Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques.

The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.

Rhesus and cynomolgus macaque immunoglobulin heavy-chain genotyping yields comprehensive databases of germline VDJ alleles.

Definition of the specific germline immunoglobulin (Ig) alleles present in an individual is a critical first step to delineate the ontogeny and evolution of antigen-specific antibody responses. Rhesus and cynomolgus macaques are important animal models for pre-clinical studies, with four main sub-groups being used: Indian- and Chinese-origin rhesus macaques and Mauritian and Indonesian cynomolgus macaques. We applied the (Ig) gene inference tool IgDiscover and performed extensive Sanger sequencing-based genomic validation to define germline VDJ alleles in these 4 sub-groups, comprising 45 macaques in total. There was allelic overlap between Chinese- and Indian-origin rhesus macaques and also between the two macaque species, which is consistent with substantial admixture. The island-restricted Mauritian cynomolgus population displayed the lowest number of alleles of the sub-groups, yet maintained high individual allelic diversity. These comprehensive databases of germline IGH alleles for rhesus and cynomolgus macaques provide a resource toward the study of B cell responses in these important pre-clinical models.

A modified vaccinia Ankara vector-based vaccine protects macaques from SARS-CoV-2 infection, immune pathology, and dysfunction in the lungs.

A combination of vaccination approaches will likely be necessary to fully control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we show that modified vaccinia Ankara (MVA) vectors expressing membrane-anchored pre-fusion stabilized spike (MVA/S) but not secreted S1 induced strong neutralizing antibody responses against SARS-CoV-2 in mice. In macaques, the MVA/S vaccination induced strong neutralizing antibodies and CD8+ T cell responses, and conferred protection from SARS-CoV-2 infection and virus replication in the lungs as early as day 2 following intranasal and intratracheal challenge. Single-cell RNA sequencing analysis of lung cells on day 4 after infection revealed that MVA/S vaccination also protected macaques from infection-induced inflammation and B cell abnormalities and lowered induction of interferon-stimulated genes. These results demonstrate that MVA/S vaccination induces neutralizing antibodies and CD8+ T cells in the blood and lungs and is a potential vaccine candidate for SARS-CoV-2.

Adeno-Associated Virus Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression.

Long-term delivery of anti-HIV monoclonal antibodies (mAbs) using adeno-associated virus (AAV) vectors holds promise for the prevention and treatment of HIV infection. We describe a therapy trial in which four rhesus monkeys were infected with SHIV-AD8 for 86 weeks before receiving the AAV-encoded mAbs 3BNC117, 10-1074, and 10E8. Although anti-drug antibody (ADA) responses restricted mAb delivery, one monkey successfully maintained 50-150 µg/mL of 3BNC117 and 10-1074 for over 2 years. Delivery of these two mAbs to this monkey resulted in an abrupt decline in plasma viremia, which remained undetectable for 38 successive measurements over 3 years. We generated two more examples of virologic suppression using AAV delivery of a cocktail of four mAbs in a 12-monkey study. Our results provide proof of concept for AAV-delivered mAbs to produce a "functional cure." However, they also serve as a warning that ADAs may be a problem for practical application of this approach in humans.

Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches.

The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.

Immune restoration by TIGIT blockade is insufficient to control chronic SIV infection.

TIGIT is a negative immune checkpoint receptor associated with T cell exhaustion in cancer and HIV. TIGIT upregulation in virus-specific CD8+ T cells and NK cells during HIV/SIV infection results in dysfunctional effector capabilities. In vitro studies targeting TIGIT on CD8+ T cells suggest TIGIT blockade as a viable strategy to restore SIV-specific T cell responses. Here, we extend these studies in vivo using TIGIT blockage in nonhuman primates in an effort to reverse T cell and NK cell exhaustion in the setting of SIV infection. We demonstrate that in vivo administration of a humanized anti-TIGIT monoclonal antibody (mAb) is well tolerated in both cynomolgus macaques and rhesus macaques. Despite sustained plasma concentrations of anti-TIGIT mAb, we observed no consistent improvement in NK or T cell cytolytic capacity. TIGIT blockade minimally enhanced T cell proliferation and virus-specific T cell responses in both magnitude and breadth though plasma viral loads in treated animals remained stable indicating that anti-TIGIT mAb treatment alone was insufficient to increase anti-SIV CD8+ T cell function. The enhancement of virus-specific T cell proliferative responses observed in vitro with single or dual blockade of TIGIT and/or PD-1 highlights TIGIT as a potential target to reverse T cell dysfunction. Our studies, however, reveal that targeting the TIGIT pathway alone may be insufficient in the setting of viremia and that combining immune checkpoint blockade with other immunotherapeutics may be a future path forward for improved viral control or elimination of HIV.IMPORTANCEUpregulation of the immune checkpoint receptor TIGIT is associated with HIV-mediated T cell dysfunction and correlates with HIV disease progression. Compelling evidence exists for targeting immune checkpoint receptor pathways that would potentially enhance immunity and refocus effector cell efforts toward viral clearance. In this report, we investigate TIGIT blockade as an immunotherapeutic approach to reverse immune exhaustion during chronic SIV/SHIV infection in a nonhuman primate model of HIV infection. We show that interfering with the TIGIT signaling axis alone is insufficient to improve viral control despite modest improvement in T cell immunity. Our data substantiate the use of targeting multiple immune checkpoint receptors to promote synergy and ultimately eliminate HIV-infected cells.

Compartmentalized SARS-CoV-2 Replication in the Upper vs Lower Respiratory Tract After Intranasal Inoculation or Aerosol Exposure.

Nonhuman primate models are essential for the development of vaccines and antivirals against infectious diseases. Rhesus macaques are a widely utilized infection model for SARS-CoV-2. We compared cellular tropism and virus replication in rhesus macaques inoculated with SARS-CoV-2 via the intranasal route or via exposure to aerosols. Intranasal inoculation resulted in replication in the upper respiratory tract with limited involvement in the lower respiratory tract, whereas exposure to aerosols resulted in infection throughout the respiratory tract. In comparison with multiroute inoculation, intranasal and aerosol inoculation resulted in reduced SARS-CoV-2 replication in the respiratory tract.

A 3-month-old neonatal rhesus macaque HFMD model caused by coxsackievirus B1 infection and viral tissue tropism.

Coxsackievirus B1 (CVB1), an enterovirus with multiple clinical presentations, has been associated with potential long-term consequences, including hand, foot, and mouth disease (HFMD), in some patients. However, the related animal models, transmission dynamics, and long-term tissue tropism of CVB1 have not been systematically characterized. In this study, we established a model of CVB1 respiratory infection in rhesus macaques and evaluated the clinical symptoms, viral load, and immune levels during the acute phase (0-14 days) and long-term recovery phase (15-30 days). We also investigated the distribution, viral clearance, and pathology during the long-term recovery period using 35 postmortem rhesus macaque tissue samples collected at 30 days postinfection (d.p.i.). The results showed that the infected rhesus macaques were susceptible to CVB1 and exhibited HFMD symptoms, viral clearance, altered cytokine levels, and the presence of neutralizing antibodies. Autopsy revealed positive viral loads in the heart, spleen, pancreas, soft palate, and olfactory bulb tissues. HE staining demonstrated pathological damage to the liver, spleen, lung, soft palate, and tracheal epithelium. At 30 d.p.i., viral antigens were detected in visceral, immune, respiratory, and muscle tissues but not in intestinal or neural tissues. Brain tissue examination revealed viral meningitis-like changes, and CVB1 antigen expression was detected in occipital, pontine, cerebellar, and spinal cord tissues at 30 d.p.i. This study provides the first insights into CVB1 pathogenesis in a nonhuman primate model of HFMD and confirms that CVB1 exhibits tissue tropism following long-term infection.

Same-Sex Sexual Behavior, Age-Class, and Coalitions in Male Rhesus Macaques (Macaca mulatta).

In the present study, relations between same-sex sexual behavior (SSB), age-class, and coalitional behavior in male rhesus macaques were examined in a re-analysis of data first analyzed and reported by Clive et al. (2023). Age-class as a focal variable was indicated in an extensive literature review, which showed that male non-adult (juvenile, adolescent) participation in SSB is extensive in this and related primate species and associated with various benefits. Clive et al. (2023) excluded juveniles from their analysis. In the re-analysis (n = 995 mounting events), it was found that non-adult involvement was substantial (51%). Most dyads contained at least one non-adult (76%). Young and prime adult mounters most often selected non-adults to mount. Mounters were often sexually motivated: most for adolescents (72%); equally for juveniles (57%) and adults (56%). Finally, the highest rate of SSB with coalitional context appeared in adolescent-adult dyads involved in multiple repeated mounts. SSB, age-class, special friendships, bonding, and coalitions were linked, as reported in some other primate species and human societies cross-culturally. Employing age-class in male SSB analysis improved description and explanation.

Stable HIV decoy receptor expression after in vivo HSC transduction in mice and NHPs: Safety and efficacy in protection from SHIV.

We aim to develop an in vivo hematopoietic stem cell (HSC) gene therapy approach for persistent control/protection of HIV-1 infection based on the stable expression of a secreted decoy protein for HIV receptors CD4 and CCR5 (eCD4-Ig) from blood cells. HSCs in mice and a rhesus macaque were mobilized from the bone marrow and transduced by an intravenous injection of HSC-tropic, integrating HDAd5/35++ vectors expressing rhesus eCD4-Ig. In vivo HSC transduction/selection resulted in stable serum eCD4-Ig levels of ∼100 µg/mL (mice) and >20 µg/mL (rhesus) with half maximal inhibitory concentrations (IC50s) of 1 µg/mL measured by an HIV neutralization assay. After simian-human-immunodeficiency virus D (SHIV.D) challenge of rhesus macaques injected with HDAd-eCD4-Ig or a control HDAd5/35++ vector, peak plasma viral load levels were ∼50-fold lower in the eCD4-Ig-expressing animal. Furthermore, the viral load was lower in tissues with the highest eCD4-Ig expression, specifically the spleen and lymph nodes. SHIV.D challenge triggered a selective expansion of transduced CD4+CCR5+ cells, thereby increasing serum eCD4-Ig levels. The latter, however, broke immune tolerance and triggered anti-eCD4-Ig antibody responses, which could have contributed to the inability to eliminate SHIV.D. Our data will guide us in the improvement of the in vivo approach. Clearly, our conclusions need to be validated in larger animal cohorts.

Excess prenatal loss and respiratory illnesses of infant macaques living outdoors and exposed to wildfire smoke.

Global climate change has transformed predictions of fire seasons in the near future, and record-breaking wildfire events have had catastrophic consequences in recent years. In September 2020, multiple wildfires subjected Oregon to hazardous air quality for several days. In this retrospective cohort study, we aimed to examine prenatal loss, morbidity, and mortality of rhesus (Macaca mulatta) and Japanese macaques (Macaca fuscata) exposed to poor air quality from the nearby wildfires. Detailed medical records from 2014 to 2020 of 580 macaques housed outdoors at a research facility in Beaverton, Oregon were used to evaluate the association between these health outcomes and wildfire smoke exposure. Logistic regression models estimated excess prenatal loss, hospitalization rates, respiratory problems, and mortality during and following the wildfire event, and Kruskal-Wallis statistics were used to determine if infant growth was affected by wildfire smoke exposure. Risk of pregnancy loss (relative risk = 4.1; p < 0.001) and odds of diagnosis with a respiratory problem (odds ratio = 4.47; p = 0.003) were higher in exposed infant macaques compared to nonexposed infants. Infant growth was not affected by poor air quality exposure. Our findings suggest wildfire smoke exposure poses a risk to the health of infants and pregnant individuals and should be monitored more closely in the future.

Hepatitis E virus infection upregulates ING5 expression in vitro and in vivo.

Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.

Pairing Laboratory-Housed Adult Male Rhesus Macaques (Macaca mulatta): Success Rates in Relation to Behavioral Response and Duration of Visual Contact.

While the benefits of pair housing have been well documented, less is known about increasing success in adult male macaque pair introductions. In this retrospective study, 95 unfamiliar adult male macaque (Macaca mulatta) pairs were examined to determine whether duration of visual contact, behavior, and age and weight were associated with success rate, with "success" defined as two weeks in full tactile contact without excessive behavioral indicators of incompatibility or injury requiring clinical treatment or care. Overall, the unfamiliar adult male pairs achieved a success rate of 72% and wounding requiring medical attention was rare (2%). A significant negative relationship between pair success and time in visual contact for pairs was found. Pairs who moved into tactile contact within 48-hours showed more positive social behaviors in protected and full contact and had a high rate of success (91%), while those who exhibited negative social behaviors were maintained in visual contact for longer. Nevertheless, rapid signs of compatibility were not necessary for the formation of successful pairs. While social introduction success rates steadily declined with increased periods of maintained visual contact, longer durations of 3 days to 1 week (70%), and 8+ days (58%), were still accompanied by high to moderate success, respectively. These results indicate that when negative social behavior is present early in visual contact success may be expected to decrease, but it is not necessarily indicative of incompatibility. Providing extra time in visual contact can reduce overall incidences of single housing.

Multi-omics analysis reveals changes in tryptophan and cholesterol metabolism before and after sexual maturation in captive macaques.

Rhesus macaques (Macaca mulatta, RMs) are widely used in sexual maturation studies due to their high genetic and physiological similarity to humans. However, judging sexual maturity in captive RMs based on blood physiological indicators, female menstruation, and male ejaculation behavior can be inaccurate. Here, we explored changes in RMs before and after sexual maturation based on multi-omics analysis and identified markers for determining sexual maturity. We found that differentially expressed microbiota, metabolites, and genes before and after sexual maturation showed many potential correlations. Specifically, genes involved in spermatogenesis (TSSK2, HSP90AA1, SOX5, SPAG16, and SPATC1) were up-regulated in male macaques, and significant changes in gene (CD36), metabolites (cholesterol, 7-ketolithocholic acid, and 12-ketolithocholic acid), and microbiota (Lactobacillus) related to cholesterol metabolism were also found, suggesting the sexually mature males have stronger sperm fertility and cholesterol metabolism compared to sexually immature males. In female macaques, most differences before and after sexual maturity were related to tryptophan metabolism, including changes in IDO1, IDO2, IFNGR2, IL1Β, IL10, L-tryptophan, kynurenic acid (KA), indole-3-acetic acid (IAA), indoleacetaldehyde, and Bifidobacteria, indicating that sexually mature females exhibit stronger neuromodulation and intestinal immunity than sexually immature females. Cholesterol metabolism-related changes (CD36, 7-ketolithocholic acid, 12-ketolithocholic acid) were also observed in female and male macaques. Exploring differences before and after sexual maturation through multi-omics, we identified potential biomarkers of sexual maturity in RMs, including Lactobacillus (for males) and Bifidobacterium (for females) valuable for RM breeding and sexual maturation research.

SOSIP Trimer-Specific Antibodies Isolated from a Simian-Human Immunodeficiency Virus-Infected Monkey with versus without a Pre-blocking Step with gp41.

BG505 SOSIP.664 (hereafter referred to as SOSIP), a stabilized trimeric mimic of the HIV-1 envelope spike resembling the native viral spike, is a useful tool for isolating anti-HIV-1 neutralizing antibodies. We screened long-term SHIV-AD8 infected rhesus monkeys for potency and breadth of serum neutralizing activity against autologous and heterologous viruses: SHIV-AD8, HIV-1 YU2, HIV-1 JR-CSF, and HIV-1 NL4-3. Monkey rh2436 neutralized all viruses tested and showed strong reactivity to the SOSIP trimer, suggesting this was a promising candidate for attempts at monoclonal antibody (MAb) isolation. MAbs were isolated by performing single B-cell sorts from peripheral blood mononuclear cells (PBMC) by FACS using the SOSIP trimer as a probe. An initial round of sorted cells revealed the majority of isolated MAbs were directed to the gp41 external domain portion of the SOSIP trimer and were mostly non-neutralizing against tested isolates. A second sort was performed, introducing a gp41 blocking step prior to PBMC staining and FACS sorting. These isolated MAbs bound SOSIP trimer but were no longer directed to the gp41 external domain portion. A significantly higher proportion of MAbs with neutralizing activity were obtained with this strategy. Our data show this pre-blocking step with gp41 greatly increases the yield of non-gp41-reactive, SOSIP-specific MAbs and increases the likelihood of isolating MAbs with neutralizing activity. IMPORTANCE Recent advancements in the field have focused on the isolation and use of broadly neutralizing antibodies for both prophylaxis and therapy. Finding a useful probe to isolate broad potent neutralizing antibodies while avoiding non-neutralizing antibodies is important. The SOSIP trimer has been shown to be a great tool for this purpose because it binds known broadly neutralizing antibodies. However, the SOSIP trimer can isolate non-neutralizing antibodies as well, including gp41-specific MAbs. Introducing a pre-blocking step with gp41 recombinant protein decreased the percent of gp41-specific antibodies isolated with SOSIP probe, as well as increased the number of neutralizing antibodies isolated. This method can be used as a tool to increase the chances of isolating neutralizing antibodies.

Exacerbated AIDS Progression by PD-1 Blockade during Therapeutic Vaccination in Chronically Simian Immunodeficiency Virus-Infected Rhesus Macaques after Interruption of Antiretroviral Therapy.

The persistence of cells latently infected with HIV-1, named the latent reservoir, is the major barrier to HIV-1 eradication, and the formation and maintenance of the latent reservoir might be exacerbated by activation of the immunoinhibitory pathway and dysfunction of CD8+ T cells during HIV-1 infection. Our previous findings demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred effective control of highly pathogenic SIVmac239 infection in rhesus macaques. However, to our surprise, herein we found that a therapeutic vaccination in combination with PD-1 blockade resulted in activation of the viral reservoir, faster viral rebound after treatment interruption, accelerated AIDS progression, and, ultimately, death in chronically SIV-infected macaques after antiretroviral therapy (ART) interruption. Our study further demonstrated that the SIV provirus was preferentially enriched in PD-1+CD4+ T cells due to their susceptibility to viral entry, potent proliferative ability, and inability to perform viral transcription. In addition, the viral latency was effectively reactivated upon PD-1 blockade. Together, these results suggest that PD-1 blockade may be a double-edged sword for HIV-1 immunotherapy and provide important insight toward the rational design of immunotherapy strategies for an HIV-1 cure. IMPORTANCE As it is one of the most challenging public health problems, there are no clinically effective cure strategies against HIV-1 infection. We demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred better control of highly pathogenic SIVmac239 infection in rhesus macaques. In the present study, to our surprise, PD-1 blockade during therapeutic vaccination accelerated the reactivation of latent reservoir and AIDS progression in chronically SIV-infected macaques after ART interruption. Our study further demonstrated that the latent SIV provirus was preferentially enriched in PD-1+CD4+ T cells because of its susceptibility to viral entry, inhibition of SIV transcription, and potent ability of proliferation, and the viral latency was effectively reactivated by PD-1 blockade. Therefore, PD-1 blockade might be a double-edged sword for AIDS therapy. These findings provoke interest in further exploring novel treatments against HIV-1 infection and other emerging infectious diseases.

Effects of long-term simulated microgravity on liver metabolism in rhesus macaques.

The liver is an essential multifunctional organ and constantly communicates with nearly all the tissues in the body. Spaceflight or simulated microgravity has a significant impact on the livers of rodent models, including lipid accumulation and inflammatory cell infiltration. Whether similar liver lipotoxicity could occur in humans is not known, even though altered circulating cholesterol profile has been reported in astronauts. Using a 42-day head-down bed rest (HDBR) model in rhesus macaques, the present study investigated whether simulated microgravity alters the liver of non-human primates at the transcriptome and metabolome levels. Its association with stress and intestinal changes was also explored. Compared to the controls, the HDBR monkeys showed mild liver injury, elevated ANGPTL3 level in the plasma, and accumulation of fat vacuoles and inflammatory cells in the liver. Altered transcriptome signatures with up-regulation of genes in lipid metabolisms and down-regulation of genes in innate immune defense were also found in HDBR group-derived liver samples. The metabolic profiling of the liver revealed mildly disturbed fatty acid metabolism in the liver of HDBR monkeys. The intestinal dysbiosis, its associated endotoxemia and changes in the composition of bile acids, and elevated stress hormone in HDBR monkeys may contribute to the altered lipid metabolisms in the liver. These data indicate that liver metabolic functions and gut-liver axis should be closely monitored in prolonged spaceflight to facilitate strategy design to improve and maintain metabolic homeostasis.

Insulin resistance induced by long-term sleep deprivation in rhesus macaques can be attenuated by Bifidobacterium.

Long-term sleep deprivation (SD) is a bad lifestyle habit, especially among specific occupational practitioners, characterized by circadian rhythm misalignment and abnormal sleep/wake cycles. SD is closely associated with an increased risk of metabolic disturbance, particularly obesity and insulin resistance. The incretin hormone, glucagon-like peptide-1 (GLP-1), is a critical insulin release determinant secreted by the intestinal L-cell upon food intake. Besides, the gut microbiota participates in metabolic homeostasis and regulates GLP-1 release in a circadian rhythm manner. As a commonly recognized intestinal probiotic, Bifidobacterium has various clinical indications regarding its curative effect. However, few studies have investigated the effect of Bifidobacterium supplementation on sleep disorders. In the present study, we explored the impact of long-term SD on the endocrine metabolism of rhesus monkeys and determined the effect of Bifidobacterium supplementation on the SD-induced metabolic status. Lipid concentrations, body weight, fast blood glucose, and insulin levels increased after SD. Furthermore, after 2 mo of long-term SD, the intravenous glucose tolerance test showed that the glucose metabolism was impaired and the insulin sensitivity decreased. Moreover, 1 mo of Bifidobacterium oral administration significantly reduced blood glucose and attenuated insulin resistance in rhesus macaques. Overall, our results suggested that Bifidobacterium might be used to alleviate SD-induced aberrant glucose metabolism and improve insulin resistance. Also, it might help in better understanding the mechanisms governing the beneficial effects of Bifidobacterium.NEW & NOTEWORTHY Our findings demonstrated that long-term sleep deprivation is closely associated with metabolic syndromes. Bifidobacterium administration showed a superior effect on insulin resistance caused by sleep deprivation. Overall, we provide prevention and treatment methods for long-term sleep deprivation, a bad lifestyle habit among specific occupational practitioners, such as irregular shift workers.

Greater variability in rhesus macaque (Macaca mulatta) endocranial volume among males than females.

The greater male variability (GMV) hypothesis proposes that traits are more variable among males than females, and is supported by numerous empirical studies. Interestingly, GMV is also observed for human brain size and internal brain structure, a pattern which may have implications for sex-biased neurological and psychiatric conditions. A better understanding of neuroanatomical variability in non-human primates may illuminate whether certain species are appropriate models for these conditions. Here, we tested for sex differences in the variability of endocranial volume (ECV, a proxy for brain size) in a sample of 542 rhesus macaques (Macaca mulatta) from a large pedigreed free-ranging population. We also examined the components of phenotypic variance (additive genetic and residual variance) to tease apart the potential drivers of sex differences in variability. Our results suggest that males exhibit more variable ECVs, and that this pattern reflects either balancing/disruptive selection on male behaviour (associated with alternative male mating strategies) or sex chromosome effects (associated with mosaic patterns of X chromosome gene expression in females), rather than extended neurodevelopment among males. This represents evidence of GMV for brain size in a non-human primate species and highlights the potential of rhesus macaques as a model for sex-biased brain-based disorders.

Testing the role of testosterone versus estrogens in mediating reproductive transitions in female rhesus macaques.

In male vertebrates, testosterone is generally known to coordinate reproductive trade-offs, in part by promoting the transition to the next reproduction at the expense of current parental care. The role of testosterone in reproductive transitions has been little tested in female vertebrates, especially in mammals. The present study sought to fill this gap, by first undertaking an experimental study, in which we identified DHT, androstenediol, and in particular etiocholanolone, as fecal androgen metabolites which reflect serum testosterone concentration in female rhesus macaques (Macaca mulatta). Using concentrations of fecal etiocholanolone as proxy for circulating testosterone, we then conducted a field study on 46 free-ranging rhesus macaques of Cayo Santiago, Puerto Rico, to test if testosterone mediates the trade-off between reproductive transition (a higher chance of reproducing in the next year) and current reproduction (providing more care to current offspring). While the evidence for testosterone was weak, the testing of fecal immunoreactive estrogen metabolites suggested a potential role of estrogen in reproductive trade-offs. We found large individual differences in fecal etiocholanolone concentrations during the early postpartum period that were unexplained even after accounting for sociodemographic factors such as age and dominance rank. Further investigation is needed to understand this variation. Our study suggests that the actions of testosterone in females may not have evolved to fulfil the same role in primate reproductive transitions as it does in males, and we encourage more studies to consider the function of testosterone in reproductive behaviors and life history transitions in females of mammalian taxa.