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1.
J Am Soc Nephrol ; 33(1): 238-252, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34732507

RESUMEN

BACKGROUND: Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. METHODS: We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence. RESULTS: In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. CONCLUSIONS: Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.


Asunto(s)
Autoanticuerpos/sangre , Proteínas de la Membrana/inmunología , Nefrosis Lipoidea/sangre , Nefrosis Lipoidea/etiología , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Nefrosis Lipoidea/patología , Podocitos/patología
3.
J Am Soc Nephrol ; 33(3): 654, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35064049
4.
Nucleic Acids Res ; 41(Database issue): D648-54, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23203984

RESUMEN

The metaMicrobesOnline database (freely available at http://meta.MicrobesOnline.org) offers phylogenetic analysis of genes from microbial genomes and metagenomes. Gene trees are constructed for canonical gene families such as COG and Pfam. Such gene trees allow for rapid homologue analysis and subfamily comparison of genes from multiple metagenomes and comparisons with genes from microbial isolates. Additionally, the genome browser permits genome context comparisons, which may be used to determine the closest sequenced genome or suggest functionally associated genes. Lastly, the domain browser permits rapid comparison of protein domain organization within genes of interest from metagenomes and complete microbial genomes.


Asunto(s)
Bases de Datos Genéticas , Metagenoma , Metagenómica , Filogenia , Genoma , Genoma Arqueal , Genoma Bacteriano , Genoma Fúngico , Genómica , Internet , Estructura Terciaria de Proteína , Programas Informáticos , Sintenía
5.
Cell Rep ; 43(6): 114253, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38781074

RESUMEN

Diabetic kidney disease (DKD), the most common cause of kidney failure, is a frequent complication of diabetes and obesity, and yet to date, treatments to halt its progression are lacking. We analyze kidney single-cell transcriptomic profiles from DKD patients and two DKD mouse models at multiple time points along disease progression-high-fat diet (HFD)-fed mice aged to 90-100 weeks and BTBR ob/ob mice (a genetic model)-and report an expanding population of macrophages with high expression of triggering receptor expressed on myeloid cells 2 (TREM2) in HFD-fed mice. TREM2high macrophages are enriched in obese and diabetic patients, in contrast to hypertensive patients or healthy controls in an independent validation cohort. Trem2 knockout mice on an HFD have worsening kidney filter damage and increased tubular epithelial cell injury, all signs of worsening DKD. Together, our studies suggest that strategies to enhance kidney TREM2high macrophages may provide therapeutic benefits for DKD.


Asunto(s)
Nefropatías Diabéticas , Dieta Alta en Grasa , Riñón , Macrófagos , Glicoproteínas de Membrana , Ratones Noqueados , Obesidad , Receptores Inmunológicos , Animales , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Macrófagos/metabolismo , Obesidad/metabolismo , Obesidad/patología , Obesidad/complicaciones , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Ratones , Riñón/patología , Riñón/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Femenino
6.
Nucleic Acids Res ; 38(Database issue): D396-400, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19906701

RESUMEN

Since 2003, MicrobesOnline (http://www.microbesonline.org) has been providing a community resource for comparative and functional genome analysis. The portal includes over 1000 complete genomes of bacteria, archaea and fungi and thousands of expression microarrays from diverse organisms ranging from model organisms such as Escherichia coli and Saccharomyces cerevisiae to environmental microbes such as Desulfovibrio vulgaris and Shewanella oneidensis. To assist in annotating genes and in reconstructing their evolutionary history, MicrobesOnline includes a comparative genome browser based on phylogenetic trees for every gene family as well as a species tree. To identify co-regulated genes, MicrobesOnline can search for genes based on their expression profile, and provides tools for identifying regulatory motifs and seeing if they are conserved. MicrobesOnline also includes fast phylogenetic profile searches, comparative views of metabolic pathways, operon predictions, a workbench for sequence analysis and integration with RegTransBase and other microbial genome resources. The next update of MicrobesOnline will contain significant new functionality, including comparative analysis of metagenomic sequence data. Programmatic access to the database, along with source code and documentation, is available at http://microbesonline.org/programmers.html.


Asunto(s)
Bacterias/genética , Biología Computacional/métodos , Bases de Datos Genéticas , Bases de Datos de Ácidos Nucleicos , Algoritmos , Biología Computacional/tendencias , Bases de Datos de Proteínas , Perfilación de la Expresión Génica , Genoma Bacteriano , Almacenamiento y Recuperación de la Información/métodos , Internet , Análisis de Secuencia por Matrices de Oligonucleótidos , Estructura Terciaria de Proteína , Programas Informáticos
7.
iScience ; 25(4): 104097, 2022 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-35372810

RESUMEN

High-resolution spatial transcriptomics enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation of disease processes and therapeutically actionable pathways remains unexplored. We applied Slide-seqV2 to mouse and human kidneys, in healthy and distinct disease paradigms. First, we established the feasibility of Slide-seqV2 in tissue from nine distinct human kidneys, which revealed a cell neighborhood centered around a population of LYVE1+ macrophages. Second, in a mouse model of diabetic kidney disease, we detected changes in the cellular organization of the spatially restricted kidney filter and blood-flow-regulating apparatus. Third, in a mouse model of a toxic proteinopathy, we identified previously unknown, disease-specific cell neighborhoods centered around macrophages. In a spatially restricted subpopulation of epithelial cells, we discovered perturbations in 77 genes associated with the unfolded protein response. Our studies illustrate and experimentally validate the utility of Slide-seqV2 for the discovery of disease-specific cell neighborhoods.

8.
BMC Ecol ; 11: 11, 2011 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-21524302

RESUMEN

BACKGROUND: Terabyte-scale collections of string-encoded data are expected from consortia efforts such as the Human Microbiome Project http://nihroadmap.nih.gov/hmp. Intra- and inter-project data similarity searches are enabled by rapid k-mer matching strategies. Software applications for sequence database partitioning, guide tree estimation, molecular classification and alignment acceleration have benefited from embedded k-mer searches as sub-routines. However, a rapid, general-purpose, open-source, flexible, stand-alone k-mer tool has not been available. RESULTS: Here we present a stand-alone utility, Simrank, which allows users to rapidly identify database strings the most similar to query strings. Performance testing of Simrank and related tools against DNA, RNA, protein and human-languages found Simrank 10X to 928X faster depending on the dataset. CONCLUSIONS: Simrank provides molecular ecologists with a high-throughput, open source choice for comparing large sequence sets to find similarity.


Asunto(s)
Bases de Datos Bibliográficas , Bases de Datos Factuales , Biología Molecular , Programas Informáticos , Biología Computacional , ADN , Proteínas , ARN
9.
J Clin Invest ; 131(5)2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33444290

RESUMEN

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.


Asunto(s)
Ataxia/metabolismo , Indenos/farmacología , Enfermedades Renales/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Podocitos/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/farmacología , Ubiquinona/deficiencia , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Animales , Ataxia/tratamiento farmacológico , Ataxia/genética , Ataxia/patología , Sistemas de Liberación de Medicamentos , Células HEK293 , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/genética , Enfermedades Renales/patología , Peroxidación de Lípido/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/genética , Debilidad Muscular/patología , Podocitos/patología , Proteínas Proto-Oncogénicas B-raf/genética , RNA-Seq , Ubiquinona/genética , Ubiquinona/metabolismo
10.
bioRxiv ; 2020 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-32637960

RESUMEN

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

11.
Cell Rep Med ; 1(8): 100137, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33294858

RESUMEN

Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.

12.
BMC Genomics ; 10: 351, 2009 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-19650930

RESUMEN

BACKGROUND: Initial interest in Dechloromonas aromatica strain RCB arose from its ability to anaerobically degrade benzene. It is also able to reduce perchlorate and oxidize chlorobenzoate, toluene, and xylene, creating interest in using this organism for bioremediation. Little physiological data has been published for this microbe. It is considered to be a free-living organism. RESULTS: The a priori prediction that the D. aromatica genome would contain previously characterized "central" enzymes to support anaerobic aromatic degradation of benzene proved to be false, suggesting the presence of novel anaerobic aromatic degradation pathways in this species. These missing pathways include the benzylsuccinate synthase (bssABC) genes (responsible for fumarate addition to toluene) and the central benzoyl-CoA pathway for monoaromatics. In depth analyses using existing TIGRfam, COG, and InterPro models, and the creation of de novo HMM models, indicate a highly complex lifestyle with a large number of environmental sensors and signaling pathways, including a relatively large number of GGDEF domain signal receptors and multiple quorum sensors. A number of proteins indicate interactions with an as yet unknown host, as indicated by the presence of predicted cell host remodeling enzymes, effector enzymes, hemolysin-like proteins, adhesins, NO reductase, and both type III and type VI secretory complexes. Evidence of biofilm formation including a proposed exopolysaccharide complex and exosortase (epsH) are also present. Annotation described in this paper also reveals evidence for several metabolic pathways that have yet to be observed experimentally, including a sulphur oxidation (soxFCDYZAXB) gene cluster, Calvin cycle enzymes, and proteins involved in nitrogen fixation in other species (including RubisCo, ribulose-phosphate 3-epimerase, and nif gene families, respectively). CONCLUSION: Analysis of the D. aromatica genome indicates there is much to be learned regarding the metabolic capabilities, and life-style, for this microbial species. Examples of recent gene duplication events in signaling as well as dioxygenase clusters are present, indicating selective gene family expansion as a relatively recent event in D. aromatica's evolutionary history. Gene families that constitute metabolic cycles presumed to create D. aromatica's environmental 'foot-print' indicate a high level of diversification between its predicted capabilities and those of its close relatives, A. aromaticum str EbN1 and Azoarcus BH72.


Asunto(s)
Benceno/metabolismo , Proteoma/metabolismo , Rhodocyclaceae/metabolismo , Anaerobiosis , Biodegradación Ambiental , ADN Bacteriano/genética , Regulación Bacteriana de la Expresión Génica , Biblioteca de Genes , Genoma Bacteriano , Redes y Vías Metabólicas , Rhodocyclaceae/genética , Análisis de Secuencia de ADN
15.
Genome Res ; 15(7): 1015-22, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15998914

RESUMEN

At present, hundreds of microbial genomes have been sequenced, and hundreds more are currently in the pipeline. The Virtual Institute for Microbial Stress and Survival has developed a publicly available suite of Web-based comparative genomic tools (http://www.microbesonline.org) designed to facilitate multispecies comparison among prokaryotes. Highlights of the MicrobesOnline Web site include operon and regulon predictions, a multispecies genome browser, a multispecies Gene Ontology browser, a comparative KEGG metabolic pathway viewer, a Bioinformatics Workbench for in-depth sequence analysis, and Gene Carts that allow users to save genes of interest for further study while they browse. In addition, we provide an interface for genome annotation, which like all of the tools reported here, is freely available to the scientific community.


Asunto(s)
Genoma Bacteriano , Genómica , Animales , Biología Computacional , Gráficos por Computador , Bases de Datos Genéticas , Bases de Datos de Proteínas , Estructura Terciaria de Proteína/genética , Programas Informáticos , Interfaz Usuario-Computador
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