Severe hurricanes increase recruitment and gene flow in the clonal sponge Aplysina cauliformis.

Upright branching sponges, such as Aplysina cauliformis, provide critical three-dimensional habitat for other organisms and assist in stabilizing coral reef substrata, but are highly susceptible to breakage during storms. Breakage can increase sponge fragmentation, contributing to population clonality and inbreeding. Conversely, storms could provide opportunities for new genotypes to enter populations via larval recruitment, resulting in greater genetic diversity in locations with frequent storms. The unprecedented occurrence of two Category 5 hurricanes in close succession during 2017 in the U.S. Virgin Islands (USVI) provided a unique opportunity to evaluate whether recolonization of newly available substrata on coral reefs was due to local (e.g. re-growth of remnants, fragmentation, larval recruitment) or remote (e.g. larval transport and immigration) sponge genotypes. We sampled A. cauliformis adults and juveniles from four reefs around St. Thomas and two in St. Croix (USVI). Using a 2bRAD protocol, all samples were genotyped for single-nucleotide polymorphisms (SNPs). Results showed that these major storm events favoured sponge larval recruitment but did not increase the genetic diversity of A. cauliformis populations. Recolonization of substratum post-storms via clonality was lower (15%) than expected and instead was mainly due to sexual reproduction (85%) via local larval recruitment. Storms did enhance gene flow among and within reef sites located south of St. Thomas and north of St. Croix. Therefore, populations of clonal marine species with low pelagic dispersion, such as A. cauliformis, may benefit from increased frequency and magnitude of hurricanes for the maintenance of genetic diversity and to combat inbreeding, enhancing the resilience of Caribbean sponge communities to extreme storm events.

HIV Support Source: Development of a Distress Screening Measure for Adults with HIV.

To provide an effective, multidimensional, and psychometrically valid measure to screen for distress among people with HIV, we developed and assessed the psychometric properties of HIV Support Source, a distress screening, referral, and support program designed to identify the unmet needs of adults with HIV and link them to desired resources and support. Development and testing were completed in three phases: (1) item generation and initial item pool testing (N = 375), (2) scale refinement via exploratory factor analysis (N = 220); external/internal item quality, and judging theoretical and practical implications of items, and (3) confirmatory validation (N = 150) including confirmatory factor analysis along with reliability and validity analyses to corroborate dimensionality and psychometric properties of the final measure. Nonparametric receiver operating characteristic (ROC) curve analyses determined scoring thresholds for depression and anxiety risk subscales. The final measure comprises 17-items representing four domains of concern: emotional well-being, financial and practical needs, physical well-being, and HIV treatment and sexual health, plus one screening item assessing tobacco and substance use. Our analyses showed strong internal consistency reliability, a replicable factor structure, and adequate convergent, discriminant, and known groups validity. Sensitivity of 2-item depression and 2-item anxiety risk subscales was 0.90 and 0.79, respectively. HIV Support Source is a reliable and valid multidimensional measure of distress that also screens for risk for clinically significant depression and anxiety. It can be implemented within a distress screening, referral, and follow-up program to rapidly assess and support the unmet needs of adults with HIV.

CancerSupportSourceTM -Caregiver: Development of a distress screening measure for cancer caregivers.

OBJECTIVE: Given the substantial demands of cancer caregiving, practical and psychometrically sound tools to evaluate distress among cancer caregivers are needed. CancerSupportSourceTM -Caregiver is a distress screening, referral, and support program designed to identify the unmet needs of cancer caregivers and link caregivers to desired resources and support. This study refined and finalized the CancerSupportSource-Caregiver screening measure and examined its psychometric properties. METHODS: Using an analytic sample of 400 caregivers to people with cancer, we first performed item reduction by assessing exploratory factor analysis, external/internal item quality, and judging theoretical and practical implications of items. Confirmatory factor analysis along with reliability and validity analyses were then conducted to corroborate dimensionality and psychometric properties of the final measure. Nonparametric receiver operating characteristic curve analyses determined scoring thresholds for depression and anxiety risk subscales. RESULTS: Scale refinement resulted in an 18-item measure plus one screening item assessing tobacco and substance use. Items represented five domains of caregiver concerns: emotional well-being, patient well-being, caregiving tasks, finances, and healthy lifestyle. Our analyses showed strong internal consistency and test-retest reliability, a replicable factor structure, and adequate convergent, discriminant, and known groups validity. Sensitivity of 2-item depression and 2-item anxiety risk subscales were 0.95 and 0.87, respectively. CONCLUSIONS: CancerSupportSource-Caregiver is a reliable and valid multidimensional measure of caregiver distress that also screens for risk for clinically significant depression and anxiety. It can be implemented within a distress screening, referral, and follow-up program to rapidly assess caregivers' unmet needs and enhance caregiver well-being across the care continuum.

Investigating the interactive effects of temperature, pH, and salinity on Naegleria fowleri persistence.

Naegleria fowleri causes primary amoebic meningoencephalitis, a deadly infection that occurs when free-living amoebae enter the nose via freshwater and travel to the brain. N. fowleri naturally thrives in freshwater and soil and is thought to be associated with elevated water temperatures. While environmental and laboratory studies have sought to identify what environmental factors influence its presence, many questions remain. This study investigated the interactive effects of temperature, pH, and salinity on N. fowleri in deionized and environmental waters. Three temperatures (15, 25, 35°C), pH values (6.5, 7.5, 8.5), and salinity concentrations (0.5%, 1.5%, 2.5% NaCl) were used to evaluate the growth of N. fowleri via ATP luminescent assays. Results indicated N. fowleri grew best at 25°C, and multiple interactive effects occurred between abiotic factors. Interactions varied slightly by water type but were largely driven by temperature and salinity. Lower temperature increased N. fowleri persistence at higher salinity levels, while low salinity (0.5% NaCl) supported N. fowleri growth at all temperatures. This research provided an experimental approach to assess interactive effects influencing the persistence of N. fowleri. As climate change impacts water temperatures and conditions, understanding the microbial ecology of N. fowleri will be needed minimize pathogen exposure.

Clinical characterization of primary hyperoxaluria type 3 in comparison with types 1 and 2.

BACKGROUND: Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. METHODS: Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). RESULTS: PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients. CONCLUSIONS: Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.

Recovery From Dialysis in Patients With Primary Hyperoxaluria Type 1 Treated With Pyridoxine: A Report of 3 Cases.

Primary hyperoxaluria type 1 (PH1) is a genetic disorder characterized by overproduction of oxalate and eventual kidney failure. Kidney failure is usually irreversible in PH1. However, in patients with PH1 homozygous for the G170R mutation (in which the glycine at amino acid 170 is replaced by an arginine), pyridoxine is an enzyme cofactor and decreases urinary oxalate excretion by reducing hepatic oxalate production. We report recovery from dialysis in 3 patients with PH1 homozygous for the G170R mutation in response to pharmacologic-dose pyridoxine treatment. Median age at initiation or resumption of pyridoxine treatment was 37 (range, 20-53) years, and median daily pyridoxine dose was 8.8 (range, 6.8-14.0) mg per kilogram of body weight. Duration of hemodialysis before recovery of kidney function was 10 (range, 5-19) months. Plasma oxalate concentration improved after recovery of kidney function. At a median of 3 (range, 2-46) months following discontinuation of hemodialysis, estimated glomerular filtration rate was 34 (range, 23-52) mL/min/1.73m2, plasma oxalate concentration was 8.8 (range, 4.6-11.3) µmol/L, and urinary oxalate excretion was 0.93 (range, 0.47-1.03) mmol/d. Kidney function was maintained during a median of 3.2 (range, 1.3-3.8) years of follow-up. These observations suggest that kidney failure may be reversible in a subset of patients with PH1 homozygous for the G170R mutation treated with pharmacologic-dose pyridoxine.

CancerSupportSource®-15+: development and evaluation of a short form of a distress screening program for cancer patients and survivors.

PURPOSE: CancerSupportSource® (CSS) is a distress screening program implemented at community-based organizations and hospitals nationwide. The 25-item CSS assesses distress across five domains, with capacity to screen for clinically significant depression and anxiety. This study examined psychometric properties of a shortened form to enhance screening opportunities when staff or patient burden considerations are significant. METHODS: Development and validation were completed in multiple phases. Item reduction decisions were made with 1436 cancer patients by assessing external/internal item quality and judging theoretical and practical implications of items. Pearson correlations and confirmatory factor analysis were conducted on a separate sample of 957 patients to corroborate psychometric properties and dimensionality of the shortened scale. Nonparametric receiver operating characteristic (ROC) curve analyses determined scoring thresholds for depression and anxiety risk scales. RESULTS: Scale refinement resulted in a 15-item short form plus one screening item assessing tobacco and substance use (CSS-15+). At least two items from each CSS domain were retained to preserve multidimensionality. In confirmatory analysis, the model explained 59% of the variance and demonstrated good fit. Correlation between CSS-15+ and 25-item CSS was 0.99, p < 0.001. Sensitivity of 2-item depression and 2-item anxiety risk scales in the confirmatory sample were 0.82 and 0.83, respectively. CONCLUSIONS: CSS-15+ is a brief, reliable, and valid multidimensional measure of distress. The measure retained excellent internal consistency (α = 0.94) and a stable factor structure. CSS-15+ is a practical and efficient screening tool for distress and risk for depression and anxiety among cancer patients and survivors, particularly in community-based settings.

Symptom Burden, Perceived Control, and Quality of Life Among Patients Living With Multiple Myeloma.

BACKGROUND: New therapies for multiple myeloma (MM) have improved survival rates but often expose patients to heightened toxicities and prolonged treatment, leading to increasing complications and side effects. We evaluated the association between symptom burden, perceived control over illness, and quality of life (QoL) among a national sample of patients with MM. METHODS: For this observational, cross-sectional study, we used data from the Cancer Experience Registry research initiative to examine symptom- and functioning-related concerns among 289 patients with MM across the illness trajectory. We applied hierarchical multiple linear regression analyses to explore associations between symptom burden and perceived control over illness with QoL indicators: depression, anxiety, and social satisfaction. RESULTS: In our sample, 73% of participants with MM reported currently receiving treatment; 39% experienced relapse; 56% received 1 to 2 autologous transplants, 10% received ≥3 autologous transplants, and 4% received allogeneic and autologous transplants; 30% had not received a stem cell transplant. Average time since diagnosis was 4.4 years. The most highly endorsed concerns included eating and nutrition (61%), physical activity (59%), moving around (56%), fatigue (55%), pain (52%), and sleep (46%). Only 27% believed they had control over their disease, whereas 48% perceived having control over the physical side effects of MM. Approximately one-third of the variance in anxiety and depression and nearly two-thirds of variance in social satisfaction were explained by sociodemographic, clinical, and symptom burden variables. Perceived control over illness significantly predicted depression and anxiety, but not social satisfaction. Our results highlight substantial concern among patients with MM about physical symptoms and function. Additionally, greater symptom burden significantly accounted for poorer QoL, and lower perceived control over illness was linked to depression and anxiety. CONCLUSIONS: Patients with MM and survivors experience substantive long-term QoL issues. Together, these findings point to the critical need for comprehensive symptom management, integrated palliative care, and enhancement of social and emotional support for individuals with MM.

Death of family members as an overlooked source of racial disadvantage in the United States.

Long-standing racial differences in US life expectancy suggest that black Americans would be exposed to significantly more family member deaths than white Americans from childhood through adulthood, which, given the health risks posed by grief and bereavement, would add to the disadvantages that they face. We analyze nationally representative US data from the National Longitudinal Study of Youth (n = 7,617) and the Health and Retirement Study (n = 34,757) to estimate racial differences in exposure to the death of family members at different ages, beginning in childhood. Results indicate that blacks are significantly more likely than whites to have experienced the death of a mother, a father, and a sibling from childhood through midlife. From young adulthood through later life, blacks are also more likely than whites to have experienced the death of a child and of a spouse. These results reveal an underappreciated layer of racial inequality in the United States, one that could contribute to the intergenerational transmission of health disadvantage. By calling attention to this heightened vulnerability of black Americans, our findings underscore the need to address the potential impact of more frequent and earlier exposure to family member deaths in the process of cumulative disadvantage.

Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria.

Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known.Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection.Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3.Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.

Adolescent Sleep Barriers: Profiles within a Diverse Sample of Urban Youth.

Most adolescents face numerous obstacles to good sleep, which may undermine healthy development. In this study, we used latent class analysis and identified four categories of sleep barriers in a diverse sample of 553 urban youth (57% female). The majority profile, School/Screens Barriers, reported the most homework and extracurricular barriers, along with high screen time. The Home/Screens Barriers class (i.e., high environmental noise, light, screen use) and the High/Social Barriers class (i.e., high barriers across domains, particularly social) reported the poorest sleep quality and highest depressive/anxiety symptoms. The Minimal Barriers class-predominately male, with low depressive/anxiety symptoms-reported more sleep per night. We discuss implications of our findings for targeting interventions to address poor adolescent sleep among specific clusters of students.

Breastfeeding, overweight status, and inflammation.

Research documents a host of health benefits of breastfeeding for infants and children, including long-term health conditions arising from inflammation. Here, we provide new evidence about this association, focusing on the link between breastfeeding in infancy and inflammation in early adulthood. Our study is based on the National Longitudinal Study of Adolescent to Adult Health (Add Health) which allows us investigate a potentially important mediating pathway - overweight status from early adolescence into young adulthood. Results from pathway analyses in a structural equation modeling framework indicate that, in addition to a direct pathway linking breastfeeding and inflammation, an indirect pathway through overweight status across adolescence into young adulthood partially explains the association between breastfeeding and inflammation. Overweight status, moreover, links breastfeeding to inflammation not only through proximal timing of overweight status, but also through an indirect cascading process of overweight status over the life course that is evident in adolescence. Overall, this study highlights the importance of considering breastfeeding, overweight status and inflammation as dynamic life course processes that contribute to development of health inequalities.

Creating a Reliable, Cost-Effective ELISA Simulation.

The enzyme-linked immunosorbent assay (ELISA) is a fundamental laboratory technique with direct applications across scientific research and clinical diagnostics as well as everyday life. Unfortunately, many challenges exist that inhibit both its introduction and implementation in the high school biology classroom. We present a reliable yet inexpensive way of effectively simulating this assay, allowing student exposure to several advanced topics, including immunodetection, clinical diagnostics, and qualitative and quantitative colorimetric analysis.

Assessment of Urine Proteomics in Type 1 Primary Hyperoxaluria.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1. METHODS: Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements. RESULTS: Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1α (MIP-1α) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1α, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005). CONCLUSION: PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.

Effect of the innate immune response on development of Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Theiler's murine encephalomyelitis virus (TMEV) infection of susceptible mice leads to the development of demyelinating disease in the central nervous system (CNS) associated with an inflammatory immune response. The demyelinating disease in mice has similarities to multiple sclerosis in humans and is used as an experimental model for the human disease. The innate immune response initiates the immune response to TMEV through innate immune receptors on cells that recognize components of the virus and activate intracellular signaling that leads to the expression of innate immune cytokines, chemokines, and effector molecules. The innate immune response directly affects the development of the adaptive immune response, especially the T cell response, which mediates viral clearance. However, infection of Swiss Jim Laboratory (SJL) mice with TMEV leads to a persistent virus infection of the microglia/macrophage in the CNS which contributes to the development of demyelinating disease. Susceptibility to demyelinating disease has been linked to the T cell response against the virus. However, the current studies will examine the role of the innate immune response to TMEV and the affect it has on the adaptive immune response and development of demyelinating disease following TMEV infection. The innate immune cytokines, chemokines, and effector molecules as well as the innate immune cells, both CNS resident and infiltrating peripheral cells, all contribute to the innate immune response following TMEV and may affect susceptibility to demyelinating disease.

Oxalate quantification in hemodialysate to assess dialysis adequacy for primary hyperoxaluria.

BACKGROUND: Patients with primary hyperoxaluria (PH) overproduce oxalate which is eliminated via the kidneys. If end-stage kidney disease develops they are at high risk for systemic oxalosis, unless adequate oxalate is removed during hemodialysis (HD) to equal or exceed ongoing oxalate production. The purpose of this study was to validate a method to measure oxalate removal in this unique group of dialysis patients. METHODS: Fourteen stable patients with a confirmed diagnosis of PH on HD were included in the study. Oxalate was measured serially in hemodialysate and plasma samples in order to calculate rates of oxalate removal. HD regimens were adjusted according to a given patient's historical oxalate production, amount of oxalate removal at dialysis, residual renal clearance of oxalate, and plasma oxalate levels. RESULTS: After a typical session of HD, plasma oxalate was reduced by 78.4 ± 7.7%. Eight patients performed HD 6 times/week, 2 patients 5 times/week, and 3 patients 3 times/week. Combined oxalate removal by HD and the kidneys was sufficient to match or exceed endogenous oxalate production. After a median period of 9 months, pre-dialysis plasma oxalate was significantly lower than initially (75.1 ± 33.4 vs. 54.8 ± 46.6 mmol/l, p = 0.02). CONCLUSION: This methodology can be used to individualize the dialysis prescription of PH patients to prevent oxalosis during the time they are maintained on HD and to reduce risk of oxalate injury to a transplanted kidney.

The Ifng gene is essential for Vdr gene expression and vitamin D3-mediated reduction of the pathogenic T cell burden in the central nervous system in experimental autoimmune encephalomyelitis, a multiple sclerosis model.

Compelling evidence suggests that vitamin D3 insufficiency may contribute causally to multiple sclerosis (MS) risk. Experimental autoimmune encephalomyelitis (EAE) research firmly supports this hypothesis. Vitamin D3 supports 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) synthesis in the CNS, initiating biological processes that reduce pathogenic CD4+ T cell longevity. MS is prevalent in Sardinia despite high ambient UV irradiation, challenging the vitamin D-MS hypothesis. Sardinian MS patients frequently carry a low Ifng expresser allele, suggesting that inadequate IFN-γ may undermine vitamin D3-mediated inhibition of demyelinating disease. Testing this hypothesis, we found vitamin D3 failed to inhibit EAE in female Ifng knockout (GKO) mice, unlike wild-type mice. The two strains did not differ in Cyp27b1 and Cyp24a1 gene expression, implying equivalent vitamin D3 metabolism in the CNS. The 1,25-(OH)2D3 inhibited EAE in both strains, but 2-fold more 1,25-(OH)2D3 was needed in GKO mice, causing hypercalcemic toxicity. Unexpectedly, GKO mice had very low Vdr gene expression in the CNS. Injecting IFN-γ intracranially into adult mice did not increase Vdr gene expression. Correlating with low Vdr expression, GKO mice had more numerous pathogenic Th1 and Th17 cells in the CNS, and 1,25-(OH)2D3 reduced these cells in GKO and wild-type mice without altering Foxp3+ regulatory T cells. Thus, the Ifng gene was needed for CNS Vdr gene expression and vitamin D3-dependent mechanisms that inhibit EAE. Individuals with inadequate Ifng expression may have increased MS risk despite high ambient UV irradiation because of low Vdr gene expression and a high encephalitogenic T cell burden in the CNS.

Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3.

IFN regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the unfolded protein response produce synergistically augmented IFN-ß when stimulated with pattern recognition receptor agonists such as LPS. Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we used murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic unfolded protein response inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors used distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon stimulator of IFN gene, an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of stimulator of IFN gene and TANK-binding kinase 1. Rather, IRF3 activation by tunicamycin and 2-deoxyglucose was inhibited by 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor that blocks activating transcription factor 6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-ß synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co-opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN.

CancerSupportSource-Spanish: Development of a Distress Screening Measure for Spanish-Speaking Hispanic and Latino Individuals with Cancer.

Introduction: CancerSupportSource (CSS), a distress screening and referral program, identifies unmet needs of people with cancer and links them to resources and support. We developed and validated a Spanish-language version (CSS-Spanish) to better serve Hispanic and Latino communities and promote health equity. Methods: The 25-item CSS-Spanish was created leveraging rigorous translation methods and cognitive interviews to ensure cultural relevance and topical breadth. A total of 210 Spanish-speaking Hispanic and Latino individuals completed CSS-Spanish and comparison measures. Psychometric analyses examined dimensionality and statistical validation, and determined scoring thresholds for depression and anxiety risk subscales. Results: CSS-Spanish represented key concerns across five factors and exhibited strong internal consistency and test-retest reliability, convergent validity, and known-groups validity. Risk subscales demonstrated adequate sensitivity. Conclusion: CSS-Spanish is a reliable, valid multidimensional distress screener that rapidly assesses needs of Hispanic and Latino individuals. Embedded depression and anxiety risk flags can support staff in identifying those with high-acuity needs.