Smith-specific regulatory T cells halt the progression of lupus nephritis.

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Epithelially Restricted Interferon Epsilon Protects Against Colitis.

BACKGROUND & AIMS: Type I interferon (T1IFN) signalling is crucial for maintaining intestinal homeostasis. We previously found that the novel T1IFN, IFNε, is highly expressed by epithelial cells of the female reproductive tract, where it protects against pathogens. Its function has not been studied in the intestine. We hypothesize that IFNε is important in maintaining intestinal homeostasis. METHODS: We characterized IFNε expression in mouse and human intestine by immunostaining and studied its function in the dextran sulfate sodium (DSS) colitis model using both genetic knockouts and neutralizing antibody. RESULTS: We demonstrate that IFNε is expressed in human and mouse intestinal epithelium, and expression is lost in inflammation. Furthermore, we show that IFNε limits intestinal inflammation in mouse models. Regulatory T cell (Treg) frequencies were paradoxically decreased in DSS-treated IFNε-/- mice, suggesting a role for IFNε in maintaining the intestinal Treg compartment. Colitis was ameliorated by transfer of wild-type Tregs into IFNε-/- mice. This demonstrates that IFNε supports intestinal Treg function. CONCLUSIONS: Overall, we have shown IFNε expression in intestinal epithelium and its critical role in gut homeostasis. Given its known role in the female reproductive tract, we now show IFNε has a protective role across multiple mucosal surfaces.

Heterologous Immunity Between SARS-CoV-2 and Pathogenic Bacteria.

Heterologous immunity, when the memory T cell response elicited by one pathogen recognizes another pathogen, has been offered as a contributing factor for the high variability in coronavirus disease 2019 (COVID-19) severity outcomes. Here we demonstrate that sensitization with bacterial peptides can induce heterologous immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) derived peptides and that vaccination with the SARS-CoV-2 spike protein can induce heterologous immunity to bacterial peptides. Using in silico prediction methods, we identified 6 bacterial peptides with sequence homology to either the spike protein or non-structural protein 3 (NSP3) of SARS-CoV-2. Notwithstanding the effects of bystander activation, in vitro co-cultures showed that all individuals tested (n=18) developed heterologous immunity to SARS-CoV-2 peptides when sensitized with the identified bacterial peptides. T cell recall responses measured included cytokine production (IFN-γ, TNF, IL-2), activation (CD69) and proliferation (CellTrace). As an extension of the principle of heterologous immunity between bacterial pathogens and COVID-19, we tracked donor responses before and after SARS-CoV-2 vaccination and measured the cross-reactive T cell responses to bacterial peptides with similar sequence homology to the spike protein. We found that SARS-CoV-2 vaccination could induce heterologous immunity to bacterial peptides. These findings provide a mechanism for heterologous T cell immunity between common bacterial pathogens and SARS-CoV-2, which may explain the high variance in COVID-19 outcomes from asymptomatic to severe. We also demonstrate proof-of-concept that SARS-CoV-2 vaccination can induce heterologous immunity to pathogenic bacteria derived peptides.

BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity.

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.

The complexity of cultural mismatch in higher education: Norms affecting first-generation college students' coping and help-seeking behaviors.

OBJECTIVES: First-generation college students commonly experience financial, academic, and personal challenges that are exacerbated by a cultural mismatch between independent university settings and interdependent family environments. There is a paucity of research on the influence of cultural norms, including cultural mismatch, on first-generation college students' coping and help-seeking behaviors. The present research explored how cultural norms affect coping and help seeking for academic, financial, and psychological problems among diverse first-generation college students. METHOD: Eleven individual interviews were conducted to obtain pilot data, and 8 group interviews (n = 60) were conducted to examine cultural norms, relational concerns, coping, and social support. These same 71 participants (51% Ethnic Minority; 49% White; 70% female) completed a background survey (e.g., demographics, use of resources, coping, and family obligation). RESULTS: Most students were self-reliant and underutilized social support because of concerns about negatively affecting close relationships; these relational concerns included burdening others, being judged by others, and making matters worse. Concerns about face loss and group harmony were heightened among ethnic minority students. Despite limited quantitative evidence for White-Ethnic Minority differences in coping and psychological and academic functioning, minority students reported higher levels of family obligation. CONCLUSIONS: Results revealed a mismatch between hard independence (being self-reliant, resilient, and emotionally tough) and soft independence (being self-expressive, pursuing personal interests, and gaining a sense of freedom) and illuminate how relational concerns hinder help seeking among first-generation college students. These findings support culturally tailoring outreach efforts to address norms that promote self-reliance and the underutilization of services. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

LCAT, ApoD, and ApoA1 Expression and Review of Cholesterol Deposition in the Cornea.

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies plasma cholesterol and increases the capacity of HDL to carry and potentially remove cholesterol from tissues. Cholesterol accumulates within the extracellular connective tissue matrix of the cornea stroma in individuals with genetic deficiency of LCAT. LCAT can be activated by apolipoproteins (Apo) including ApoD and ApoA1. ApoA1 also mediates cellular synthesis of HDL. This study examined the expression of LCAT by epithelial cells, keratocytes, and endothelial cells, the cell types that comprise from anterior to posterior the three layers of the cornea. LCAT and ApoD were immunolocalized to all three cell types within the cornea, while ApoA1 was immunolocalized to keratocytes and endothelium but not epithelium. In situ hybridization was used to detect LCAT, ApoD, and ApoA1 mRNA to learn what cell types within the cornea synthesize these proteins. No corneal cells showed mRNA for ApoA1. Keratocytes and endothelium both showed ApoD mRNA, but epithelium did not. Epithelium and endothelium both showed LCAT mRNA, but despite the presence of LCAT protein in keratocytes, keratocytes did not show LCAT mRNA. RNA sequencing analysis of serum-cultured dedifferentiated keratocytes (commonly referred to as corneal stromal fibroblasts) revealed the presence of both LCAT and ApoD (but not ApoA1) mRNA, which was accompanied by their respective proteins detected by immunolabeling of the cultured keratocytes and Western blot analysis of keratocyte lysates. The results indicate that keratocytes in vivo show both ApoA1 and LCAT proteins, but do not synthesize these proteins. Rather, keratocytes in vivo must take up ApoA1 and LCAT from the corneal interstitial tissue fluid.

Melatonin Affects Mitochondrial Fission/Fusion Dynamics in the Diabetic Retina.

Mitochondrial fission and fusion are dependent on cellular nutritional states, and maintaining this dynamics is critical for the health of cells. Starvation triggers mitochondrial fusion to maintain bioenergetic efficiency, but during nutrient overloads (as with hyperglycemic conditions), fragmenting mitochondria is a way to store nutrients to avoid waste of energy. In addition to ATP production, mitochondria play an important role in buffering intracellular calcium (Ca2+). We found that in cultured 661W cells, a photoreceptor-derived cell line, hyperglycemic conditions triggered an increase of the expression of dynamin-related protein 1 (DRP1), a protein marker of mitochondrial fission, and a decrease of mitofusin 2 (MFN2), a protein for mitochondrial fusion. Further, these hyperglycemic cells also had decreased mitochondrial Ca2+ but increased cytosolic Ca2+. Treating these hyperglycemic cells with melatonin, a multifaceted antioxidant, averted hyperglycemia-altered mitochondrial fission-and-fusion dynamics and mitochondrial Ca2+ levels. To mimic how people most commonly take melatonin supplements, we gave melatonin to streptozotocin- (STZ-) induced type 1 diabetic mice by daily oral gavage and determined the effects of melatonin on diabetic eyes. We found that melatonin was not able to reverse the STZ-induced systemic hyperglycemic condition, but it prevented STZ-induced damage to the neural retina and retinal microvasculature. The beneficial effects of melatonin in the neural retina in part were through alleviating STZ-caused changes in mitochondrial dynamics and Ca2+ buffering.

Change in Patient Activation and Mental Illness Symptoms After Communication Training: A Multisite Study With a Diverse Patient Sample.

OBJECTIVE: Patient activation involves patients' ability and motivation to communicate about their health and health care. Research has demonstrated that clinician or patient interventions may improve patient activation. This study explored the degree to which clinician and patient interventions affected both patient activation and symptoms of depression and anxiety in a racially and ethnically diverse clinical sample. METHODS: Data were from a randomized clinical trial that included 312 patients and 74 clinicians from 13 Massachusetts community- and hospital-based outpatient behavioral health clinics. Patients completed measures of patient activation and depression and anxiety symptoms. Secondary data analyses were conducted to examine the effect of patient and clinician interventions (DECIDE-PA and DECIDE-PC, respectively) on depression and anxiety symptoms and patient activation. A multilevel, mixed-effects simultaneous-equation model was estimated to assess the relationship between the interventions, changes in patients' symptoms, and patient activation. RESULTS: Clinicians' greater intervention dosage (i.e., more completed DECIDE-PC training sessions) was associated with patients' decreased anxiety symptoms, but associations with patient activation or depression symptoms were not significant. The effect of clinician training dosage on anxiety symptoms was stronger when patients and clinicians were not of the same race-ethnicity. The reduction in patients' anxiety symptoms appeared to increase patient activation. CONCLUSIONS: Clinician interventions designed to boost patient-clinician communication and the therapeutic alliance may serve to lessen patients' anxiety and may ultimately improve patient activation.

Pregnancy Intentions, Contraceptive Knowledge And Educational Aspirations Among Community College Students.

CONTEXT: Community college students, representing more than one-third of U.S. undergraduates, are a diverse population of young people motivated to seek higher education who are at elevated risk of unintended pregnancy. However, it is unknown how well prepared they are to prevent pregnancy and what they think about it in terms of their educational aspirations. METHODS: In-depth interviews were conducted with 57 students aged 18-25, inclusive of all genders, in three community colleges in California in 2015. Content analysis was used to code data and identify themes. RESULTS: All participants reported strong desires to prevent pregnancy in the next year and perceived their pregnancy risk as low, but many reported unprotected sex with opposite-sex partners. Participants had specific timelines for completing their degrees and believed pregnancy would make that far more challenging, but would not ultimately prevent them from achieving their goals. Female students expressed concern about the risks of exacerbated poverty, housing instability and unachieved career goals. Participants had little knowledge of their pregnancy risks and of the health benefits, side effects or effectiveness of contraceptives. They held negative beliefs about hormonal contraception (including emergency contraception, IUDs and the implant), fearing long-lasting effects and infertility. Gay or bisexual students shared concerns about contraceptives, although several were using methods for noncontraceptive reasons. CONCLUSION: Many community college students not desiring pregnancy have limited awareness of pregnancy risk and prevention.

Macrophages Shed Excess Cholesterol in Unique Extracellular Structures Containing Cholesterol Microdomains.

OBJECTIVE: Cells use various mechanisms to maintain cellular cholesterol homeostasis including efflux of cholesterol from the cellular plasma membrane to cholesterol acceptors such as HDLs (high-density lipoproteins). Little is known about the transfer of cholesterol from cells into the extracellular matrix. Using a unique monoclonal antibody that detects ordered cholesterol arrays (ie, cholesterol micro[or nano]-domains), we previously identified that particles containing these cholesterol domains accumulate in the extracellular matrix during cholesterol enrichment of human monocyte-derived macrophages and are found in atherosclerotic lesions. In this study, we further investigate these deposited particles containing cholesterol microdomains and discover their unexpected morphology. APPROACH AND RESULTS: Although appearing spherical at the resolution of the conventional fluorescence microscope, super-resolution immunofluorescence and atomic force microscopy of in situ cholesterol microdomains, and immunoelectron microscopy of isolated cholesterol microdomains revealed that the microdomains are not vesicles or 3-dimensional crystals but rather appear as branching irregularly shaped deposits of varying size. These cholesterol microdomain-containing deposits are shed from the plasma membrane into the extracellular matrix. CONCLUSIONS: To date, research on cellular excretion of excess cholesterol has demonstrated cellular cholesterol efflux in the form of membranous vesicles and discoidal HDL particles released into the fluid-phase medium. Shedding of plasma membrane cholesterol microdomains provides an additional mechanism for cells such as macrophages to maintain plasma membrane cholesterol homeostasis. Furthermore, recognition that macrophages shed cholesterol microdomains into the extracellular matrix is important to our understanding of extracellular buildup of cholesterol in atherosclerosis.

Analysis of Serum Interleukin (IL)-1ß and IL-18 in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1ß and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. Here, IL-1ß and IL-18 were quantified by enzyme-linked immunosorbent assay in the serum of healthy controls (HCs) and SLE patients from a prospectively followed cohort. Disease activity and organ damage were assessed using SLE disease activity index 2000 (SLEDAI-2K) and SLE damage index scores (SDI), respectively. 184 SLE patients (mean age 44.9 years, 91% female, 56% double-stranded deoxyribonucleic acid positive) were compared to 52 HC. SLE patients had median [IQR] SLEDAI-2K of 4 [2,6], and SDI of 1 [0-2]. Serum IL-18 levels were statistically significantly higher in SLE patients compared to HCs. Univariable linear regression analyses showed that patients with active renal disease or irreversible organ damage had statistically significantly elevated serum IL-18 levels. The association between serum IL-18 and active renal disease was confirmed in multivariable analysis after adjusting for ethnicity and organ damage. High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1ß levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1ß have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.

Circadian Regulation of Mitochondrial Dynamics in Retinal Photoreceptors.

Energy expenditure and metabolism in the vertebrate retina are under circadian control, as we previously reported that the overall retinal ATP content and various signaling molecules related to metabolism display daily or circadian rhythms. Changes in the fission and fusion process of mitochondria, the major organelles producing ATP, in retinal photoreceptors are largely dependent on light exposure, but whether mitochondrial dynamics in photoreceptors and retinal neurons are under circadian control is not clear. Herein, we investigated the possible roles of circadian oscillators in regulating mitochondrial dynamics, mitophagy, and redox states in the chicken retina and mammalian photoreceptors. After entrainment to 12:12-h light-dark (LD) cycles for several days followed by free-running in constant darkness (DD), chicken embryonic retinas and cone-derived 661W cells were collected in either LD or DD at 6 different zeitgeber time (ZT) or circadian time (CT) points. The protein expression of mitochondrial dynamin-related protein 1 (DRP1), mitofusin 2 (MFN2), and PTEN-induced putative kinase 1 (PINK1) displayed daily rhythms, but only DRP1 was under circadian control in the chicken retinas and cultured 661W cells. In addition, cultured chicken retinal cells responded to acute oxidative stress differently from 661W cells. Using pMitoTimer as a mitochondrial redox indicator, we found that the mitochondrial redox states were more affected by light exposure than regulated by circadian oscillators. Thus, this study demonstrates that the influence of cyclic lights might outweigh the circadian regulation of complex mitochondrial dynamics in light-sensing retinal cells.

Developmental and contextual correlates of mental health and help-seeking among Asian American college students.

Guided by an integrative contextual framework of immigrant youth development (García Coll & Marks, 2012), this study investigated the potential role of developmental (e.g., ethnic identity) and contextual factors (e.g., perceived discrimination, stereotyping) in mental health outcomes and help-seeking attitudes, and variations across gender and nativity among Asian American college students. Online surveys assessing perceived subtle and blatant racism, ethnic identity, the internalization of the model minority stereotype, depressive symptoms, anxiety symptoms, and attitudes toward seeking help from mental health professionals were administered to Asian American college student participants (n = 465) from diverse ethnic backgrounds and geographic regions in the United States. The findings support prior research indicating that perceived subtle racism and blatant racism are positively associated with depressive and anxiety symptoms. Further, only certain dimensions of ethnic identity and internalization of the model minority stereotype were found to be associated with mental health outcomes and help-seeking attitudes. The findings did not indicate a significant association between perceived racism and help-seeking attitudes. There were also no significant differences in the relationships among variables across gender and nativity, with the exception of the association between ethnic identity and help-seeking attitudes across gender. The study identified potential risk and protective factors in mental health, while underscoring the multidimensional aspects of social and contextual factors that contribute to mental health and help seeking among Asian American college students. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses.

L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4) expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Müller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3-/-) mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3-/- mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3-/- mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported.

Psychological Vulnerability and Gambling in Later Life.

OBJECTIVES: Because behavioral problems often emerge from maladaptive coping methods, we investigated whether unmet basic psychological needs evolve toward a level of psychological vulnerability that puts older adults who gamble at risk for becoming problem gamblers. METHODS: Data from a community sample of 379 adults ages 60 and above were analyzed using structural equation modeling. Participants responded to items regarding their demographics, gambling frequency, engagement in at-risk gambling behaviors, and the extent to which their basic psychological needs were met. RESULTS: Satisfaction of basic psychological needs among older adults who gamble was negatively associated with their being at risk for developing a gambling problem. Satisfaction of basic psychological needs also mediated the negative effect of socioeconomic status on at-risk gambling behavior. CONCLUSION: Social workers should become mindful of how older adults, who are confronting psychological vulnerabilities in later life, might well turn to gambling as a maladaptive coping mechanism.As per journal style, abstract must not exceed100 words. Please amend accordingly.

Impact of the Act FAST stroke campaign delivered by student pharmacists on the primary prevention of stroke.

OBJECTIVES: To evaluate the impact of an Act FAST educational intervention performed by student pharmacists on knowledge of stroke recognition and management. DESIGN: Stroke preparedness and knowledge of primary prevention were assessed with the use of pre- and post-intervention surveys targeting community members at health fairs. The intervention was an Act FAST educational session with blood pressure and blood glucose screenings provided by student pharmacists. Act FAST is a quick tool to help recognize and respond to a stroke. The acronym FAST stands for Face, Arms, Speech, and Time. SETTING: Community health fairs in Vallejo, CA. PARTICIPANTS: Community members 18 years of age and older. INTERVENTION: Act FAST educational session delivered by student pharmacists. MAIN OUTCOME MEASURES: Knowledge of signs, symptoms, management, and risk factors of strokes as defined by the American Heart Association. RESULTS: Following the Act FAST educational intervention, total knowledge of signs, symptoms, and management of stroke significantly increased from moderate to high (n = 112; 95% confidence interval [CI] 1.419-2.188; P <0.0001). Total knowledge of risk factors of stroke also significantly increased following the educational intervention (n = 88; 95% CI 0.6496-1.746; P <0.0001). CONCLUSION: The Act FAST educational intervention delivered by student pharmacists increased knowledge of signs, symptoms, immediate management, and modifiable risk factors of stroke. This suggests that student pharmacists may have a positive impact on community members' preparedness and knowledge of primary prevention of stroke. The Act FAST campaign may be a useful tool for all training health care professionals.

The Effects of Metformin on Obesity-Induced Dysfunctional Retinas.

Purpose: The purpose of this study was to determine the effects of metformin on dysfunctional retinas in obesity-induced type 2 diabetic mice. Methods: A high-fat diet (HFD)-induced diabetic mouse model (C57BL/6J) was used in this study. After 2 months of the HFD regimen, HFD mice were given daily metformin through oral gavage. Body weights, glucose tolerance, and retinal light responses were monitored regularly. Fluorescein angiography (FA) was used to assess changes in retinal vasculature. Ocular tissues (retina, vitreous, and lens) were harvested and analyzed for molecular changes as determined by immunofluorescent staining, Western blot analysis, and cytokine profiling. Results: Starting 1 month after the diet regimen, mice fed the HFD had mildly compromised retinal light responses as measured by electroretinography (ERG), which worsened over time compared to that in the control. In HFD mice treated with metformin, systemic glucose levels reverted back to normal, and their weight gain slowed. Metformin reversed HFD-induced changes in phosphorylated protein kinase B (pAKT), extracellular signal-regulated kinase (pERK), and 5'AMP-activated protein kinase (pAMPK) in the retina. However, metformin treatments for 3 months did not restore the retinal light responses nor lessen the HFD-induced retinal neovascularization, even though it did reduce intraocular inflammation. Conclusions: Although metformin was able to reverse systemic changes induced by HFD, it was not able to restore HFD-caused retinal light responses or deter neovascularization.

CD8+ T Cells Effect Glomerular Injury in Experimental Anti-Myeloperoxidase GN.

Observations in patients with ANCA-associated vasculitis suggest that CD8+ T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8+ T cells mediate disease in experimental ANCA-associated vasculitis. CD8+ T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-γ, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8+ T cell MPO epitope (MPO431-439) and found that cotransfer of MPO431-439-specific CD8+ T cell clones exacerbated disease mediated by MPO-specific CD4+ cells in Rag1-/- mice. Transfer of MPO431-439-specific CD8+ cells without CD4+ cells mediated glomerular injury when MPO was planted in glomeruli. These results show a pathogenic role for MPO-specific CD8+ T cells, provide evidence that CD8+ cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8+, CD4+, and B cell epitopes.

Model Minority Stereotype: Influence on Perceived Mental Health Needs of Asian Americans.

This study examined the influence of the model minority stereotype on the perceived mental health functioning of Asian Americans. It was hypothesized that college students would perceive Asian Americans as having fewer mental health problems and clinical symptoms than Whites due to the model minority stereotype. Four hundred and twenty-five undergraduate students from a predominately White college campus in the American northeast were randomly exposed to one of four conditions: (1) a clinical vignette describing a White college student suffering from adjustment disorder; (2) the same vignette describing an Asian American college student; (3) a newspaper article describing a success story of Whites and the White clinical vignette; (4) the same newspaper article and clinical vignette describing an Asian American. Following exposure to one of the conditions, participants completed a memory recall task and measures of colorblindness, attitudes towards Asian Americans, attitudes towards out-group members, and perceived mental health functioning. Participants exposed to the vignettes primed with the positive/model minority stereotype perceived the target regardless of race/ethnicity as having better mental health functioning and less clinical symptoms than the condition without the stereotype. Additionally, the stereotype primer was found to be a modest predictor for the perception of mental health functioning in Asian American vignettes. Results shed light on the impact of the model minority stereotype on the misperception of Asian Americans' mental health status, contributing to the invisibility or neglect of this minority group's mental health needs.

Deletion of miR-150 Exacerbates Retinal Vascular Overgrowth in High-Fat-Diet Induced Diabetic Mice.

Diabetic retinopathy (DR) is the leading cause of blindness among American adults above 40 years old. The vascular complication in DR is a major cause of visual impairment, making finding therapeutic targets to block pathological angiogenesis a primary goal for developing DR treatments. MicroRNAs (miRs) have been proposed as diagnostic biomarkers and potential therapeutic targets for various ocular diseases including DR. In diabetic animals, the expression levels of several miRs, including miR-150, are altered. The expression of miR-150 is significantly suppressed in pathological neovascularization in mice with hyperoxia-induced retinopathy. The purpose of this study was to investigate the functional role of miR-150 in the development of retinal microvasculature complications in high-fat-diet (HFD) induced type 2 diabetic mice. Wild type (WT) and miR-150 null mutant (miR-150-/-) male mice were given a HFD (59% fat calories) or normal chow diet. Chronic HFD caused a decrease of serum miR-150 in WT mice. Mice on HFD for 7 months (both WT and miR-150-/-) had significant decreases in retinal light responses measured by electroretinograms (ERGs). The retinal neovascularization in miR-150-/--HFD mice was significantly higher compared to their age matched WT-HFD mice, which indicates that miR-150 null mutation exacerbates chronic HFD-induced neovascularization in the retina. Overexpression of miR-150 in cultured endothelial cells caused a significant reduction of vascular endothelial growth factor receptor 2 (VEGFR2) protein levels. Hence, deletion of miR-150 significantly increased the retinal pathological angiogenesis in HFD induced type 2 diabetic mice, which was in part through VEGFR2.