CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

Flipping the Classroom in Otolaryngology Residencies.

Objective To understand the use of the flipped classroom (FC) - learning core content prior to an academic session, with class time devoted to applying this content - in otolaryngology residency education. Methods An electronic survey of 107 otolaryngology program directors (PDs), including demographic details, the flipped classroom perception instrument (FCPI), and the otolaryngology programs' current use of FC. Results Forty-four (41%) PDs completed the FCPI. Seventy-one point one (71.1%) of respondents were male, 60% were 30-49 years, and the remainder were older. Sixty-two percent (62%) had fellowships associated with their program, 21.7% of programs used the FC model Very Often, 17.4% Somewhat Often, 28.3% Sometimes, 17.4% Somewhat Rarely, 8.7% Very Rarely, and 6.5% Never. Attitudes toward FC principles were positive with modes "strongly agree" for all, except for "online modules enhance learning" where the mode was "slightly agree" with significantly higher scores for PDs over age 50 than for those younger (4.17 vs. 3.63, p=0.033). There were no other significant differences comparing male vs. female PDs, younger vs. older PDs, smaller vs. larger programs, programs with or without fellowships, programs with 100% vs. <100% board exam pass rates, or programs in different geographical regions. The pre-class activity mean score was 4.34 (95% CI 4.12-4.56) and the in-class mean score was 4.18 (95% CI 3.99-4.37). There was no significant correlation between the likelihood of using a flipped classroom and attitude scores. Conclusion PDs value both the pre-class and interactive in-class principles of FCs but only 37.8% of programs use FC often, suggesting that practical approaches to implementation in this group could improve education in this population.

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene.

Breast cancer patients presenting with symptomatic brain metastases have poor prognosis, and current chemotherapeutic agents are largely ineffective. In this study, we evaluated the hypomethylating agent azacitidine (AZA) for its potential as a novel therapeutic in preclinical models of brain metastasis of breast cancer. We used the parental triple-negative breast cancer MDA-MB-231 (231) cells and their brain colonizing counterpart (231Br) to ascertain phenotypic differences in response to AZA. We observed that 231Br cells have higher metastatic potential compared to 231 cells. With regard to therapeutic value, the AZA IC50 value in 231Br cells is significantly lower than that in parental cells (P < .01). AZA treatment increased apoptosis and inhibited the Wnt signaling transduction pathway, angiogenesis, and cell metastatic capacity to a significantly higher extent in the 231Br line. AZA treatment in mice with experimental brain metastases significantly reduced tumor burden (P = .0112) and increased survival (P = .0026) compared to vehicle. Lastly, we observed a decreased expression of keratin 18 (an epithelial maker) in 231Br cells due to hypermethylation, elucidating a potential mechanism of action of AZA in treating brain metastases from breast cancer.

eHealth Literacy in Otolaryngology Patients.

OBJECTIVES: The aim of this study was to compare eHealth literacy-one's perception of one's ability to use the Internet for health care-among otolaryngology patients in 3 geographic settings of the same department. SETTING: An academic otolaryngology department. METHOD: Patients' opinions and perceptions of their eHealth literacy were assessed with a validated paper survey administered in the summer of 2017. RESULTS: Of 381 asked, 351 people completed the survey, 149 at a university town teaching hospital clinic (group A), 101 at a nearby rural clinic (group B), and 101 at a remote rural clinic (group C). Mean scores were 30.80, 28.97, and 29.03 for groups A, B, and C, respectively. The overall mean was 29.76 ± 5.97. Three surveys reported the minimum score of 8, and 26 reported the maximum score of 40. Results were statistically significantly different among all sites (P = .001), between groups A and B (P = .027), and between groups A and C (P = .0175). Women reported higher eHealth literacy (30.13 ± 6.27) than men (28.87 ± 5.11) (P = .045). Participant age and role (patient or parent of a patient) were statistically insignificant. Mean scores were similar to those previously reported in other patient populations. CONCLUSIONS: Otolaryngology patients in a university town had better eHealth literacy than patients in more rural settings, suggesting that online medical resources and access points are less likely to be useful in rural populations.

In Vivo Evaluation of the Visual Pathway in Streptozotocin-Induced Diabetes by Diffusion Tensor MRI and Contrast Enhanced MRI.

Visual function has been shown to deteriorate prior to the onset of retinopathy in some diabetic patients and experimental animal models. This suggests the involvement of the brain's visual system in the early stages of diabetes. In this study, we tested this hypothesis by examining the integrity of the visual pathway in a diabetic rat model using in vivo multi-modal magnetic resonance imaging (MRI). Ten-week-old Sprague-Dawley rats were divided into an experimental diabetic group by intraperitoneal injection of 65 mg/kg streptozotocin in 0.01 M citric acid, and a sham control group by intraperitoneal injection of citric acid only. One month later, diffusion tensor MRI (DTI) was performed to examine the white matter integrity in the brain, followed by chromium-enhanced MRI of retinal integrity and manganese-enhanced MRI of anterograde manganese transport along the visual pathway. Prior to MRI experiments, the streptozotocin-induced diabetic rats showed significantly smaller weight gain and higher blood glucose level than the control rats. DTI revealed significantly lower fractional anisotropy and higher radial diffusivity in the prechiasmatic optic nerve of the diabetic rats compared to the control rats. No apparent difference was observed in the axial diffusivity of the optic nerve, the chromium enhancement in the retina, or the manganese enhancement in the lateral geniculate nucleus and superior colliculus between groups. Our results suggest that streptozotocin-induced diabetes leads to early injury in the optic nerve when no substantial change in retinal integrity or anterograde transport along the visual pathways was observed in MRI using contrast agent enhancement. DTI may be a useful tool for detecting and monitoring early pathophysiological changes in the visual system of experimental diabetes non-invasively.

Fibroblasts From Longer-Lived Species of Primates, Rodents, Bats, Carnivores, and Birds Resist Protein Damage.

Species differ greatly in their rates of aging. Among mammalian species life span ranges from 2 to over 60 years. Here, we test the hypothesis that skin-derived fibroblasts from long-lived species of animals differ from those of short-lived animals in their defenses against protein damage. In parallel studies of rodents, nonhuman primates, birds, and species from the Laurasiatheria superorder (bats, carnivores, shrews, and ungulates), we find associations between species longevity and resistance of proteins to oxidative stress after exposure to H(2)O(2) or paraquat. In addition, baseline levels of protein carbonyl appear to be higher in cells from shorter-lived mammals compared with longer-lived mammals. Thus, resistance to protein oxidation is associated with species maximal life span in independent clades of mammals, suggesting that this cellular property may be required for evolution of longevity. Evaluation of the properties of primary fibroblast cell lines can provide insights into the factors that regulate the pace of aging across species of mammals.