Significance: Arginine–vasopressin (AVP) acting on V1a receptors (Avpr1as) represents a key signaling mechanism in a brain circuit that increases the expression of social communication and aggression. We produced Syrian hamsters that completely lack Avpr1as (Avpr1aknockout [KO] hamsters) using the CRISPR-Cas9 system to more fully examine the role of Avpr1a in the expression of social behaviors. We confirmed the absence of Avpr1as in these hamsters by demonstrating 1) a complete lack of Avpr1a-specific receptor binding throughout the brain, 2) a behavioral insensitivity to centrally administered AVP, and 3) an absence of the well-known blood-pressure response produced by activating Avpr1as. Unexpectedly, however,Avpr1aKO hamsters displayed more social communication behavior and aggression toward same-sex conspecifics than did their wild-type (WT) littermates.

Background: Age predisposes individuals to a myriad of disorders involving inflammation; this includes stress-related neuropsychiatric disorders such as depression and anxiety, and neurodegenerative diseases. Obesity can further exacerbate these effects in the brain. We investigated whether an inexpensive dietary supplement, s-adenosylmethionine (SAMe), could improve age- and/or obesity-related inflammatory and affective measures in the hippocampus. Methods: Mice were placed on their diets at six weeks of age and then aged to 14 months, receiving SAMe (0.1 g/kg of food) for the final six weeks of the experiment. Prior to tissue collection, mice were tested for anxiety-like behaviors in the open field test and for metabolic outcomes related to type 2 diabetes. Results: SAMe treatment significantly improved outcomes in aged control mice, where fasting glucose decreased, liver glutathione levels increased, and hippocampal microglia morphology improved. SAMe increased transforming growth factor β-1 mRNA in both control mice, potentially accounting for improved microglial outcomes. Obese mice demonstrated increased anxiety-like behavior, where SAMe improved some, but not all, open field measures. Conclusions: In summary, SAMe boosted antioxidant levels, improved diabetic measures, and hippocampal inflammatory and behavioral outcomes in aged mice. The effects of SAMe in obese mice were more subdued, but it could still provide some positive outcomes for obese individuals dealing with anxiety and having difficulty changing their behaviors to improve health outcomes.

Defining how antibodies achieve broad neutralization across antigenically related flaviviruses could inform rational vaccine design. Here, we describe 3A06, a human monoclonal antibody isolated from a dengue-infected donor that potently neutralizes dengue virus serotypes 1-3 (DENV1-3) and Zika virus (ZIKV). Binding studies show that 3A06 selectively recognizes envelope (E) protein dimers, but not monomeric E, EDIII, or viral lysates, indicating strict dependence on a quaternary epitope. Affinity measurements reveal stronger binding to DENV1, DENV3, and ZIKV E dimers, with weaker binding to DENV2 and DENV4. High-resolution structural analysis of 3A06 Fab bound to a chimeric ZIKV particle shows that the antibody engages a quaternary epitope spanning three E protomers at the dimer interface. Strikingly, structural and functional analyses demonstrate that epitope recognition is dominated by the antibody light chain, with somatic mutations driving neutralization potency. While the IgG1 form neutralizes DENV1-3 and ZIKV, subclass switching to IgG3 enables neutralization of all four dengue serotypes. Structural studies using intact IgG3 with DENV support the hypothesis that the enhanced breadth is mediated by extended reach and flexibility of the IgG3 Fc-hinge scaffold. These results reveal a previously unrecognized class of flavivirus broadly neutralizing antibodies and demonstrate how antibody light chain and subclass architecture can be engineered to overcome viral diversity. Our findings provide a structural blueprint for the rational design of universal flavivirus vaccines.