As one of the most clinically relevant human habitats, the human mouth is colonized by a set of microorganisms, including bacteria, archaea, fungi, and viruses. Increasing evidence has supported that these microbiota contribute to the two commonest oral diseases of man (dental caries and periodontal diseases), presenting significant risk factors to human health conditions, such as tumor, diabetes mellitus, cardiovascular diseases, bacteremia, preterm birth, and low birth weight in infants. It is widely accepted that oral microorganisms cause diseases mainly by a synergistic or cooperative way, and the interspecies interactions within the oral community play a crucial role in determining whether oral microbiota elicit diseases or not. Since a comprehensive understanding of the complex interspecies interactions within a community needs the knowledge of its endogenous residents, a plenty of research have been carried out to explore the oral microbial diversity. In this review, we focus on the recent progress in this field, including the oral microbiome composition and its association with human diseases.

Through long-term laboratory selection (over 200 generations), we have generated Drosophila melanogaster populations that tolerate severe, normally lethal, levels of hypoxia. Because of initial experiments suspecting genetic mechanisms underlying this adaptation, we compared the genomes of the hypoxia-selected flies with those of controls using deep resequencing. By applying unique computing and analytical methods we identified a number of DNA regions under selection, mostly on the X chromosome. Several of the hypoxia-selected regions contained genes encoding or regulating the Notch pathway. In addition, previous expression profiling revealed an activation of the Notch pathway in the hypoxia-selected flies. We confirmed the contribution of Notch activation to hypoxia tolerance using a specific γ-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), which significantly reduced adult survival and life span in the hypoxiaselected flies. We also demonstrated that flies with loss-of-function Notch mutations or RNAi-mediated Notch knockdown had a significant reduction in hypoxia tolerance, but those with a gain-of-function had a dramatic opposite effect. Using the UAS-Gal4 system, we also showed that specific overexpression of the Notch intracellular domain in glial cells was critical for conferring hypoxia tolerance. Unique analytical tools and genetic and bioinformatic strategies allowed us to discover that Notch activation plays a major role in this hypoxia tolerance in Drosophila melanogaster.evolution | next-generation sequencing O xygen homoeostasis is essential for development, growth, and integrity of cells, tissues, and organisms. Limited oxygen supply to cells and tissues (hypoxia) has a wide range of physiologic and potentially pathologic consequences, ranging from ischemic/hypoxic heart disease, stroke, and pulmonary hypertension to a number of obstetrical/perinatal complications, to high-altitude illnesses, to organ transplantation, and finally to intratumor hypoxia and cancer progression. Despite the clinical importance and societal disease impact of such a wide range of disorders, the molecular underpinnings of susceptibility or tolerance of cells or tissues to lack of O 2 are not well understood. Many studies have investigated the mechanisms that lead to injury when cells are deprived of O 2 , but to potentially treat or prevent the consequences of hypoxia necessitates also the understanding of the inherent tissue mechanisms that are critical for tolerance and survival. To do so, we use a long-term laboratory selection strategy that unmasks mechanisms that play an important role in hypoxia tolerance in a genetic model, Drosophila melanogaster (1, 2). In this attempt, starting with 27 isofemale D. melanogaster strains, and applying decreasing levels of O 2 over >200 generations, we generated Drosophila populations that tolerate severe levels of hypoxia, which are lethal to the original parental lines. These hypoxia-adapted flies (AF) pass the tolerance trait ...

Hypoxia-induced cell injury has been related to multiple pathological conditions. In order to render hypoxia-sensitive cells and tissues resistant to low O2 environment, in this current study, we used Drosophila melanogaster as a model to dissect the mechanisms underlying hypoxia-tolerance. A D. melanogaster strain that lives perpetually in an extremely low-oxygen environment (4% O2, an oxygen level that is equivalent to that over about 4,000 m above Mt. Everest) was generated through laboratory selection pressure using a continuing reduction of O2 over many generations. This phenotype is genetically stable since selected flies, after several generations in room air, survive at this low O2 level. Gene expression profiling showed striking differences between tolerant and naïve flies, in larvae and adults, both quantitatively and qualitatively. Up-regulated genes in the tolerant flies included signal transduction pathways (e.g., Notch and Toll/Imd pathways), but metabolic genes were remarkably down-regulated in the larvae. Furthermore, a different allelic frequency and enzymatic activity of the triose phosphate isomerase (TPI) was present in the tolerant versus naïve flies. The transcriptional suppressor, hairy, was up-regulated in the microarrays and its binding elements were present in the regulatory region of the specifically down-regulated metabolic genes but not others, and mutations in hairy significantly reduced hypoxia tolerance. We conclude that, the hypoxia-selected flies: (a) altered their gene expression and genetic code, and (b) coordinated their metabolic suppression, especially during development, with hairy acting as a metabolic switch, thus playing a crucial role in hypoxia-tolerance.

The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment.