Murphy, J. T. | Search bioRxiv

bioRxiv2026

Impaired proteostasis is an early feature of the diabetic heart in humans and mice

Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.

molecular biology↗

bioRxiv2017

Agent-based network model predicts strong benefits to youth-centered HIV treatment-as-prevention efforts

We used an agent-based network model to examine the effect of targeting different risk groups with unsuppressed HIV viral load for linkage or re-linkage to HIV-related treatment services in a heterosexual population with annual testing. Our model identifies prevention strategies that can reduce incidence to negligible levels (i.e., less than 0.1 infections per 100 person-years) 20 years after a targeted Treatment-as-Prevention (TasP) campaign. The model assumes that most (default 95%) of the population is reachable (i.e., could, in principle, be linked to effective care) and a modest (default 5% per year) probability of a treated person dropping out of care. Under random allocation or CD4-based targeting, the default version of our model predicts that the TasP campaign would need to suppress viral replication in ~80% of infected people to halt the epidemic. Under age-based strategies, by contrast, this percentage drops to 50% to 60% (for strategies targeting those <30 and <25, respectively). Age-based targeting did not need to be highly exclusive to yield significant benefits; e.g. the scenario that targeted those <25 years old saw ~80% of suppressed individuals fall outside the target group. This advantage to youth-based targeting remained in sensitivity analyses in which key age-related risk factors were eliminated one by one. As testing rates increase in response to UNAIDS 90-90-90 goals, we suggest that efforts to link all young people to effective care could be an effective long-term method for ending the HIV epidemic. Linking greater numbers of young people to effective care will be critical for developing countries in which a demographic \"youth bulge\" is starting to increase the number of young people at risk for HIV infection.

epidemiology↗