Gut microbiota composition in Himalayan and Andean populations and its relationship with diet, lifestyle and adaptation to the high-altitude environment.

Human populations living at high altitude evolved a number of biological adjustments to cope with a challenging environment characterised especially by reduced oxygen availability and limited nutritional resources. This condition may also affect their gut microbiota composition. Here, we explored the impact of exposure to such selective pressures on human gut microbiota by considering different ethnic groups living at variable degrees of altitude: the high-altitude Sherpa and low-altitude Tamang populations from Nepal, the high-altitude Aymara population from Bolivia, as well as a low-altitude cohort of European ancestry, used as control. We thus observed microbial profiles common to the Sherpa and Aymara, but absent in the low-altitude cohorts, which may contribute to the achievement of adaptation to high-altitude lifestyle and nutritional conditions. The collected evidences suggest that microbial signatures associated to these rural populations may enhance metabolic functions able to supply essential compounds useful for the host to cope with high altitude-related physiological changes and energy demand. Therefore, these results add another valuable piece of the puzzle to the understanding of the beneficial effects of symbiosis between microbes and their human host even from an evolutionary perspective.

Evidence of Polygenic Adaptation to High Altitude from Tibetan and Sherpa Genomes.

Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high-altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole-genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude.

Percutaneous coronary injection of bone marrow cells in small experimental animals: small is not too small.

Intracoronary infusion of bone marrow cells (BMCs) is thought to induce cardiac regeneration in ischemic heart disease and dilated cardiomyopathy. The aim of our study was to develop a new method to inject BMCs into coronary arteries of small experimental animals. Transient atrioventricular block (AVB) was induced in 25 rats and 39 hamsters by intracarotid injection of adenosine 5'-triphosphate (ATP). Contrast echocardiography was obtained. BMCs (0.2-0.5 ml) were collected through femoral puncture, stained with PKH26 and injected into the carotid artery (CA). Animals were immediately sacrificed or followed for 1 month. To evaluate BMCs transfer from CA to myocardium, AVB and BMCs injections were performed in 10 hamsters subjected to coronary ligation for 30 min. Induction of transient AVB was possible in all animals by injecting 20-30 mg of ATP. Animals recovered a basal cardiac activity spontaneously or by dopamine injection. Flash injection of contrast medium through the CA induced staining of aortic root, coronary arteries, and myocardium. BMCs injection was possible in all cases. No immediate or late ECG changes were observed. Immediately after injection in healthy animals, histological examination showed the presence of BMCs in small coronary arteries and, after 1 month, the absence of infarction. In ischemic hearts, the presence of BMCs in the myocardium was observed 24h after ischemia. ATP-induced AVB block allows for percutaneous intracoronary injection of BMCs in small experimental animals with no immediate or late mortality and morbidity. This method offers new perspectives for the investigation of BMCs coronary infusion and engraftment in heart diseases.

The genomic landscape of Nepalese Tibeto-Burmans reveals new insights into the recent peopling of Southern Himalayas.

While much research attention has focused on demographic processes that enabled human diffusion on the Tibetan plateau, little is known about more recent colonization of Southern Himalayas. In particular, the history of migrations, admixture and/or isolation of populations speaking Tibeto-Burman languages, which is supposed to be quite complex and to have reshaped patterns of genetic variation on both sides of the Himalayan arc, remains only partially elucidated. We thus described the genomic landscape of previously unsurveyed Tibeto-Burman (i.e. Sherpa and Tamang) and Indo-Aryan communities from remote Nepalese valleys. Exploration of their genomic relationships with South/East Asian populations provided evidence for Tibetan admixture with low-altitude East Asians and for Sherpa isolation. We also showed that the other Southern Himalayan Tibeto-Burmans derived East Asian ancestry not from the Tibetan/Sherpa lineage, but from low-altitude ancestors who migrated from China plausibly across Northern India/Myanmar, having experienced extensive admixture that reshuffled the ancestral Tibeto-Burman gene pool. These findings improved the understanding of the impact of gene flow/drift on the evolution of high-altitude Himalayan peoples and shed light on migration events that drove colonization of the southern Himalayan slopes, as well as on the role played by different Tibeto-Burman groups in such a complex demographic scenario.

Experimental ischemic cardiomyopathy: insights into remodeling, physiological adaptation, and humoral response.

Ligation of the left anterior descending coronary artery (LAD) is used to induce experimental myocardial infarction (MI). Most previous studies have focused on the early postoperative period, while data on mid-term follow-up are scanty. This study examined the mid-term effects of LAD ligation in 95 MI rats and 28 controls. The following parameters were evaluated: systemic blood pressure (SBP), heart rate (HR), and plasma brain natriuretic peptide (BNP) level. In addition, M-mode and B-mode echocardiography, histologic examinations, and cardiac hydroxyproline assays were performed. Forty-seven perioperative and 5 late deaths were recorded. Left ventricular dilation, observed 1 mo after MI, did not progress with time. Septal thickening was similar in the 2 groups, while wall thickening was lower in the MI rats at 1 mo only. Stroke volume was diminished in MI rats, while cardiac output was depressed only at 1 and 2 mo, due to increased heart rate. SBP was unchanged and plasma BNP level was similar in the 2 groups. The infarcted area (mean +/- SD) was 35 +/- 10%. The ventricles in MI rats were heavier and had increased hydroxyproline content. In conclusion, these data show that LAD ligation is not only a model of acute MI, but at mid-term it provides a model of chronic ischemic dilated cardiomyopathy.

Echocardiographic assessment of 537 dogs with mitral valve prolapse and leaflet involvement.

In this work we investigated which mitral valve leaflet was most often involved in mitral valve prolapse with degenerative mitral valve disease and whether there was an association with breed, age, gender, or weight. Five hundred and thirty-seven dogs with mitral valve prolapse-degenerative mitral valve disease were assessed; the cross-breed dog was the most represented breed (248 dogs, 46.2%). Mitral valve prolapse was more common in male dogs, and the average age was 11.3 +/- 2.8 years. Prolapse of the anterior leaflet was present in 48.4% of dogs, prolapse of the the posterior leaflet in 7.1%, and bileaflet prolapse was present in 44.5%; this distribution is different than that typically found in humans. There was a significant correlation between severity of mitral regurgitation and severity of mitral valve prolapse or ISACHC class, and between severity of mitral valve prolapse and ISACHC class. There was no relationship between the particular affected leaflet(s) and severity of mitral regurgitation, severity of mitral valve prolapse, or ISACHC class. Our findings suggest that the susceptibility to the mitral valve prolapse-degenerative mitral valve disease is not confined to a specific breeds and that the specific leaflet prolapsing is different in dogs compared with humans.

Amniotic membrane patching promotes ischemic rat heart repair.

The amniotic membrane has long been applied for wound healing and treatment of ophthalmological disorders, even though the mechanisms underlying its actions remain to be clarified. Recently, cells derived from fetal membranes of human term placenta have raised strong interest in regenerative medicine for their stem cell potential and immunomodulatory features. Our study aimed to investigate the possible utility of amniotic membrane to limit postischemic cardiac injury. A fragment of human amniotic membrane was applied onto the left ventricle of rats that had undergone ischemia through left anterior descending coronary artery ligation. Echocardiographic assessment of morphological and functional cardiac parameters was then performed over a 3-month period. We demonstrated that application of an amniotic membrane fragment onto ischemic rat hearts could significantly reduce postischemic cardiac dysfunction. The amniotic membrane-treated rats showed higher preservation of cardiac dimensions and improved cardiac contractile function in terms of higher left ventricle ejection fraction, fractional shortening, and wall thickening. These improvements were apparent by day 7 after application of the amniotic membrane, persisted for at least 2 months, and occurred independently of cardiac injury severity. No engraftment of amniotic cells was detected into host cardiac tissues. Our results suggest that use of amniotic membrane may constitute a convenient vehicle for supplying cells that produce cardioprotective soluble factors, and reinforce the notion that this tissue constitutes a cell source with clinical potential that has yet to be completely revealed.