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Certain types of bacteria in the gut can leverage the immune system to decrease the severity of stroke, according to new research from Weill Cornell Medicine. This finding can help mitigate stroke -- which is the second leading cause of death worldwide. In the study, published March 28 in Nature Medicine, mice received a combination of antibiotics. Two weeks later, the researcher team -- which included collaborators at Memorial Sloan Kettering Cancer Center -- induced the most common type of stroke, called ischemic stroke, in which an obstructed blood vessel prevents blood from reaching the brain. Mice treated with antibiotics experienced a stroke that was about 60 percent smaller than rodents that did not receive the medication. The microbial environment in the gut directed the immune cells there to protect the brain, the investigators said, shielding it from the stroke's full force. "Our experiment shows a new relationship between the brain and the intestine," said Dr. Josef Anrather, the Finbar and Marianne Kenny Research Scholar in Neurology and an associate professor of neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. "The intestinal microbiota shape stroke outcome, which will impact how the medical community views stroke and defines stroke risk." The findings suggest that modifying the microbiotic makeup of the gut can become an innovative method to prevent stroke. This could be especially useful to high-risk patients, like those undergoing cardiac surgery or those who have multiple obstructed blood vessels in the brain. Further investigation is needed to understand exactly which bacterial components elicited their protective message. However, the researchers do know that the bacteria did not interact with the brain chemically, but rather influenced neural survival by modifying the behavior of immune cells. Immune cells from the gut made their way to the outer coverings of the brain, called the meninges, where they organized and directed a response to the stroke. "One of the most surprising findings was that the immune system made strokes smaller by orchestrating the response from outside the brain, like a conductor who doesn't play an instrument himself but instructs the others, which ultimately creates music," said Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine. The newfound connection between the gut and the brain holds promising implications for preventing stroke in the future, which the investigators say might be achieved by changing dietary habits in patients or "at risk" individuals. "Dietary intervention is much easier to accomplish than drug use, and it could reach a broad base," Dr. Anrather said. "This is a little far off from the current study -- it's music of the future. But diet has the biggest effect of composition of microbiota, and once beneficial and deleterious species are identified, we can address them with dietary intervention."

Yao Y.,Rockefeller University | Yao Y.,University of Minnesota | Norris E.H.,Rockefeller University | Mason C.E.,New York Medical College | And 4 more authors.
Nature Communications | Year: 2016

Muscle-resident PDGFRβ+ cells, which include pericytes and PW1 + interstitial cells (PICs), play a dual role in muscular dystrophy. They can either undergo myogenesis to promote muscle regeneration or differentiate into adipocytes and other cells to compromise regeneration. How the differentiation and fate determination of PDGFRβ+ cells are regulated, however, remains unclear. Here, by utilizing a conditional knockout mouse line, we report that PDGFRβ+ cell-derived laminin inhibits their proliferation and adipogenesis, but is indispensable for their myogenesis. In addition, we show that laminin alone is able to partially reverse the muscle dystrophic phenotype in these mice at the molecular, structural and functional levels. Further RNAseq analysis reveals that laminin regulates PDGFRβ+ cell differentiation/fate determination via gpihbp1. These data support a critical role of laminin in the regulation of PDGFRβ+ cell stemness, identify an innovative target for future drug development and may provide an effective treatment for muscular dystrophy. © 2016, Nature Publishing Group. All rights reserved.

Kamel H.,Feil Family Brain and Mind Research Institute | Hunter M.,York College | Moon Y.P.,York College | Yaghi S.,York College | And 8 more authors.
Stroke | Year: 2015

Background and Purpose-Electrocardiographic left atrial abnormality has been associated with stroke independently of atrial fibrillation (AF), suggesting that atrial thromboembolism may occur in the absence of AF. If true, we would expect an association with cryptogenic or cardioembolic stroke rather than noncardioembolic stroke. Methods-We conducted a case-cohort analysis in the Northern Manhattan Study, a prospective cohort study of stroke risk factors. P-wave terminal force in lead V1 was manually measured from baseline ECGs of participants in sinus rhythm who subsequently had ischemic stroke (n=241) and a randomly selected subcohort without stroke (n=798). Weighted Cox proportional hazard models were used to examine the association between P-wave terminal force in lead V1 and stroke etiologic subtypes while adjusting for baseline demographic characteristics, history of AF, heart failure, diabetes mellitus, hypertension, tobacco use, and lipid levels. Results-Mean P-wave terminal force in lead V1 was 4452 (±3368) μV∗ms among stroke cases and 3934 (±2541) μV∗ms in the subcohort. P-wave terminal force in lead V1 was associated with ischemic stroke (adjusted hazard ratio per SD, 1.20; 95% confidence interval, 1.03-1.39) and the composite of cryptogenic or cardioembolic stroke (adjusted hazard ratio per SD, 1.31; 95% confidence interval, 1.08-1.58). There was no definite association with noncardioembolic stroke subtypes (adjusted hazard ratio per SD, 1.14; 95% confidence interval, 0.92-1.40). Results were similar after excluding participants with a history of AF at baseline or new AF during follow-up. Conclusions-ECG-defined left atrial abnormality was associated with incident cryptogenic or cardioembolic stroke independently of the presence of AF, suggesting atrial thromboembolism may occur without recognized AF. © 2015 American Heart Association, Inc.

Li S.,New York Medical College | Labaj P.P.,University of Vienna | Zumbo P.,New York Medical College | Sykacek P.,University of Vienna | And 12 more authors.
Nature Biotechnology | Year: 2014

High-throughput RNA sequencing (RNA-seq) enables comprehensive scans of entire transcriptomes, but best practices for analyzing RNA-seq data have not been fully defined, particularly for data collected with multiple sequencing platforms or at multiple sites. Here we used standardized RNA samples with built-in controls to examine sources of error in large-scale RNA-seq studies and their impact on the detection of differentially expressed genes (DEGs). Analysis of variations in guanine-cytosine content, gene coverage, sequencing error rate and insert size allowed identification of decreased reproducibility across sites. Moreover, commonly used methods for normalization (cqn, EDASeq, RUV2, sva, PEER) varied in their ability to remove these systematic biases, depending on sample complexity and initial data quality. Normalization methods that combine data from genes across sites are strongly recommended to identify and remove site-specific effects and can substantially improve RNA-seq studies. © 2014 Nature America, Inc.

Afshinnekoo E.,New York Medical College | Afshinnekoo E.,Queens College, City University of New York | Meydan C.,New York Medical College | Chowdhury S.,New York Medical College | And 51 more authors.
Cell Systems | Year: 2015

Summary The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can match a station's history, such as marine-associated bacteria in a hurricane-flooded station. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of cities. © 2015 The Authors.

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