Offspring affected with in utero Zika virus infection retain molecular footprints in the bone marrow and blood cells.

Congenital virus infections, for example cytomegalovirus and rubella virus infections, commonly affect the central nervous and hematological systems in fetuses and offspring. However, interactions between emerging congenital Zika virus and hematological system-bone marrow and blood-in fetuses and offspring are mainly unknown. Our overall goal was to determine whether silent in utero Zika virus infection can cause functional and molecular footprints in the bone marrow and blood of fetuses and offspring. We specifically focused on silent fetal infection because delayed health complications in initially asymptomatic offspring were previously demonstrated in animal and human studies. Using a well-established porcine model for Zika virus infection and a set of cellular and molecular experimental tools, we showed that silent in utero infection causes multi-organ inflammation in fetuses and local inflammation in the fetal bone marrow. In utero infection also caused footprints in the offspring bone marrow and PBMCs. These findings should be considered in a broader clinical context because of growing concerns about health sequelae in cohorts of children affected with congenital Zika virus infection in the Americas. Understanding virus-induced molecular mechanisms of immune activation and inflammation in fetuses may provide targets for early in utero interventions. Also, identifying early biomarkers of in utero-acquired immunopathology in offspring may help to alleviate long-term sequelae.

Identification and Mechanistic Characterization of a Peptide Inhibitor of Glycogen Synthase Kinase (GSK3ß) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein.

Glycogen synthase kinase 3-beta (GSK3ß) is a critical regulator of several cellular pathways involved in neurodevelopment and neuroplasticity and as such is a potential focus for the discovery of new neurotherapeutics toward the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3ß have been focused on developing small molecule inhibitors that compete with adenosine triphosphate (ATP) through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The disrupted in schizophrenia 1 (DISC1) protein has previously been shown to bind and inhibit GSK3ß activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3ß in a noncompetitive mode distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3ß: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3ß binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3ß.

From Beef to Bees: High-Throughput Kinome Analysis to Understand Host Responses of Livestock Species to Infectious Diseases and Industry-Associated Stress.

Within human health research, the remarkable utility of kinase inhibitors as therapeutics has motivated efforts to understand biology at the level of global cellular kinase activity (the kinome). In contrast, the diminished potential for using kinase inhibitors in food animals has dampened efforts to translate this research approach to livestock species. This, in our opinion, was a lost opportunity for livestock researchers given the unique potential of kinome analysis to offer insight into complex biology. To remedy this situation, our lab developed user-friendly, cost-effective approaches for kinome analysis that can be readily incorporated into most research programs but with a specific priority to enable the technology to livestock researchers. These contributions include the development of custom software programs for the creation of species-specific kinome arrays as well as comprehensive deconvolution and analysis of kinome array data. Presented in this review are examples of the application of kinome analysis to highlight the utility of the technology to further our understanding of two key complex biological events of priority to the livestock industry: host immune responses to infectious diseases and animal stress responses. These advances and examples of application aim to provide both mechanisms and motivation for researchers, particularly livestock researchers, to incorporate kinome analysis into their research programs.