Biology subjects

Cummings, D.

Publications and source records attributed to Cummings, D..

6 recordsLinked to original sources

bioRxiv2026

Comparison of lumbar paraspinal muscle size and density between members of the US Framingham Heart Study and Tsimane forager-horticulturalists of Bolivia

Paraspinal muscles support and move the spine, and reduced size and density of these muscles is associated with increased risk of vertebral fracture and back pain. We test the hypothesis that subsistence-oriented forager-horticulturalists (Bolivian Tsimane) have larger and denser paraspinal muscles, and smaller age-related differences in paraspinal muscle size and density, than more sedentary post-industrialized suburbanites (Framingham Heart Study [FHS]). We measured cross-sectional area (CSA) and density of trunk extensors and psoas major at L3 from computed tomography scans of 411 FHS and 330 Tsimane (50% women, aged 50-90 years). Sex-stratified linear regressions determined associations of muscle CSA and density with age and cohort (Tsimane or FHS [ref.]), with and without an age-cohort interaction term. Covariates were height and weight. After adjusting for covariates, Tsimane women had 11-14% larger and denser extensors, and 17-26% smaller and less-dense psoas major, than FHS women. Tsimane men had 8-21% smaller and less-dense psoas major than FHS men. The age-related difference in extensors density was 41% smaller for Tsimane men than for FHS men. There were no other significant age-related cohort differences in muscle CSA or density. We observed a different balance in the size and density of trunk extensors versus psoas major between Tsimane and FHS. A possible explanation for this observation is cohort differences in the amount and types of physical activity, although future work is required to determine the influence of lifestyle and environmental factors on paraspinal muscle size and density.

evolutionary biology↗

bioRxiv2024

Boosting of CAR-T cells with rhabdovirus is limited by type I interferon and rapid contraction

Rhabdovirus vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing rhabdovirus vaccines to boost adoptively transferred T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and a personalized vaccine, which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vesicular stomatitis virus (VSV) vaccine encoding the CAR-target. Boosting CAR-engineered tumour-specific T cells with paired VSV vaccines was associated with robust T cell expansion and delayed tumour progression in syngeneic models. CAR-T cell expansion and anti-tumour function was enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with VSV encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells to achieve long-term tumour control.

immunology↗

bioRxiv2021

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population

In post-industrial settings, APOE4 is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing baseline innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N=1266), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized-LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized-LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low BMIs. These results suggest the relationship between APOE4 and lipids is likely beneficial for pathogen-driven immune responses, and unlikely to increase cardiovascular risk in an active subsistence population.

evolutionary biology↗

bioRxiv2018

Complement 3 signaling is necessary for the developmental refinement of olfactory bulb circuitry

The olfactory system depends upon organizational maps that are developmentally refined and maintained, however the cellular and molecular mechanisms that underlie these processes are unknown. Studies have shown that microglia and complement molecules are important for the developmental refinement of circuitry within the visual system, thus we asked whether they played a similar role in the olfactory system through the formation of the olfactory bulb (OB) maps, the glomerular and intrabulbar maps. Our findings revealed that microglia in mature animals engulf olfactory sensory neuron (OSN) axons and the synaptic terminals of tufted cells in the glomerular and intrabulbar maps respectively, suggesting microglia could anatomically shape the mature OB circuitry. To determine the mechanisms underlying this axonal pruning activity we used complement 3 (C3) and complement receptor 3 (CR3) knockout mice to investigate if C3 signaling was necessary for precise OB map development. Our results demonstrate that glomerular and intrabulbar map disorganization as typically present in early postnatal mice persists into adulthood when C3 signaling is disrupted. These data clearly establish the C3/CR3 pathway as necessary for the proper developmental refinement of both olfactory maps. We further present the olfactory system as a unique platform to study the role of glia in the development and adult refinement of regenerating circuits.

neuroscience↗

bioRxiv2017

Preliminary results of models to predict areas in the Americas with increased likelihood of Zika virus transmission in 2017.

Numerous Zika virus vaccines are being developed. However, identifying sites to evaluate the efficacy of a Zika virus vaccine is challenging due to the general decrease in Zika virus activity. We compare results from three different modeling approaches to estimate areas that may have increased relative risk of Zika virus transmission during 2017. The analysis focused on eight priority countries (i.e., Brazil, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Panama, and Peru). The models projected low incidence rates during 2017 for all locations in the priority countries but identified several subnational areas that may have increased relative risk of Zika virus transmission in 2017. Given the projected low incidence of disease, the total number of participants, number of study sites, or duration of study follow-up may need to be increased to meet the efficacy study endpoints.

epidemiology↗

bioRxiv2017

Timescales of influenza A/H3N2 antibody dynamics

Human immunity influences the evolution and impact of novel influenza strains. Because individuals are infected with multiple influenza strains during their lifetime and each virus can generate a cross-reactive antibody response, it is challenging to quantify the processes that shape observed immune responses, or to reliably detect recent infection from serological samples. Using a Bayesian model of antibody dynamics at multiple timescales, we explain complex cross-reactive antibody landscapes by inferring participants histories of infection with serological data from cross-sectional and longitudinal studies of influenza A/H3N2 in southern China and Vietnam. We show an individuals influenza antibody profile can be explained by a short-lived, broadly cross-reactive response that decays within a year to leave a smaller long-term response acting against a narrower range of strains. We also demonstrate that accounting for dynamic immune responses can provide a more accurate alternative to traditional definitions seroconversion for the estimation of infection attack rates. Our work provides a general model for explaining mechanisms of influenza immunity acting at multiple timescales based on contemporary serological data, and suggests a two-armed immune response to influenza infection consistent with competitive dynamics between B cell populations. This approach to analysing multiple timescales for antigenic responses could also be applied to other multi-strain pathogens such as dengue and related flaviviruses.

epidemiology↗