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The pandemic of the coronavirus disease 2019 (COVID-19) has created the largest global health crisis in almost a century. Low frequencies of functional SARSCoV-2-specific CD4+ and CD8+ T cells in the lungs of COVID-19 patients have been associated with severe cases of COVID-19. Low levels of T cell-attracting CXCL9, CXCL10, and CXCL11 chemokines in infected lungs may not be sufficient for the migration of CD4+ and CD8+ T cells from circulation into infected lungs. We hypothesize that a coronavirus vaccine strategy that boosts the frequencies of functional SARS-CoV-2-specific CD4+ and CD8+ T cells in the lungs would lead to better protection from COVID-19-like symptoms. In the present study, we designed and pre-clinically tested the safety, immunogenicity, and protective efficacy of a novel multi-epitope/CXCL11 prime/pull mucosal coronavirus vaccine. This prime/pull vaccine strategy consists of intranasal delivery of a lung-tropic adeno-associated virus type 9 vector that incorporates highly conserved human CD4+ and CD8+ cell epitopes of SARS-CoV-2 (prime) followed by recruitment of the primed T cells into the lungs using the T cell-attracting chemokine, CXCL-11 (pull). We demonstrated that the immunization of HLA-DR*0101/HLA-A*0201/hACE2 triple transgenic mice with this multi-epitope/CXCL11 prime/pull coronavirus mucosal vaccine: (i) increased the frequencies of functional CD4+ and CD8+ TEM, TCM, and TRM cells in the lungs and (ii) reduced COVID-19-like symptoms, lowered virus replication, and prevented deaths following challenge with SARS-CoV-2. These findings demonstrate that bolstering the number of functional lung-resident memory CD4+ and CD8+ T cells improved protection against SARS-CoV-2 infection, COVID-19-like symptoms, and death. [ABSTRACT FROM AUTHOR]

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) has been implicated as an important mediator of the increasingly evident cardioprotective benefits exerted by sodium-glucose transport protein 2 channel inhibitors (SGLT2i). However, the exact nature of the relationship between CaMKII and SGLT2i remains unclear. Here, we find that empagliflozin but not dapagliflozin attenuated susceptibility to atrial fibrillation (AF) in a type 2 diabetic (T2D) mouse model. However, both empagliflozin and dapagliflozin protected from diabetic cardiomyopathy in T2D mice. We then used real-time microscopy of neonatal rat ventricular cardiomyocytes (NRVMs) with the CaMKII biosensor - CaMKAR to demonstrate that direct inhibition of CaMKII is not essential for the effects of SGLT2i in these cells. Therefore, we conclude that the benefits of SGLT2i in heart disease likely occur through indirect modulation of CaMKII activity, or possibly through an alternative pathway altogether.

Importance: Although the current rate of SARS-CoV-2 infections has decreased significantly, COVID-19 still ranks very high as a cause of death worldwide. As of October 2023, the weekly mortality rate is still at 600 deaths in the United States alone, which surpasses even the worst mortality rates recorded for influenza. Thus, the long-term outlook of COVID-19 is still a serious concern outlining the need for the next-generation vaccine. This study found that a prime/pull coronavirus vaccine strategy increased the frequency of functional SARS-CoV-2-specific CD4 + and CD8 + memory T cells in the lungs of SARS-CoV-2-infected triple transgenic HLA-DR*0101/HLA-A*0201/hACE2 mouse model, thereby resulting in low viral titer and reduced COVID-19-like symptoms., Competing Interests: L.B.M. has an equity interest in TechImmune, LLC, a company that may potentially benefit from the research results and serves on the company's Scientific Advisory Board. L.B.M.'s relationship with TechImmune, LLC has been reviewed and approved by the University of California, Irvine, in accordance with its conflict-of-interest policies.

Four major mucosal-associated chemokines, CCL25, CCL28, CXCL14, and CXCL17, play an important role in protecting mucosal surfaces from infectious pathogens. However, their role in protection against genital herpes remains to be fully explored. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). In this study, we investigated the role of the CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. We report a significant increase in the frequencies of HSV-specific memory CCR10+CD44+CD8+ T cells, expressing high levels of CCR10, in herpes-infected asymptomatic (ASYMP) women compared with symptomatic women. Similarly, a significant increase in the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP C57BL/6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and memory CCR10+B220+CD27+ B cells in the VM of HSV-infected ASYMP mice. Inversely, compared with wild-type C57BL/6 mice, the CCL28 knockout (CCL28-/-) mice (1) appeared to be more susceptible to intravaginal infection and reinfection with HSV type 2, and (2) exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and of memory CD27+B220+ B cells in the infected VM. These findings suggest a critical role of the CCL28/CCR10 chemokine axis in the mobilization of antiviral memory B and T cells within the VM to protect against genital herpes infection and disease., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Background: During adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ 9 -tetrahydrocannabinol (THC), might persistently alter microglia function., Methods: We administered THC (5 mg/kg, intraperitoneal) once daily to male and female mice from postnatal day (PND) 30 to PND44 and examined the transcriptome of purified microglia in adult animals (PND70 and PND120) under baseline conditions or following either of two interventions known to recruit microglia: lipopolysaccharide injection and repeated social defeat. We used high-dimensional mass cytometry by time-of-flight to map brain immune cell populations after lipopolysaccharide challenge., Results: Adolescent THC exposure produced in mice of both sexes a state of microglial dyshomeostasis that persisted until young adulthood (PND70) but receded with further aging (PND120). Key features of this state included broad alterations in genes involved in microglia homeostasis and innate immunity along with marked impairments in the responses to lipopolysaccharide- and repeated social defeat-induced psychosocial stress. The endocannabinoid system was also dysfunctional. The effects of THC were prevented by coadministration of either a global CB 1 receptor inverse agonist or a peripheral CB 1 neutral antagonist and were not replicated when THC was administered in young adulthood (PND70-84)., Conclusions: Daily low-intensity CB 1 receptor activation by THC during adolescence may disable critical functions served by microglia until young adulthood with potentially wide-ranging consequences for brain and mental health., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Both cirrhosis and acute respiratory illness (ARI) carry substantial disease and financial burden. To compare hospitalized patients with cirrhosis with ARI to cirrhotic patients without ARI, a retrospective cohort study was conducted using the California Office of Statewide Health Planning and Development database. To balance the groups, propensity score matching (PSM) was used. We identified a total of 46,192 cirrhotic patients during the three study periods (14,049, 15,699, and 16,444 patients, respectively). Among patients hospitalized with cirrhosis, the ARI prevalence was higher in older age groups (p < 0.001), the Asian population (p = 0.002), non-Hispanic population (p = 0.001), and among Medicare patients (p < 0.001). Compared to controls, patients with ARI had 53.8% higher adjusted hospital charge ($122,555 vs. $79,685 per patient per admission, p < 0.001) and 35.0% higher adjusted in-hospital mortality (p < 0.001). Older patients, patients with alcoholic liver disease or liver cancer were at particularly higher risk (adjusted hazard ratio = 2.94 (95% CI: 2.26-3.83), 1.22 (95% CI: 1.02-1.45), and 2.17 (95% CI: 1.76-2.68) respectively, p = 0.028 to <0.001). Mortality rates and hospital charges in hospitalized cirrhotic patients with ARI were higher than in cirrhotic controls without ARI. Preventive efforts such as influenza and pneumococcal vaccination, especially in older patients and those with liver cancer, or alcoholic liver disease, would be of value.

Background & Aims: Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Unlike other liver diseases, HBV can cause HCC in the absence of cirrhosis. We investigated whether features of HCC in patients with HBV infection without cirrhosis and survival times differ from those of patients who develop HCC after cirrhosis., Methods: We performed a retrospective cohort study of 487 consecutive cases of HBV-related HCC who were seen from 2000 through 2014 at a tertiary care center. Laboratory values, imaging results, and treatment information were obtained from subjects' medical records. Symptoms of HCC included weight loss, abdominal pain, or new hepatic decompensation. The primary outcome was overall survival, which was categorized as short-term survival (up to 3 years after the diagnosis of HCC) or long-term survival (3-10 years after diagnosis)., Results: The mean tumor size at diagnosis was significantly larger in patients without cirrhosis (6.4 ± 4.3 cm) than in patients with cirrhosis (5.0 ± 3.8 cm) (P = .0009). A significantly larger proportion of patients without cirrhosis had symptoms at diagnosis (43.8% vs 35.4% in patients without cirrhosis, P = .09). A significantly higher proportion of patients without cirrhosis survived for the long-term (P = .003), but there was no significant difference between groups in short-term survival (P = .37). Notably, the same proportions of asymptomatic patients with and without cirrhosis survived for the short-term (64.3% vs 64.2%, P = .73), but a lower proportion of asymptomatic patients with cirrhosis survived for the long-term (P = .015). In multivariate Cox regression analysis, cirrhosis was an independent predictor of death in 3-10 years (hazard ratio, 3.76; P = .003) but not in less than 3 years (P = .48). Symptoms at diagnosis predicted death within 3 years (hazard ratio, 1.76; P =.006) but not in 3-10 years (P = .15)., Conclusions: Patients with HBV infection and HCC without cirrhosis present with larger tumors, and a larger percentage have symptoms of cancer than patients with cirrhosis. This may indicate that HCC surveillance is less than optimal for patients with HBV infection without cirrhosis. Despite this suboptimal surveillance, patients without cirrhosis have higher long-term survival than those with cirrhosis, especially when asymptomatic at diagnosis., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Studies of biparental mammals demonstrate that males may undergo systematic changes in body mass as a consequence of changes in reproductive status; however, these studies typically have not teased apart effects of specific social and reproductive factors, such as cohabitation with a female per se , cohabitation with a breeding female specifically, and engagement in paternal care. We aimed to determine whether California mouse ( Peromyscus californicus ) fathers undergo systematic changes in body mass and if so, which specific social/reproductive factor(s) might contribute to these changes. We compared mean weekly body masses over a 5-week period in 1) males housed with another male vs. males housed with a non-reproductive (tubally ligated) female; 2) males housed with a tubally ligated female vs. males housed with a female that was undergoing her first pregnancy; and 3) experienced fathers housed with vs. without pups during their mate's subsequent pregnancy. Body mass did not differ between males housed with another male and those housed with a non-reproductive female; however, males housed with a non-reproductive female were significantly heavier than those housed with a primiparous female. Among experienced fathers, those housed with pups from their previous litter underwent significant increases in body mass across their mates' pregnancy, whereas fathers housed without pups did not. These results suggest that male body mass is reduced by cohabitation with a breeding (pregnant) female, but not by cohabitation with a non-reproductive female, and that increases in body mass across the mate's pregnancy are associated with concurrent care of offspring rather than cohabitation with a pregnant female. Additional work is needed to determine the mechanisms and functional significance, if any, of these changes in male body mass with reproductive condition.