Age-associated dementia among older people aging with HIV in the United States: a modeling study.

OBJECTIVE: Almost 400 000 people with HIV (PWH) in the United States are over age 55 years and at risk for age-associated dementias (AAD), including Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID). We projected the cumulative incidence and mortality associated with AAD among PWH at least 60 years in the United States compared with the general population. DESIGN/METHODS: Integrating the CEPAC and AgeD-Pol models, we simulated two cohorts of 60-year-old male and female individuals: PWH, and the general US population. We estimated AAD incidence and AAD-associated mortality rates. Projected outcomes included AAD cumulative incidence, life expectancy, and quality-adjusted life-years (QALYs). We performed sensitivity and scenario analyses on AAD-specific (e.g. incidence) and HIV-specific (e.g. disengagement from HIV care) parameters, as well as premature aging among PWH. RESULTS: We projected that 22.1%/16.3% of 60-year-old male individuals/female individuals with HIV would develop AAD by 80 years compared with 15.9%/13.3% of male individuals/female individuals in the general population. Accounting for age-associated and dementia-associated quality of life, 60-year-old PWH would have a lower life expectancy (QALYs): 17.4 years (14.1 QALYs) and 16.8 years (13.4 QALYs) for male and female individuals, respectively, compared with the general population [male individuals, 21.7 years (18.4 QALYs); female individuals, 24.7 years (20.2 QALYs)]. AAD cumulative incidence was most sensitive to non-HIV-related mortality, engagement in HIV care, and AAD incidence rates. CONCLUSION: Projected estimates of AAD-associated morbidity, mortality, and quality of life can inform decision-makers and health systems planning as the population of PWH ages. Improved AAD prevention, treatment, and supportive care planning are critical for people aging with HIV.

Genomics analysis of Drosophila sechellia response to Morinda citrifolia fruit diet.

Drosophila sechellia is an island endemic host specialist that has evolved to consume the toxic fruit of Morinda citrifolia, also known as noni fruit. Recent studies by our group and others have examined genome-wide gene expression responses of fruit flies to individual highly abundant compounds found in noni responsible for the fruit's unique chemistry and toxicity. In order to relate these reductionist experiments to the gene expression responses to feeding on noni fruit itself, we fed rotten noni fruit to adult female D. sechellia and performed RNA-sequencing. Combining the reductionist and more wholistic approaches, we have identified candidate genes that may contribute to each individual compound and those that play a more general role in response to the fruit as a whole. Using the compound specific and general responses, we used transcription factor prediction analyses to identify the regulatory networks and specific regulators involved in the responses to each compound and the fruit itself. The identified genes and regulators represent the possible genetic mechanisms and biochemical pathways that contribute to toxin resistance and noni specialization in D. sechellia.

MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome-like Behaviors in Mice.

BACKGROUND: Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development. METHODS: Multiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS. RESULTS: We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior. CONCLUSIONS: Taken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding-deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.