation of complex metabolic traits, i.e. thermotolerance and the Crabtree effect. Our findings illustrate how multidimensional evolution in both metabolic network structure and individual enzymes drives phenotypic variations. 相似文献
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Xuanxiao Xie Jennifer Shrimpton Gina M. Doody Philip G. Conaghan Frederique Ponchel 《Aging cell》2021,20(4)
BackgroundAge‐related immune deficiencies are thought to be responsible for increased susceptibility to infection in older adults, with alterations in lymphocyte populations becoming more prevalent over time. The loss of humoral immunity in ageing was attributed to the diminished numbers of B cells and the reduced ability to generate immunoglobulin.AimsTo compare the intrinsic B‐cell capacity for differentiation into mature plasma cells (PCs), between young and old donors, using in vitro assays, providing either effective T‐cell help or activation via TLR engagement.MethodsB cells were isolated from healthy individuals, in younger (30–38 years) and older (60–64 years) donors. An in vitro model system of B‐cell differentiation was used, analysing 5 differentiation markers by flow cytometry, under T‐dependent (TD: CD40/BCR stimulation) or T‐independent (TI: TLR7/BCR activation) conditions. Antibody secretion was measured by ELISA and gene expression using qPCR.ResultsTI and TD differentiation resulted in effective proliferation of B cells followed by their differentiation into PC. B‐cell‐executed TI differentiation was faster, all differentiation marker and genes being expressed earlier than under TD differentiation (day 6), although generating less viable cells and lower antibody levels (day 13). Age‐related differences in B‐cell capacity for differentiation were minimal in TD differentiation. In contrast, in TI differentiation age significantly affected proliferation, viability, differentiation, antibody secretion and gene expression, older donors being more efficient.ConclusionAltogether, B‐cell differentiation into PC appeared similar between age groups when provided with T‐cell help, in contrast to TI differentiation, where multiple age‐related changes suggest better capacities in older donors. These new findings may help explain the emergence of autoantibodies in ageing. 相似文献
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Yongxiang Zhang Jingkai Wang Chao Yu Kaishun Xia Biao Yang Yuang Zhang Liwei Ying Chenggui Wang Xianpeng Huang Qixin Chen Li Shen Fangcai Li Chengzhen Liang 《Cell proliferation》2022,55(1)
In recent years, single‐cell sequencing (SCS) technologies have continued to advance with improved operating procedures and reduced cost, leading to increasing practical adoption among researchers. These emerging technologies have superior abilities to analyse cell heterogeneity at a single‐cell level, which have elevated multi‐omics research to a higher level. In some fields of research, application of SCS has enabled many valuable discoveries, and musculoskeletal system offers typical examples. This article reviews some major scientific issues and recent advances in musculoskeletal system. In addition, combined with SCS technologies, the research of cell or tissue heterogeneity in limb development and various musculoskeletal system clinical diseases also provides new possibilities for treatment strategies. Finally, this article discusses the challenges and future development potential of SCS and recommends the direction of future applications of SCS to musculoskeletal medicine. 相似文献
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Peter Contos Jennifer L. Wood Nicholas P. Murphy Heloise Gibb 《Ecology and evolution》2021,11(12):7187
- Restoration ecology has historically focused on reconstructing communities of highly visible taxa while less visible taxa, such as invertebrates and microbes, are ignored. This is problematic as invertebrates and microbes make up the vast bulk of biodiversity and drive many key ecosystem processes, yet they are rarely actively reintroduced following restoration, potentially limiting ecosystem function and biodiversity in these areas.
- In this review, we discuss the current (limited) incorporation of invertebrates and microbes in restoration and rewilding projects. We argue that these groups should be actively rewilded during restoration to improve biodiversity, ecosystem function outcomes, and highlight how they can be used to greater effect in the future. For example, invertebrates and microbes are easily manipulated, meaning whole communities can potentially be rewilded through habitat transplants in a practice that we refer to as “whole‐of‐community” rewilding.
- We provide a framework for whole‐of‐community rewilding and describe empirical case studies as practical applications of this under‐researched restoration tool that land managers can use to improve restoration outcomes.
- We hope this new perspective on whole‐of‐community restoration will promote applied research into restoration that incorporates all biota, irrespective of size, while also enabling a better understanding of fundamental ecological theory, such as colonization and competition trade‐offs. This may be a necessary consideration as invertebrates that are important in providing ecosystem services are declining globally; targeting invertebrate communities during restoration may be crucial in stemming this decline.
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Sen I O&#x;Donoghue Andrea Schafferhans Neblina Sikta Christian Stolte Sandeep Kaur Bosco K Ho Stuart Anderson James B Procter Christian Dallago Nicola Bordin Matt Adcock Burkhard Rost 《Molecular systems biology》2021,17(9)
We modeled 3D structures of all SARS‐CoV‐2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post‐translational modifications, block host translation, and disable host defenses; a further ˜29% self‐assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is—and is not—known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria‐COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark. 相似文献