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1.
Genome Biol ; 22(1): 93, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785070

RESUMO

The human microbiome is increasingly mined for diagnostic and therapeutic biomarkers using machine learning (ML). However, metagenomics-specific software is scarce, and overoptimistic evaluation and limited cross-study generalization are prevailing issues. To address these, we developed SIAMCAT, a versatile R toolbox for ML-based comparative metagenomics. We demonstrate its capabilities in a meta-analysis of fecal metagenomic studies (10,803 samples). When naively transferred across studies, ML models lost accuracy and disease specificity, which could however be resolved by a novel training set augmentation strategy. This reveals some biomarkers to be disease-specific, with others shared across multiple conditions. SIAMCAT is freely available from siamcat.embl.de .

2.
Nat Ecol Evol ; 5(2): 195-203, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398106

RESUMO

Resource competition and metabolic cross-feeding are among the main drivers of microbial community assembly. Yet the degree to which these two conflicting forces are reflected in the composition of natural communities has not been systematically investigated. Here, we use genome-scale metabolic modelling to assess the potential for resource competition and metabolic cooperation in large co-occurring groups (up to 40 members) across thousands of habitats. Our analysis reveals two distinct community types, which are clustered at opposite ends of a spectrum in a trade-off between competition and cooperation. At one end are highly cooperative communities, characterized by smaller genomes and multiple auxotrophies. At the other end are highly competitive communities, which feature larger genomes and overlapping nutritional requirements, and harbour more genes related to antimicrobial activity. The latter are mainly present in soils, whereas the former are found in both free-living and host-associated habitats. Community-scale flux simulations show that, whereas competitive communities can better resist species invasion but not nutrient shift, cooperative communities are susceptible to species invasion but resilient to nutrient change. We also show, by analysing an additional data set, that colonization by probiotic species is positively associated with the presence of cooperative species in the recipient microbiome. Together, our results highlight the bifurcation between competitive and cooperative metabolism in the assembly of natural communities and its implications for community modulation.


Assuntos
Microbiota , Nutrientes
3.
Artigo em Inglês | MEDLINE | ID: mdl-33257833

RESUMO

The human gut microbiome has emerged as a major player in human health and disease. The liver, as the first organ to encounter microbial products that cross the gut epithelial barrier, is affected by the gut microbiome in many ways. Thus, the gut microbiome might play a major part in the development of liver diseases. The common end stage of liver disease is decompensated cirrhosis and the further development towards acute-on-chronic liver failure (ACLF). These conditions have high short-term mortality. There is evidence that translocation of components of the gut microbiota, facilitated by different pathogenic mechanisms such as increased gut epithelial permeability and portal hypertension, is an important driver of decompensation by induction of systemic inflammation, and thereby also ACLF. Elucidating the role of the gut microbiome in the aetiology of decompensated cirrhosis and ACLF deserves further investigation and improvement; and might be the basis for development of diagnostic and therapeutic strategies. In this Review, we focus on the possible pathogenic, diagnostic and therapeutic role of the gut microbiome in decompensation of cirrhosis and progression to ACLF.

4.
Nucleic Acids Res ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33237311

RESUMO

Cellular life depends on a complex web of functional associations between biomolecules. Among these associations, protein-protein interactions are particularly important due to their versatility, specificity and adaptability. The STRING database aims to integrate all known and predicted associations between proteins, including both physical interactions as well as functional associations. To achieve this, STRING collects and scores evidence from a number of sources: (i) automated text mining of the scientific literature, (ii) databases of interaction experiments and annotated complexes/pathways, (iii) computational interaction predictions from co-expression and from conserved genomic context and (iv) systematic transfers of interaction evidence from one organism to another. STRING aims for wide coverage; the upcoming version 11.5 of the resource will contain more than 14 000 organisms. In this update paper, we describe changes to the text-mining system, a new scoring-mode for physical interactions, as well as extensive user interface features for customizing, extending and sharing protein networks. In addition, we describe how to query STRING with genome-wide, experimental data, including the automated detection of enriched functionalities and potential biases in the user's query data. The STRING resource is available online, at https://string-db.org/.

5.
Nat Commun ; 11(1): 5881, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208748

RESUMO

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.

6.
Nucleic Acids Res ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33156333

RESUMO

The InterPro database (https://www.ebi.ac.uk/interpro/) provides an integrative classification of protein sequences into families, and identifies functionally important domains and conserved sites. InterProScan is the underlying software that allows protein and nucleic acid sequences to be searched against InterPro's signatures. Signatures are predictive models which describe protein families, domains or sites, and are provided by multiple databases. InterPro combines signatures representing equivalent families, domains or sites, and provides additional information such as descriptions, literature references and Gene Ontology (GO) terms, to produce a comprehensive resource for protein classification. Founded in 1999, InterPro has become one of the most widely used resources for protein family annotation. Here, we report the status of InterPro (version 81.0) in its 20th year of operation, and its associated software, including updates to database content, the release of a new website and REST API, and performance improvements in InterProScan.

7.
Environ Microbiol ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33185929

RESUMO

Bacteria and fungi are of uttermost importance in determining environmental and host functioning. Despite close interactions between animals, plants, their associated microbiomes, and the environment they inhabit, the distribution and role of bacteria and especially fungi across host and environments as well as the cross-habitat determinants of their community compositions remain little investigated. Using a uniquely broad global dataset of 13 483 metagenomes, we analysed the microbiome structure and function of 25 host-associated and environmental habitats, focusing on potential interactions between bacteria and fungi. We found that the metagenomic relative abundance ratio of bacteria-to-fungi is a distinctive microbial feature of habitats. Compared with fungi, the cross-habitat distribution pattern of bacteria was more strongly driven by habitat type. Fungal diversity was depleted in host-associated communities compared with those in the environment, particularly terrestrial habitats, whereas this diversity pattern was less pronounced for bacteria. The relative gene functional potential of bacteria or fungi reflected their diversity patterns and appeared to depend on a balance between substrate availability and biotic interactions. Alongside helping to identify hotspots and sources of microbial diversity, our study provides support for differences in assembly patterns and processes between bacterial and fungal communities across different habitats.

8.
Nucleic Acids Res ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084874

RESUMO

OGEE is an Online GEne Essentiality database. Gene essentiality is not a static and binary property, rather a context-dependent and evolvable property in all forms of life. In OGEE we collect not only experimentally tested essential and non-essential genes, but also associated gene properties that contributes to gene essentiality. We tagged conditionally essential genes that show variable essentiality statuses across datasets to highlight complex interplays between gene functions and environmental/experimental perturbations. OGEE v3 contains gene essentiality datasets for 91 species; almost doubled from 48 species in previous version. To accommodate recent advances on human cancer essential genes (as known as tumor dependency genes) that could serve as targets for cancer treatment and/or drug development, we expanded the collection of human essential genes from 16 cell lines in previous to 581. These human cancer cell lines were tested with high-throughput experiments such as CRISPR-Cas9 and RNAi; in total, 150 of which were tested by both techniques. We also included factors known to contribute to gene essentiality for these cell lines, such as genomic mutation, methylation and gene expression, along with extensive graphical visualizations for ease of understanding of these factors. OGEE v3 can be accessible freely at https://v3.ogee.info.

9.
Nucleic Acids Res ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33104802

RESUMO

SMART (Simple Modular Architecture Research Tool) is a web resource (https://smart.embl.de) for the identification and annotation of protein domains and the analysis of protein domain architectures. SMART version 9 contains manually curated models for more than 1300 protein domains, with a topical set of 68 new models added since our last update article (1). All the new models are for diverse recombinase families and subfamilies and as a set they provide a comprehensive overview of mobile element recombinases namely transposase, integrase, relaxase, resolvase, cas1 casposase and Xer like cellular recombinase. Further updates include the synchronization of the underlying protein databases with UniProt (2), Ensembl (3) and STRING (4), greatly increasing the total number of annotated domains and other protein features available in architecture analysis mode. Furthermore, SMART's vector-based protein display engine has been extended and updated to use the latest web technologies and the domain architecture analysis components have been optimized to handle the increased number of protein features available.

10.
Int J Mol Sci ; 21(15)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32718059

RESUMO

DNA mismatch repair-deficient colorectal cancers (CRCs) accumulate numerous frameshift mutations at repetitive sequences recognized as microsatellite instability (MSI). When coding mononucleotide repeats (cMNRs) are affected, tumors accumulate frameshift mutations and premature termination codons (PTC) potentially leading to truncated proteins. Nonsense-mediated RNA decay (NMD) can degrade PTC-containing transcripts and protect from such faulty proteins. As it also regulates normal transcripts and cellular physiology, we tested whether NMD genes themselves are targets of MSI frameshift mutations. A high frequency of cMNR frameshift mutations in the UPF3A gene was found in MSI CRC cell lines (67.7%), MSI colorectal adenomas (55%) and carcinomas (63%). In normal colonic crypts, UPF3A expression was restricted to single chromogranin A-positive cells. SILAC-based proteomic analysis of KM12 CRC cells revealed UPF3A-dependent down-regulation of several enzymes involved in cholesterol biosynthesis. Furthermore, reconstituted UPF3A expression caused alterations of 85 phosphosites in 52 phosphoproteins. Most of them (38/52, 73%) reside in nuclear phosphoproteins involved in regulation of gene expression and RNA splicing. Since UPF3A mutations can modulate the (phospho)proteomic signature and expression of enzymes involved in cholesterol metabolism in CRC cells, UPF3A may influence other processes than NMD and loss of UPF3A expression might provide a growth advantage to MSI CRC cells.

11.
Sci Rep ; 10(1): 11597, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665666

RESUMO

Inspired by recent proteomic data demonstrating the upregulation of carbon and glycogen metabolism in aging human hematopoietic stem and progenitor cells (HPCs, CD34+ cells), this report addresses whether this is caused by elevated glycolysis of the HPCs on a per cell basis, or by a subpopulation that has become more glycolytic. The average glycogen content in individual CD34+ cells from older subjects (> 50 years) was 3.5 times higher and more heterogeneous compared to younger subjects (< 35 years). Representative glycolytic enzyme activities in HPCs confirmed a significant increase in glycolysis in older subjects. The HPCs from older subjects can be fractionated into three distinct subsets with high, intermediate, and low glucose uptake (GU) capacity, while the subset with a high GU capacity could scarcely be detected in younger subjects. Thus, we conclude that upregulated glycolysis in aging HPCs is caused by the expansion of a more glycolytic HPC subset. Since single-cell RNA analysis has also demonstrated that this subpopulation is linked to myeloid differentiation and increased proliferation, isolation and mechanistic characterization of this subpopulation can be utilized to elucidate specific targets for therapeutic interventions to restore the lineage balance of aging HPCs.

12.
Nat Rev Microbiol ; 18(9): 491-506, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32499497

RESUMO

Studying within-species variation has traditionally been limited to culturable bacterial isolates and low-resolution microbial community fingerprinting. Metagenomic sequencing and technical advances have enabled culture-free, high-resolution strain and subspecies analyses at high throughput and in complex environments. This holds great scientific promise but has also led to an overwhelming number of methods and terms to describe infraspecific variation. This Review aims to clarify these advances by focusing on the diversity within bacterial and archaeal species in the context of microbiomics. We cover foundational microevolutionary concepts relevant to population genetics and summarize how within-species variation can be studied and stratified directly within microbial communities with a focus on metagenomics. Finally, we describe how common applications of within-species variation can be achieved using metagenomic data. We aim to guide the selection of appropriate terms and analytical approaches to facilitate researchers in benefiting from the increasing availability of large, high-resolution microbiome genetic sequencing data.

13.
Nature ; 581(7808): 310-315, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433607

RESUMO

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.


Assuntos
Disbiose/epidemiologia , Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Bacteroides/isolamento & purificação , Estudos de Coortes , Estudos Transversais , Faecalibacterium/isolamento & purificação , Fezes/microbiologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Inflamatórias Intestinais/microbiologia , Masculino , Obesidade/microbiologia , Prevalência
14.
Nat Rev Microbiol ; 18(8): 428-445, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32398798

RESUMO

A planetary-scale understanding of the ocean ecosystem, particularly in light of climate change, is crucial. Here, we review the work of Tara Oceans, an international, multidisciplinary project to assess the complexity of ocean life across comprehensive taxonomic and spatial scales. Using a modified sailing boat, the team sampled plankton at 210 globally distributed sites at depths down to 1,000 m. We describe publicly available resources of molecular, morphological and environmental data, and discuss how an ecosystems biology approach has expanded our understanding of plankton diversity and ecology in the ocean as a planetary, interconnected ecosystem. These efforts illustrate how global-scale concepts and data can help to integrate biological complexity into models and serve as a baseline for assessing ecosystem changes and the future habitability of our planet in the Anthropocene epoch.

15.
New Phytol ; 227(4): 1189-1199, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32279325

RESUMO

Plant nutrient-acquisition strategies drive soil processes and vegetation performance, but their effect on the soil microbiome remains poorly understood. This knowledge is important to predict the shifts in microbial diversity and functions due to increasing changes in vegetation traits under global change. Here we documented the topsoil microbiomes of 145 boreal and temperate terrestrial sites in the Baltic region that broadly differed in vegetation type and nutritional traits, such as mycorrhizal types and symbiotic nitrogen-fixation. We found that sites dominated by arbuscular mycorrhizal (AM) vegetation harbor relatively more AM fungi, bacteria, fungal saprotrophs, and pathogens in the topsoil compared with sites dominated by ectomycorrhizal (EM) plants. These differences in microbiome composition reflect the rapid nutrient cycling and negative plant-soil feedback in AM soils. Lower fungal diversity and bacteria : fungi ratios in EM-dominated habitats are driven by monodominance of woody vegetation as well as soil acidification by EM fungi, which are associated with greater diversity and relative abundance of carbohydrate-active enzymes. Our study suggests that shifts in vegetation related to global change and land use may strongly alter the topsoil microbiome structure and function.

16.
ISME J ; 14(5): 1247-1259, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32047279

RESUMO

Microbial organisms inhabit virtually all environments and encompass a vast biological diversity. The pangenome concept aims to facilitate an understanding of diversity within defined phylogenetic groups. Hence, pangenomes are increasingly used to characterize the strain diversity of prokaryotic species. To understand the interdependence of pangenome features (such as the number of core and accessory genes) and to study the impact of environmental and phylogenetic constraints on the evolution of conspecific strains, we computed pangenomes for 155 phylogenetically diverse species (from ten phyla) using 7,000 high-quality genomes to each of which the respective habitats were assigned. Species habitat ubiquity was associated with several pangenome features. In particular, core-genome size was more important for ubiquity than accessory genome size. In general, environmental preferences had a stronger impact on pangenome evolution than phylogenetic inertia. Environmental preferences explained up to 49% of the variance for pangenome features, compared with 18% by phylogenetic inertia. This observation was robust when the dataset was extended to 10,100 species (59 phyla). The importance of environmental preferences was further accentuated by convergent evolution of pangenome features in a given habitat type across different phylogenetic clades. For example, the soil environment promotes expansion of pangenome size, while host-associated habitats lead to its reduction. Taken together, we explored the global principles of pangenome evolution, quantified the influence of habitat, and phylogenetic inertia on the evolution of pangenomes and identified criteria governing species ubiquity and habitat specificity.


Assuntos
Biodiversidade , Células Procarióticas , Ecossistema , Tamanho do Genoma , Filogenia
17.
Bioinformatics ; 36(4): 1213-1218, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605112

RESUMO

MOTIVATION: Untargeted mass spectrometry (MS/MS) is a powerful method for detecting metabolites in biological samples. However, fast and accurate identification of the metabolites' structures from MS/MS spectra is still a great challenge. RESULTS: We present a new analysis method, called SubFragment-Matching (SF-Matching) that is based on the hypothesis that molecules with similar structural features will exhibit similar fragmentation patterns. We combine information on fragmentation patterns of molecules with shared substructures and then use random forest models to predict whether a given structure can yield a certain fragmentation pattern. These models can then be used to score candidate molecules for a given mass spectrum. For rapid identification, we pre-compute such scores for common biological molecular structure databases. Using benchmarking datasets, we find that our method has similar performance to CSI: FingerID and those very high accuracies can be achieved by combining our method with CSI: FingerID. Rarefaction analysis of the training dataset shows that the performance of our method will increase as more experimental data become available. AVAILABILITY AND IMPLEMENTATION: SF-Matching is available from http://www.bork.embl.de/Docu/sf_matching. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Metabolômica , Espectrometria de Massas em Tandem , Bases de Dados de Compostos Químicos , Bases de Dados Factuais , Aprendizado de Máquina
19.
Nucleic Acids Res ; 48(D1): D621-D625, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31647096

RESUMO

Microbiology depends on the availability of annotated microbial genomes for many applications. Comparative genomics approaches have been a major advance, but consistent and accurate annotations of genomes can be hard to obtain. In addition, newer concepts such as the pan-genome concept are still being implemented to help answer biological questions. Hence, we present proGenomes2, which provides 87 920 high-quality genomes in a user-friendly and interactive manner. Genome sequences and annotations can be retrieved individually or by taxonomic clade. Every genome in the database has been assigned to a species cluster and most genomes could be accurately assigned to one or multiple habitats. In addition, general functional annotations and specific annotations of antibiotic resistance genes and single nucleotide variants are provided. In short, proGenomes2 provides threefold more genomes, enhanced habitat annotations, updated taxonomic and functional annotation and improved linkage to the NCBI BioSample database. The database is available at http://progenomes.embl.de/.


Assuntos
Bases de Dados Genéticas , Genoma Arqueal , Genoma Bacteriano , Genômica , Biologia Computacional/métodos , Ecossistema , Internet , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Células Procarióticas , Reprodutibilidade dos Testes , Software
20.
BMJ Open ; 9(11): e032617, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753895

RESUMO

INTRODUCTION: The healthy 'eubiosis' microbiome in infancy is regarded as the microbiome derived from term, vaginally delivered, antibiotic free, breastfed infants at 4-6 months. Dysbiosis is regarded as a deviation from a healthy state with reduced microbial diversity and deficient capacity to control drug-resistant organisms. Preterm infants are highly sensitive to early gut dysbiosis. Latter has been associated with sepsis and necrotising enterocolitis, but may also contribute to long-term health problems. Probiotics hold promise to reduce the risk for adverse short-term outcomes but the evidence from clinical trials remains inconclusive and none has directly assessed the effects of probiotics on the microbiome at high resolution. METHODS AND ANALYSIS: A randomised, double blind, placebo-controlled study has been designed to assess the safety and efficacy of the probiotic mix of Bifidobacterium longum and infantis and Lactobacillus acidophilus in the prevention of gut dysbiosis in preterm infants between 28+0 and 32+6 weeks of gestation. The study is conducted in 18 German neonatal intensive care units. Between April 2018 and March 2020, 654 preterm infants of 28+0-32+6 weeks of gestation will be randomised in the first 48 hours of life to 28 days of once daily treatment with either probiotics or placebo. The efficacy endpoint is the prevention of gut dysbiosis at day 30 of life. A compound definition of gut dysbosis is used: (1) colonisation with multidrug-resistant organisms or gram-negative bacteria with high epidemic potential or (2) a significant deviation of the gut microbiota composition as compared with healthy term infants. Dysbiosis is determined by (1) conventional microbiological culture and (2) phylogenetic microbiome analysis by high-throughput 16S rRNA and metagenome sequencing. Persistence of dysbiosis will be assessed at 12-month follow-up visits. Side effects and adverse events related to the intervention will be recorded. Key secondary endpoint(s) are putative consequences of dysbiosis. A subgroup of infants will be thoroughly phenotyped for immune parameters using chipcytometry. ETHICS AND DISSEMINATION: Ethics approval was obtained in all participating sites. Results of the trial will be published in peer-review journals, at scientific meetings, on the website (www.primal-study.de) and via social media of parent organisations. TRIAL REGISTRATION NUMBER: DRKS00013197; Pre-results.


Assuntos
Bifidobacterium longum subspecies infantis , Bifidobacterium longum , Disbiose/prevenção & controle , Recém-Nascido Prematuro , Lactobacillus acidophilus , Probióticos/administração & dosagem , Método Duplo-Cego , Enterocolite Necrosante/prevenção & controle , Fezes/microbiologia , Microbioma Gastrointestinal , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Estudos Multicêntricos como Assunto , RNA Ribossômico 16S/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Sepse/prevenção & controle
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