University of Tennessee Health Science Center

About: University of Tennessee Health Science Center is a education organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 15716 authors who have published 26884 publications receiving 1176697 citations.

Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

Abstract: Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans-expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.

Risk of Fracture in Women with Type 2 Diabetes: the Women’s Health Initiative Observational Study

Abstract: Context: Some but not all studies have shown higher rates of fracture in individuals with type 2 diabetes. Objective: The objective of the study was to determine the risk of fracture in postmenopausal women with type 2 diabetes and determine whether risk varies by fracture site, ethnicity, and baseline bone density. Design, Setting, and Participants: Women with clinically diagnosed type 2 diabetes at baseline in the Women’s Health Initiative Observational Cohort, a prospective study of postmenopausal women (n = 93,676), were compared with women without diagnosed diabetes and risk of fracture overall and at specific sites determined. Main Outcome Measures: All fractures and specific sites separately (hip/pelvis/upper leg; lower leg/ankle/knee; foot; upper arm/shoulder/elbow; lower arm/wrist/hand; spine/tailbone) were measured. Bone mineral density (BMD) in a subset also was measured. Results: The overall risk of fracture after 7 yr of follow-up was higher in women with diabetes at baseline after controllin...

Azole antifungal resistance in Candida albicans and emerging non-albicans Candida Species

Abstract: Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species.

Phylogeny and Divergence-Date Estimates of Rapid Radiations in Muroid Rodents Based on Multiple Nuclear Genes

Abstract: The muroid rodents are the largest superfamily of mammals, containing nearly one third of all mammal species. We report on a phylogenetic study comprising 53 genera sequenced for four nuclear genes, GHR, BRCA1, RAG1, and c-myc, totaling up to 6400 nucleotides. Most relationships among the subfamilies are resolved. All four genes yield nearly identical phylogenies, differing only in five key regions, four of which may represent particularly rapid radiations. Support is very strong for a fundamental division of the mole rats of the subfamilies Spalacinae and Rhizomyinae from all other muroids. Among the other "core" muroids, a rapid radiation led to at least four distinct lineages: Asian Calomyscus ,a nAfrican clade of at least four endemic subfamilies, including the diverse Nesomyinae of Madagascar, a hamster clade with maximum diversity in the New World, and an Old World clade including gerbils and the diverse Old World mice and rats (Murinae). The Deomyinae, recently removed from the Murinae, is well supported as the sister group to the gerbils (Gerbillinae). Four key regions appear to represent rapid radiations and, despite a large amount of sequence data, remain poorly resolved: the base of the "core" muroids, among the five cricetid (hamster) subfamilies, within a large clade of Sigmodontinae endemic to South America, and among major geographic lineages of Old World Murinae. Because of the detailed taxon sampling within the Murinae, we are able to refine the fossil calibration of a rate-smoothed molecular clock and apply this clock to date key events in muroid evolution. We calculate rate differences among the gene regions and relate those differences to relative contribution of each gene to the support for various nodes. The among-gene variance in support is greatest for the shortest branches. We present a revised classification for this largest but most unsettled mammalian superfamily. (Adaptive radiation; calibration; classification; molecular clock; Murinae; Sigmodontinae.)

Added value of physical performance measures in predicting adverse health-related events: results from the Health, Aging And Body Composition Study.

Abstract: OBJECTIVES: To determine how three different physical performance measures (PPMs) combine for added utility in predicting adverse health events in elders. DESIGN: Prospective cohort study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Three thousand twenty-four well-functioning older persons (mean age 73.6). MEASUREMENTS: Timed gait, repeated chair stands, and balance (semi- and full-tandem, and single leg stands each held for 30 seconds) tests were administered at baseline. Usual gait speed was categorized to distinguish high- and low-risk participants using the previously established 1-m/s cutpoint. The same population-percentile (21.3%) was used to identify cutpoints for the repeated chair stands (17.1 seconds) and balance (53.0 seconds) tests. Cox proportional hazard analyses were performed to evaluate the added value of PPMs in predicting mortality, hospitalization, and (severe) mobility limitation events over 6.9 years of follow-up. RESULTS: Risk estimates for developing adverse health-related events were similarly large for each of the three high-risk groups considered separately. Having more PPM scores at the high-risk level was associated with a greater risk of developing adverse health-related events. When all three PPMs were considered, having only one poor performance was sufficient to indicate a highly significantly higher risk of (severe) lower extremity and mortality events. CONCLUSION: Although gait speed is considered to be the most important predictor of adverse health events, these findings demonstrate that poor performance on other tests of lower extremity function are equally prognostic. This suggests that chair stand and standing balance performance may be adequate substitutes when gait speed is unavailable.