The Public Health Exposome: A Population-Based, Exposure Science Approach to Health Disparities Research

The lack of progress in reducing health disparities suggests that new approaches are needed if we are to achieve meaningful, equitable, and lasting reductions. Current scientific paradigms do not adequately capture the complexity of the relationships between environment, personal health and population level disparities. The public health exposome is presented as a universal exposure tracking framework for integrating complex relationships between exogenous and endogenous exposures across the lifespan from conception to death. It uses a social-ecological framework that builds on the exposome paradigm for conceptualizing how exogenous exposures “get under the skin”. The public health exposome approach has led our team to develop a taxonomy and bioinformatics infrastructure to integrate health outcomes data with thousands of sources of exogenous exposure, organized in four broad domains: natural, built, social, and policy environments. With the input of a transdisciplinary team, we have borrowed and applied the methods, tools and terms from various disciplines to measure the effects of environmental exposures on personal and population health outcomes and disparities, many of which may not manifest until many years later. As is customary with a paradigm shift, this approach has far reaching implications for research methods and design, analytics, community engagement strategies, and research training

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

Mastermind Mutations Generate a Unique Constellation of Midline Cells within the Drosophila CNS

Background: The Notch pathway functions repeatedly during the development of the central nervous system in metazoan organisms to control cell fate and regulate cell proliferation and asymmetric cell divisions. Within the Drosophila midline cell lineage, which bisects the two symmetrical halves of the central nervous system, Notch is required for initial cell specification and subsequent differentiation of many midline lineages. Methodology/Principal Findings: Here, we provide the first description of the role of the Notch co-factor, mastermind, in the central nervous system midline of Drosophila. Overall, zygotic mastermind mutations cause an increase in midline cell number and decrease in midline cell diversity. Compared to mutations in other components of the Notch signaling pathway, such as Notch itself and Delta, zygotic mutations in mastermind cause the production of a unique constellation of midline cell types. The major difference is that midline glia form normally in zygotic mastermind mutants, but not in Notch and Delta mutants. Moreover, during late embryogenesis, extra anterior midline glia survive in zygotic mastermind mutants compared to wild type embryos. Conclusions/Significance: This is an example of a mutation in a signaling pathway cofactor producing a distinct centra

Chaperone-Mediated In Vitro Disassembly of Polyoma- and Papillomaviruses

Hsp70 chaperones play a role in polyoma- and papillomavirus assembly, as evidenced by their interaction in vivo with polyomavirus capsid proteins at late times after virus infection and by their ability to assemble viral capsomeres into capsids in vitro. We studied whether Hsp70 chaperones might also participate in the uncoating reaction. In vivo, Hsp70 coimmunoprecipitated with polyomavirus virion VP1 at 3 h after infection of mouse cells. In vitro, prokaryotic and eukaryotic Hsp70 chaperones efficiently disassembled polyoma- and papillomavirus-like particles and virions in energy-dependent reactions. These observations support a role for cell chaperones in the disassembly of these viruses

Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis

SUMMARY Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by complex neuronal and glial phenotypes. Recently, RNA-based mechanisms have been linked to ALS via RNA-binding proteins such as TDP-43, which has been studied in vivo using models ranging from yeast to rodents. We have developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of pathology, including motor neuron loss, locomotor dysfunction and reduced survival. Here we report the phenotypic consequences of expressing wild-type and four different ALS-linked TDP-43 mutations in neurons and glia. We show that TDP-43-driven neurodegeneration phenotypes are dose- and age-dependent. In motor neurons, TDP-43 appears restricted to nuclei, which are significantly misshapen due to mutant but not wild-type protein expression. In glia and in the developing neuroepithelium, TDP-43 associates with cytoplasmic puncta. TDP-43-containing RNA granules are motile in cultured motor neurons, although wild-type and mutant variants exhibit different kinetic properties. At the neuromuscular junction, the expression of TDP-43 in motor neurons versus glia leads to seemingly opposite synaptic phenotypes that, surprisingly, translate into comparable locomotor defects. Finally, we explore sleep as a behavioral readout of TDP-43 expression and find evidence of sleep fragmentation consistent with hyperexcitability, a suggested mechanism in ALS. These findings support the notion that although motor neurons and glia are both involved in ALS pathology, at the cellular level they can exhibit different responses to TDP-43. In addition, our data suggest that individual TDP-43 alleles utilize distinct molecular mechanisms, which will be important for developing therapeutic strategies

Specificity of the Receptor for the Major Sex Pheromone Component in Heliothis virescens

In a previous study, the Drosophila melanogaster OR67d(GAL4);UAS system was used to functionally characterize the receptor for the major component of the sex pheromone in the tobacco budworm, Heliothis virescens Fabricius (Lepidoptera: Noctuidae), HvOR13. Electrophysiological and behavioral assays showed that transgenic flies expressing HvOR13 responded to (Z)-11-hexadecenal (Z11-16:Ald). However, tests were not performed to determine whether these flies would also respond to secondary components of the H. virescens sex pheromone. Thus, in this study the response spectrum of HvOR13 expressed in this system was examined by performing single cell recordings from odor receptor neuron in trichoid T1 sensilla on antennae of two Or67d(GAL4 [1]); UAS-HvOR13 lines stimulated with Z11-16:Ald and six H. virescens secondary pheromone components. Fly courtship assays were also performed to examine the behavioral response of the Or67d(GAL4[1]); UAS-HvOR13 flies to Z11-16:Ald and the secondary component Z9-14:Ald. Our combined electrophysiological and behavioral studies indicated high specificity and sensitivity of HvOR13 to Z11-16:Ald. Interestingly, a mutation leading to truncation in the HvOR13 C-terminal region affected but did not abolish pheromone receptor response to Z11-16:Ald. The findings are assessed in relationship to other HvOR13 heterologous expression studies, and the role of the C-terminal domain in receptor function is discussed. A third line expressing HvOR15 was also tested but did not respond to any of the seven pheromone components