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The vomeronasal system plays an essential role in sensing various environmental chemical cues. Here we show that mice exposed to blood and, consequently, hemoglobin results in the activation of vomeronasal sensory neurons expressing a specific vomeronasal G protein-coupled receptor, Vmn2r88, which is mediated by the interaction site, Gly17, on hemoglobin. The hemoglobin signal reaches the medial amygdala (MeA) in both male and female mice. However, it activates the dorsal part of ventromedial hypothalamus (VMHd) only in lactating female mice. As a result, in lactating mothers, hemoglobin enhances digging and rearing behavior. Manipulation of steroidogenic factor 1 (SF1)-expressing neurons in the VMHd is sufficient to induce the hemoglobin-mediated behaviors. Our results suggest that the oxygen-carrier hemoglobin plays a role as a chemosensory signal, eliciting behavioral responses in mice in a state-dependent fashion. The vomeronasal system regulates sensing of various environmental cues. Here, the authors show that exposure to hemoglobin results in the activation of Vmn2r88+ vomeronasal sensory neurons in both male and female mice. However, exposure to hemoglobin enhances digging and rearing behaviour in lactating female mice only.

Mating drive is balanced by a need to safeguard resources for offspring, yet the neural basis for negative regulation of mating remains poorly understood. In rodents, pheromones critically regulate sexual behavior. Here, we observe suppression of adult female sexual behavior in mice by exocrine gland-secreting peptide 22 (ESP22), a lacrimal protein from juvenile mice. ESP22 activates a dedicated vomeronasal receptor, V2Rp4, and V2Rp4 knockout eliminates ESP22 effects on sexual behavior. Genetic tracing of ESP22-responsive neural circuits reveals a critical limbic system connection that inhibits reproductive behavior. Furthermore, V2Rp4 counteracts a highly related vomeronasal receptor, V2Rp5, that detects the male sex pheromone ESP1. Interestingly, V2Rp4 and V2Rp5 are encoded by adjacent genes, yet couple to distinct circuits and mediate opposing effects on female sexual behavior. Collectively, our study reveals molecular and neural mechanisms underlying pheromone-mediated sexual rejection, and more generally, how inputs are routed through olfactory circuits to evoke specific behaviors. Sex pheromones that increase mating have been reported across a number of different species, yet there is little known about pheromones that suppress female mating drive. This study reports that juvenile female mice release a pheromone, ESP22, which suppresses sexual receptivity of adult female mice by evoking a robust rejection behavior upon male mounting.

IgM antibodies have been known for decades to enhance humoral immune responses in an antigen-specific fashion. This enhancement has been thought to be dependent on complement activation by IgM–antigen complexes; however, recent genetic studies render this mechanism unlikely. Here, we describe a likely alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) on B cells produced significantly less antibody to protein antigen during both primary and memory responses. This immune deficiency was accompanied by impaired germinal center formation and decreased plasma and memory B-cell generation. FcμR did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, FcμR-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that FcμR is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the FcμR for regulating immunity and tolerance and suggest that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least two pathways: complement activation and FcμR.

•cCHP nanogel is a safe vaccine delivery system for nasally administered compounds.•Radiolabeled cCHP-nanogel was used in traditional biodistribution assays of mice.•We used a new PET method to assess the biodistribution of cCHP-nanogel in macaques.•In both animals, the CNS was free of nasally administered cCHP-nanogel.•Assessing the biodistribution of both vaccines and delivery systems is important. Cationic cholesteryl-group–bearing pullulan nanogel (cCHP-nanogel) is an effective drug-delivery system for nasal vaccines. However, cCHP-nanogel-based nasal vaccines might access the central nervous system due to its close proximity via the olfactory bulb in the nasal cavity. Using real-time quantitative tracking of the nanogel-based nasal botulinum neurotoxin and pneumococcal vaccines, we previously confirmed the lack of deposition of vaccine antigen in the cerebrum or olfactory bulbs of mice and non-human primates (NHPs), rhesus macaques. Here, we used positron emission tomography to investigate the biodistribution of the drug-delivery system itself, cCHP-nanogel after mice and NHPs were nasally administered with 18F-labeled cCHP nanogel. The results generated by the PET analysis of rhesus macaques were consistent with the direct counting of radioactivity due to 18F or 111In in dissected mouse tissues. Thus, no depositions of cCHP-nanogel were noted in the cerebrum, olfactory bulbs, or eyes of both species after nasal administration of the radiolabeled cCHP-nanogel compound. Our findings confirm the safe biodistribution of the cCHP-nanogel-based nasal vaccine delivery system in mice and NHPs.

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.

Nontypeable Haemophilus influenzae (NTHi) strains form a major group of pathogenic bacteria that colonizes the nasopharynx and causes otitis media in young children. At present, there is no licensed vaccine for NTHi. Because NTHi colonizes the upper respiratory tract and forms biofilms that cause subsequent infectious events, a nasal vaccine that induces NTHi-specific secretory IgA capable of preventing biofilm formation in the respiratory tract is desirable. Here, we developed a cationic cholesteryl pullulan–based (cCHP nanogel) nasal vaccine containing the NTHi surface antigen P6 (cCHP-P6) as a universal vaccine antigen, because P6 expression is conserved among 90% of NTHi strains. Nasal immunization of mice with cCHP-P6 effectively induced P6-specific IgA in mucosal fluids, including nasal and middle ear washes. The vaccine-induced P6-specific IgA showed direct binding to the NTHi via the surface P6 proteins, resulting in the inhibition of NTHi biofilm formation. cCHP-P6 nasal vaccine thus protected mice from intranasal NTHi challenge by reducing NTHi colonization of nasal tissues and eventually eliminated the bacteria. In addition, the vaccine-induced IgA bound to different NTHi clinical isolates from patients with otitis media and inhibited NTHi attachment in a three-dimensional in vitro model of the human nasal epithelial surface. Therefore, the cCHP-P6 nanogel nasal vaccine induced effective protection in the airway mucosa, making it a strong vaccine candidate for preventing NTHi-induced infectious diseases, such as otitis media, sinusitis, and pneumonia.

Background and Objectives: Nutritional management in patients with subarachnoid hemorrhage (SAH) during the acute phase is important; however, there is no proper evidence or recommendations on the appropriate nutrients for early enteral nutrition. This study compared the influence the two different tube-feeding liquid diets for early enteral nutrition might have on the prognosis of patients with SAH. Materials and Methods: In a seven-year period, this single-center retrospective study included 245 patients with aneurysmal SAH who underwent craniotomy and aneurysm neck clipping and received enteral nutrition. The patients were divided into two groups according to the nutrient received: (1) high-protein whey peptide oligomeric formula diet (oligomeric group, 109 patients); and (2) high eicosapentaenoic acid-containing polymeric formula diet (polymeric group, 136 patients). The modified Rankin Scale (mRS) score at discharge was evaluated as the primary outcome. The presence or absence of diarrhea (watery stool and mushy stool) during the period from initiation of enteral nutrition to discharge from the stroke unit was also evaluated. Results: There were no significant differences in patient characteristics between groups. The time until initiation of enteral feeding in the oligomeric and polymeric groups was 2.8 ± 2.3 and 2.9 ± 2.2 days, respectively. The proportion of patients with mRS scores of 0–1 was significantly higher in the oligomeric group (25.7%) than in the polymeric group (14.7%) (p = 0.036), while the incidence of watery stool was significantly lower in the oligomeric group (15.8% to 34.3% in the polymeric group) (p = 0.003). Multivariate analyses confirmed that the oligomeric diet and the presence or absence of diarrhea significantly affected the mRS scores. Conclusions: The adoption of early enteral nutrition with high-protein whey peptide digestive nutrients might be associated with superior mRS scores at discharge and decreased diarrhea in patients with SA, indicating that the choice of nutrients might affect the outcome and prognosis.

Although green and yellow vegetables have beneficial effects against type 2 diabetes, the relationship of their nutritive content with insulin resistance is poorly understood. The aim of this study was to examine the associations of serum β-carotene and retinol concentrations with glucose and insulin concentrations. We recruited 951 Japanese men and women ages 30 to 79 y who were not undergoing treatment for diabetes and measured their serum β-carotene and retinol concentrations. A 75-g oral glucose tolerance test was performed and the homeostasis model assessment for insulin resistance (HOMA-IR) and the Matsuda Index were calculated as measures of insulin resistance. Several confounding factors were adjusted for with multivariable logistic models. Multivariable-adjusted odds ratios of the highest quartile of serum β-carotene compared with the lowest quartile for HOMA-IR >1.6 and Matsuda Index <4.9 were 0.56 (95% confidence interval, 0.34–0.94) and 0.62 (0.37–1.02), respectively. When stratified by sex and overweight status, these associations were observed for women and non-overweight individuals. Serum retinol concentration was not associated with either index. Furthermore, according to the nutritional survey, serum β-carotene concentration was associated with green and yellow vegetable intake (P = 0.01). Our findings suggest that higher serum β-carotene levels, associated with higher intake of green and yellow vegetables, confer beneficial effects against insulin resistance. •This study found that higher serum β-carotene was associated with higher intake of green and yellow vegetables, and also was associated with lower risk for insulin resistance.•This study suggested that higher serum β-carotene have a potential protective effect against insulin resistance.•We conducted oral glucose tolerance tests and assessed insulin resistance using by 1- and 2-h postloaded serum insulin and glucose levels.

Our current study focused on elucidating the role of specific chemokine–receptor interactions in antigen (Ag)-specific immune cell migration from nasal to genital mucosal tissues. This cellular migration is critical to induce effective Ag-specific immune responses against sexually transmitted genital infections. In this study, nasal immunization with live attenuated HSV-2 TK− induced the upregulation of CCR5 expression in effector immune cells, including CD4+ T cells, in Ag-priming sites and vaginal tissue. The CCR5 ligands CCL3, CCL4, and CCL5 all showed upregulated expression in vaginal tissue; in particular, CCL5 expression was highly enhanced in the stromal cells of vaginal tissue after nasal immunization. Intravaginal blockade of CCL5 by using neutralizing antibody diminished the number of HSV-2-specific effector cells in the vagina. Furthermore, loss of CCR5, a receptor for CCL5, impaired the migration of nasally primed Ag-specific effector cells from the airway to vagina. Effector cells adoptively transferred from CCR5-deficient mice failed to migrate into vaginal tissue, consequently increasing recipient mice's susceptibility to HSV-2 vaginal infection. These results indicate that the CCR5–CCL5 chemokine pathway is required for the migration and retention of nasally primed Ag-specific effector cells in vagina for providing protective immunity against HSV-2 infection.

Respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection, especially in children and the elderly. Various vaccines containing the major transmembrane surface proteins of RSV (proteins F and G) have been tested; however, they have either afforded inadequate protection or are associated with the risk of vaccine-enhanced disease (VED). Recently, F protein-based maternal immunization and vaccines for elderly patients have shown promising results in phase III clinical trials, however, these vaccines have been administered by injection. Here, we examined the potential of using the ectodomain of small hydrophobic protein (SHe), also an RSV transmembrane surface protein, as a nasal vaccine antigen. A vaccine was formulated using our previously developed cationic cholesteryl-group-bearing pullulan nanogel as the delivery system, and SHe was linked in triplicate to pneumococcal surface protein A as a carrier protein. Nasal immunization of mice and cotton rats induced both SHe-specific serum IgG and mucosal IgA antibodies, preventing viral invasion in both the upper and lower respiratory tracts without inducing VED. Moreover, nasal immunization induced greater protective immunity against RSV in the upper respiratory tract than did systemic immunization, suggesting a critical role for mucosal RSV-specific IgA responses in viral elimination at the airway epithelium. Thus, our nasal vaccine induced effective protection against RSV infection in the airway mucosa and is therefore a promising vaccine candidate for further development.