The TLR7/8 agonist INI-4001 enhances the immunogenicity of a Powassan virus-like-particle vaccine.

Powassan virus (POWV) is a pathogenic tick-borne flavivirus that causes fatal neuroinvasive disease in humans. There are currently no approved therapies or vaccines for POWV infection. Here, we develop a POW virus-like-particle (POW-VLP) based vaccine adjuvanted with the novel synthetic Toll-like receptor 7/8 agonist INI-4001.

Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances.

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1) neurons are responsible for the pulsatile release of gonadotropin-releasing hormone (GnRH). In females, the behavior of Kiss1 neurons, expressing Kiss1, neurokinin B (NKB), and dynorphin (Dyn), varies throughout the ovarian cycle.

Effects of COVID-19 virus-like particles on the behavioral and cognitive performance of human apolipoprotein E targeted replacement mice.

Introduction: The effects of viral infections might be apolipoprotein E (apoE) isoform-dependent. In humans, there are three major apoE isoforms, E2, E3, and E4. E4 is associated with the enhanced entry of several viruses into the brain and their disease progression.

Third intracellular loop of HCMV US28 is necessary for signaling and viral reactivation.

The human cytomegalovirus (HCMV) encoded chemokine receptor US28 plays a critical role in viral pathogenesis, mediating several processes such as cellular migration, differentiation, transformation, and viral latency and reactivation. Despite significant research examining the signal transduction pathways utilized by US28, the precise mechanism by which US28 activates these pathways remains unclear. We performed a mutational analysis of US28 to identify signaling domains that are critical for functional activities.

Evaluation of dimethandrolone undecanoate in non-human primates as a candidate for long-acting injectable male contraceptive.

Background: Dimethandrolone undecanoate (DMAU) is under development as a single agent hormonal male contraceptive. DMAU is a prodrug hydrolyzed by esterase(s) to the active metabolite dimethandrolone (DMA) which has dual androgenic and progestogenic actions. Phase 1 clinical trial results show DMAU to be well-tolerated as an oral contraceptive in healthy men; however, delivery of DMAU as a long-acting injectable rather than a daily oral formulation would provide user compliance benefits and address oral bioavailability concerns.

Rapid systemic spread and minimal immune responses following SIVsab intrarectal transmission in African green monkeys.

African green monkeys (AGMs) are natural hosts of SIV whose infection does not progress to AIDS. Since early events of infection may be critical to pathogenesis in nonnatural hosts, we investigated early SIV infection in 29 adult male AGMs intrarectally inoculated with SIVsab92018 (SIVsab) and serially sacrificed throughout acute into early chronic infection to understand patterns of viral establishment, dissemination, and their effect on disease progression. Using this model, we showed that foci of virus replication could be detected at the site of inoculation and in the draining lymphatics as early as 1-3 days postinfection (dpi).

Dysregulation of astrocytic Aquaporin-1 in the brains of oldest-old rhesus macaques: the NIA caloric restriction study.

Aquaporin-1 (AQP1) is a highly conserved water-channel protein, found to be expressed by astrocytes in adult humans and non-human primates (NHPs). Upregulation of cortical AQP1 expression occurs with cancer, injury, and neurodegenerative disease, but minimal information is available about the effects of normative aging on AQP1 expression. This study leverages tissues from the oldest-old rhesus macaques, some greater than 40 years of age, from the National Institute on Aging longitudinal study of caloric restriction (CR).

Comparative lifespan and healthspan of nonhuman primate species common to biomedical research.

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Sex-specific Kaplan-Meier survival curves were computed in 12 translational aging models: baboon, bonnet macaque, chimpanzee, common marmoset, coppery titi monkey, cotton-top tamarin, cynomolgus macaque, Japanese macaque, pigtail macaque, rhesus macaque, squirrel monkey, and vervet/African green. After employing strict inclusion criteria, primary results are based on 12,269 NHPs that survived to adulthood and died of natural/health-related causes.

Preparation of Frozen Non-Human Primate Fetal Islets for Combined Single Nuclei RNA-Sequencing and ATAC-Sequencing, and Bulk Metabolomics.

One challenge in studies using tissue collected from multiple cohorts is avoiding batch effects when preparing for large-scale multi-omic experiments, such as combined single-cell RNA sequencing and metabolomics. The method in the current study utilizes flash-frozen pancreatic islets from fetal non-human primates collected over a span of two years for input into single-nucleus RNA sequencing and ATAC sequencing assays. The cytosolic fraction generated during nuclear extraction was retained for downstream capillary electrophoresis-mass spectrometry and subsequent metabolite quantification.

Attenuation of Ampullary Anoctamin 1 by the Peritoneal Fluid in Rhesus Macaques with Spontaneous Endometriosis.

Altered peristaltic and ciliary dysfunction is a feature of females with endometriosis. To further explore this premise, we examined the ampulla of rhesus macaques (Macaca mulatta) with and without spontaneous endometriosis for the expression of adenylate kinase 7 (AK7), a mitochondrial-dwelling nucleotide converting enzyme with critical roles in cellular kinesis, forkhead protein box J1 (FOXJ1), a marker of cilia abundance, and Anoctamin 1 (ANO1) as a marker of both smooth muscle contraction and ciliogenesis. We further performed an in vitro experiment that treated ampullary segments with peritoneal fluid from animals with and without endometriosis.

Spirometry Versus Forced Oscillation to Assess Lung Function Outcome at 5 Years of Age.

Background: Spirometry is the gold standard for assessing airway function for clinical studies; however, obtaining high-quality data in young children remains challenging. Since the forced oscillation technique (FOT) requires less subject cooperations, there has been increasing interest in FOT, particularly in young children. We evaluated whether spirometry and FOT in young children provides comparable ability to detect a treatment effect.

Classification of Human Ovarian Follicle Morphology: Recommendations of the NICHD-Sponsored Ovarian Nomenclature Workshop.

Objective: To develop a consensus on histologic human ovarian follicle staging nomenclature, provide guidelines for follicle density calculation, and assess changes due to fixation to enhance communication among clinicians and ovarian biology researchers in order to gain a deeper understanding of human fertility.

Methods: Beginning in March 2021, the Ovarian Nomenclature Workshop's Follicle Classification Working Subgroup was organized by the Pediatric and Adolescent Gynecology program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Results: The Follicle Working Subgroup recommends consolidation and expansion of the current classification systems to include six stages of normal preantral follicles, five stages of normal antral follicles, as well as categories of corpus lutea, abnormal preantral follicles, abnormal antral follicles, and other distinct follicle types.

The aged female rhesus macaque as a translational model for human menopause and hormone therapy.

Progress in understanding the causes of physiological and behavioral changes in post-menopausal women is hampered by the paucity of animal models that accurately recapitulate these age-associated changes. Here we evaluate the translational potential of female rhesus macaques (Macaca mulatta). Like women, these long-lived diurnal primates show marked neuroendocrine changes during aging, as well as perturbed sleep-wake cycles and cognitive decline.

A model of lymphocryptovirus-associated post-transplant lymphoproliferative disorder in immunosuppressed Mauritian cynomolgus macaques.

Immunocompromised individuals are at risk for developing lymphocryptovirus-associated lymphoproliferative diseases, such as Epstein Barr virus (EBV)-associated B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD). We previously reported development of cynomolgus lymphocryptovirus (CyLCV)-associated PTLD in Mauritian cynomolgus macaques (MCMs) undergoing hematopoietic stem cell transplantation (HSCT), which mirrored EBV-PTLD in transplant patients. Here, we sought to develop a MCM model of lymphocryptovirus-associated lymphoproliferative disease in immunosuppressed MCMs without HSCT.

Anti-Müllerian hormone as a predictor of oocyte yield following controlled ovarian stimulation in the rhesus macaque.

Anti-Müllerian hormone (AMH) is widely used in the clinic as a biomarker for ovarian reserve and to predict ovarian response to gonadotropin stimulation. Patients with higher AMH levels tend to yield more oocytes and have better outcomes from assisted reproductive technology (ART) procedures. The goal of this study is to determine if AMH can be used to predict the outcome of controlled ovarian stimulation in rhesus macaques, which are commonly used in biomedical research, to refine animal use while maximizing oocyte yield.

Stem cell transplantation and allogeneic immunity: post treatment control or HIV cure?

Purpose Of Review: Long-lasting HIV remission has been reported in a small group of people with HIV (PWH) following allogenic hematopoietic stem cell transplants (HSCT) for the treatment of hematologic malignancies. While the mechanisms of HIV remission following release from antiretroviral therapy (ART) were not initially known, subsequent findings from clinical cases and preclinical nonhuman primate studies have implicated mechanisms of clearance. Here, we review the six currently published human cases of long-term ART-free HIV remission.

Impact of Dolutegravir plus Lamivudine as First-Line Antiretroviral Treatment on HIV-1 Reservoir and Inflammatory Markers in Peripheral Blood.

Objective: To compare the effects of first-line antiretroviral treatment (ART) with dolutegravir plus lamivudine (DTG+3TC) versus DTG plus emtricitabine/tenofovir alafenamide (FTC/TAF) on the evolution of the HIV-1 reservoir and immune activation biomarkers in people with HIV (PWH).

Methods: DUALITY was a 48-week, single-center, randomized, open-label clinical trial in ART-naïve PWH. Participants were randomized (1:1) to receive ART with DTG+3TC (2DR group) or DTG+FTC/TAF (3DR group).

Distinct chemical structures inhibit the CEMIP hyaluronidase and promote oligodendrocyte progenitor cell maturation.

Growing evidence supports pathogenic roles for chronically elevated hyaluronidase activity in numerous conditions. Elevated expression of one such hyaluronidase, the Cell Migration Inducing and hyaluronan binding Protein (CEMIP), has been implicated in the pathogenesis and progression of several cancers as well as demyelinating diseases in the central nervous system (CNS). Developing effective and selective CEMIP inhibitors could therefore have efficacy in treating a variety of conditions where CEMIP is chronically elevated.

Refinements in Clinical and Behavioral Management for Macaques on Infectious Disease Protocols.

Providing optimal clinical and behavioral care is a key component of promoting animal welfare for macaques and other nonhuman primates (NHPs) in research. This overlap between critical areas of management is particularly important for NHPs on infectious disease protocols, which often have unique challenges. For example, traditionally these NHPs were often housed alone, which can have behavioral and clinical consequences.