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Background: Recent studies have suggested that IgE sensitization to α-gal is associated with coronary artery disease (CAD). However, the B cell subtype(s) responsible for production of IgE to α-gal and mechanisms mediating this production remain elusive.Methods: Single cell multi-omics sequencing, was utilized to phenotype B cells obtained from 60 subjects that had undergone coronary angiography in whom serum IgE was evaluated by ImmunoCAP. Bioinformatics approaches were used to identify B cell subtype(s) and transcriptomic signatures associated with α-gal sensitization. In vitro characterization of chemokine/chemokine receptor pairs on switched memory B cells associated with IgE to α-gal was performed.Results: Of the 60 patients, 17 (28%) were positive for IgE to α-gal. CITESeq identified CCR6+ class-switched memory (SWM) B cells and CXCR4 expresssion on these CCR6+ SWM B cells as significantly associated with IgE sensitization to α-gal but not to other common allergens (peanut or inhalants). In vitro studies of enriched human B cells revealed significantly greater IgE on SWM B cells with high CCR6 and CXCR4 expression 10 days after cells were treated with IL-4 and CD40 to stimulate class switch recombination. Both CCL20 (CCR6 ligand) and CXCL12 (ligand for CXCR4) increased the expression of IgE on SWM B cells expressing their receptors. However, they appeared to have unique pathways mediating this effect as only CCL20 increased activation-induced cytidine deaminase (AID), while CXCL12 drove proliferation of CXCR4+ SWM B cells. Lastly, correlation analysis indicated an association between CAD severity and the frequency of both CCR6+ SWM and CXCR4+ SWM B cells.Conclusions: CCR6+ SWM B cells were identified as potential producers of IgE to α-gal in CAD patients. Additionally, our findings highlighted non-chemotaxis roles of CCL20/CCR6 and CXCL12/CXCR4 signaling in mediating IgE class switching and cell proliferation of SWM B cells respectively. Results may have important implications for a better understanding and better therapeutic approaches for subjects with IgE sensitization to α-gal.

We demonstrate a simplified method for dissipative generation of an entangled state of two trapped-ion qubits. Our implementation produces its target state faster and with higher fidelity than previous demonstrations of dissipative entanglement generation and eliminates the need for auxiliary ions. The entangled singlet state is generated in $\sim$7 ms with a fidelity of 0.949(4). The dominant source of infidelity is photon scattering. We discuss this error source and strategies for its mitigation., 12 pages, 6 figures

Infecting approximately one-third of the world’s population, the neurotropic protozoan Toxoplasma gondii has been associated with cognition and several neuropsychiatric diseases including schizophrenia and bipolar disorder. Findings have been mixed, however, about the relationship between Toxoplasma gondii and depression, with some studies reporting positive associations and others finding no associations. To further investigate the association between Toxoplasma gondii and depression, we used data from the UK Biobank and the National Health and Examination Survey (NHANES). Results from adjusted multiple-regression modeling showed no significant associations between Toxoplasma gondii and depression in either the UK Biobank or NHANES datasets. Further, we found no significant interactions between Toxoplasma gondii and age, sex, educational attainment, and income in either dataset that affected the association between Toxoplasma gondii and depression. These results from two community-based datasets suggest that in these samples, Toxoplasma gondii is not associated with depression. Differences between our findings and other findings showing an association between Toxoplasma gondii and depression could be due to several factors including differences in socioeconomic variables, differences in Toxoplasma gondii strain, and use of different covariates in statistical modeling.

Background: Being overweight or obese is one of the most harmful risk factors to the health of a population. The cause of obesity is complex and multifactorial, but the primary cause is a nutrient poor diet. Despite excess intake of calories, obese individuals commonly have a lack of phytonutrients. Phytonutrients such as chlorophyll, carotenoids, and anthocyanins have all been shown to have anti-obesity effects. National data shows that states in with the lowest intakes of fruit and vegetable intake also have higher obesity rates. The data available depicts that a low fruit and vegetable intake, thus low phytonutrient intake, is correlated with excess adiposity.Methods: Fifty subjects from Thibodaux, Louisiana were randomly selected to participate. Three 24-hour food recalls were used to calculate phytonutrient content of the diets using the phytonutrient index. A food frequency questionnaire was also administered to determine intake of specific phytonutrients (carotenoids, anthocyanins, and carotenoids). Body adiposity was measured using body mass index (BMI), waist circumference, and fat percentage. Pearson correlation was used to assess correlations between phytonutrient index and body adiposity measures. Analysis of variance (ANOVA) with post-hoc tests was used to determine differences in PI and phytonutrient intakes among the BMI, waist circumference and percent body fat groups.Results: Participants who met healthy standards for BMI, waist circumference, and fat percentage all averaged much higher PI scores compared to those classified as obese/overweight. The data showed a strong inverse relationship between PI and BMI (r = -0.753, p = 0.00), waist circumference (r = -0.730, p = 0.00), and body fat percentage (r = -0.701, p = 0.00). Higher weekly intakes of chlorophyll, carotenoid, and anthocyanin rich foods had better body composition in comparison to those who consumed less (p

Allergic diseases represent a major cause of morbidity in modern industrialized and developing countries. The origins and development of allergic immune responses have proven difficult to unravel and remain an important scientific objective. House dust mites (HDM) and ticks represent two important causes of allergic disease. Investigations into HDM fecal particles and tick bites have revealed insights which have and will continue to shape our understanding of allergic immunity. In the present review, focus is given to the role of innate immunity in shaping the respective responses to HDM and ticks. The HDM fecal particle represents a rich milieu of molecules that can be recognized by pathogen-recognition receptors of the innate immune system. Factors in tick saliva and/or tissue damage resultant from tick feeding are thought to activate innate immune signaling that promotes allergic pathways. Recent evidence indicates that innate sensing involves not only the direct recognition of allergenic agents/organisms, but also indirect sensing of epithelial barrier disruption. Although fecal particles from HDM and bites from ticks represent two distinct causes of sensitization, both involve a complex array of molecules that contribute to an innate response. Identification of specific molecules will inform our understanding of the mechanisms that contribute to allergic immunity, however the key may lie in the combination of molecules delivered to specific sites in the body.

Infecting approximately one-third of the world’s human population, Toxoplasma gondii has been associated with cognitive function. Here, we sought to further characterize the association between Toxoplasma gondii and cognitive function in a community sample of adults aged approximately 40 to70 years. Using adjusted linear regression models, we found associations of Toxoplasma gondii seropositivity with worse reasoning (b = -.192, p < .05) and matrix pattern completion (b = -.681, p < .01), of higher anti-Toxoplasma gondii p22 antibody levels with worse reasoning (b = -.078, p < .01) and slower Trails (numeric) performance (b = 5.962, p < .05), of higher anti-Toxoplasma gondii sag1 levels with worse reasoning (b = -.081, p < .05) and worse matrix pattern completion (b = -.217, p < .05), and of higher mean of the anti-Toxoplasma gondii p22 and sag1 levels with worse reasoning (b = -.112, p < .05), slower Trails (numeric) performance (b = 9.195, p < .05), and worse matrix pattern completion (b = -.245, p < .05). Neither age nor educational attainment moderated associations between the measures of Toxoplasma gondii seropositivity or serointensity. Sex, however, moderated the association between the sag1 titer and digit-symbol substitution and the association between the mean of the p22 and sag1 levels and digit-symbol substitution, and income moderated the association between Toxoplasma gondii seropositivity and numeric memory and the association between the p22 level and symbol-digit substitution. Based on the available neuropsychological tasks in this study, Toxoplasma gondii seropositivity and serointensity were associated with some aspects of poorer executive function in adults., Author summary Toxoplasma gondii is a parasite that reproduces in cats but that can infect other animals and humans. Toxoplasma gondii has an affinity for the brain and infection results in a long-term immune response that may have negative effects. Animal models have shown that Toxoplasma gondii can affect behavior and cognition (thinking). In humans, the association is less clear, but there are associations between infection and variety of psychiatric and neurological conditions such as schizophrenia and epilepsy. Toxoplasma gondii may even increase the risk of dementia. If true, it is possible that the presence of this infection may affect thinking long before the onset of dementia. We sought to determine if the presence of antibodies in the blood to Toxoplasma gondii, which is the immune system’s response to past infections, might be associated with performance on measures of cognition. We analyzed a large dataset, the UK Biobank, which includes measures of cognition and blood test results for antibodies to Toxoplasma gondii. We found that both the presence of antibodies as well as the amount of these antibodies were related to some aspects of cognition, particularly problem solving and reasoning in otherwise healthy adults ages 40 to 69 years.

Objective Insomnia is associated with suicidality, although the mechanisms of this association are unclear. This study sought to replicate previous findings showing that insomnia symptoms but not sleep duration are associated with frequency of suicidal ideation in adults. We further investigated whether depression or sleep duration moderates the association between insomnia symptoms and frequency of suicidal ideation. Materials and Methods We used the 2005–2006 cycle of the National Health and Nutrition Examination Survey to replicate previously reported findings from the 2007–2008 cycle. We used ordered logistic regression to determine whether insomnia symptoms were associated with frequency of suicidal ideation independently of depression and other potential confounds. To extend these findings, we tested whether depression or sleep duration moderated the association between insomnia symptoms and frequency of suicidal ideation. We further replicated these findings in parallel analyses using the combined data from the 2005–2006 and 2007–2008 cycles. Results This study replicated previous results showing that insomnia symptoms are associated with frequency of suicidal ideation in the NHANES 2005–2006 cycle (OR = 1.09, p < 0.05), even after adjusting for potentially confounding variables, including depression. Neither depression nor sleep duration moderated this association. Difficulty with sleep maintenance insomnia symptoms were most robustly associated with frequency of suicidal ideation (OR ≥ 1.97, p < 0.05). Sleep duration was not robustly associated with suicidal ideation. Conclusions In this study, we found that insomnia symptoms were uniquely associated with frequency of suicidal ideation. This association cannot be explained by the shared association with depression or sleep duration.

Studies of meat allergic patients have shown that eating meat poses a serious acute health risk that can induce severe cutaneous, gastrointestinal, and respiratory reactions. Allergic reactions in affected individuals following meat consumption are mediated predominantly by IgE antibodies specific for galactose-α-1,3-galactose (α-gal), a blood group antigen of non-primate mammals and therefore present in dietary meat. α-gal is also found within certain tick species and tick bites are strongly linked to meat allergy. Thus, it is thought that exposure to tick bites promotes cutaneous sensitization to tick antigens such as α-gal, leading to the development of IgE-mediated meat allergy. The underlying immune mechanisms by which skin exposure to ticks leads to the production of α-gal-specific IgE are poorly understood and are key to identifying novel treatments for this disease. In this review, we summarize the evidence of cutaneous exposure to tick bites and the development of mammalian meat allergy. We then provide recent insights into the role of B cells in IgE production in human patients with mammalian meat allergy and in a novel mouse model of meat allergy. Finally, we discuss existing data more generally focused on tick-mediated immunomodulation, and highlight possible mechanisms for how cutaneous exposure to tick bites might affect B cell responses in the skin and gut that contribute to loss of oral tolerance.

Total brain gray-matter and white-matter volumes can be indicators of overall brain health. Among the factors associated with gray-matter and white-matter volumes is exposure to air pollution. Using data from the UK Biobank, we sought to determine associations between several components of air pollution&mdash, PM2.5, PM2.5&ndash, 10, PM10, nitrogen dioxide, and nitrogen oxides&mdash, and total gray-matter and total white-matter volumes in multivariable regression models in a large sample of adults. We found significant inverse associations between PM2.5 concentration and total white-matter volume and between PM2.5, PM2.5&ndash, 10, PM10, nitrogen dioxide, and nitrogen oxide concentrations and total gray-matter volume in models adjusted for age, sex, body-mass index, self-assessment of overall health, frequency of alcohol use, smoking status, educational attainment, and income. These findings of pollutant-associated decreases in total gray-matter and total white-matter volumes are in the context of mean PM2.5 concentrations near the upper limit of the World Health Organization&rsquo, s recommendations. Similarly, mean PM10 concentrations were below the recommended upper limit, and nitrogen dioxide concentration was slightly above. Still, there are many areas in the world with much higher concentrations of these pollutants, which could be associated with larger effects. If replicated, these findings suggest that air pollution could be a risk factor for neurodegeneration.

Neighborhood effects, or the development of community by neighborhoods, are often studied in an urban context. Previous research has neglected to examine the influence of neighborhoods in nonurban settings. Our case study, however, contributes to the existing literature as it takes place in a small, rural-to-urban town at an important point in time where the town was urbanizing. We find that neighborhood effects also influence community satisfaction and attachment in Creekdale, an urbanizing town. Using survey data (N = 1006) drawn from the Creekdale Community Citizens Viewpoint Survey (CCVS), we find that, contrary to conventional wisdom, population size and density does not matter necessarily for an individual&rsquo, s community attachment and satisfaction, community experience is shaped by neighborhood effects.

OBJECTIVES: The primary aim of this study was to determine if phytonutrient intake, measured by the phytonutrient index (PI), is correlated with body composition in participants in Thibodaux, Louisiana. In addition, a second aim was to examine if intake of certain phytonutrient rich foods (based on green, reddish/purple, and yellow/orange colored fruits and vegetables) correlates with body fat percentage, waist circumference, and Body Mass Index (BMI). METHODS: Participants Fifty (50) participants, ages18–54 selected. Exclusions were morbidly obese (BMI > 40 kg/m(2)) and pregnant subjects. Procedures Body adiposity was measured by waist circumference, BMI, and fat percentage. Subjects completed three pass 24-hour food recalls (two weekdays/one weekend day. Each completed FFQ to determine the intake of the specific color. Caloric intake was estimated using ESHA software and used for PI calculation. PI formula estimated how much of the subject's energy intake was from phytonutrient rich foods (phytonutrient-rich kcal/total intake kcal) × 100.Phytonutrient rich foods primarily include fruits and vegetables, but also legumes, olive oil, and wine. Pearson correlation was used to assess correlations between phytonutrient index and body adiposity measures. Background data on every participant was gathered such as age, sex, health status, and race. IBM SPSS Statistics was used to analyze the data. Results considered statistically significant if p-value Fcrit). Participants with various health conditions had an average PI lower than the population average (38.1 + 22.1). This was true of participants with type 2 diabetes (22 + 17.7), hypertension (17.4 + 11.6), hyperlipidemia (21.6 + 19.4), and osteoarthritis (24.3 + 27.4). CONCLUSIONS: The data in this study demonstrates that there is a strong correlation between higher phytonutrient intake and improved body composition (and disease prevalence). However this correlation remained consistent despite which type of phytonutrients were consumed. These findings conclude that overall diet quality seems to make the most difference, but the phytonutrients in fruits/vegetables are thought to be a key reason for those benefits. FUNDING SOURCES: Louisiana Tech University. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

Ecological economics arose as a normative transdiscipline aiming to generate knowledge and tools to help transition the economy toward a scale which is sustainable within the bounds of the earth system. Yet it remains unclear in practice how to legitimize its explicitly normative agenda. One potential means for legitimation can be found in deliberative social and political theory. We review how deliberative theory has informed ecological economics, pointing to three uses: first, to support valuation of non-market goods and services; second, to inform environmental decision-making more broadly; third, to ground alternative theories of development and wellbeing. We argue that deliberation has been used as problem-solving theory, but that its more radical implications have rarely been embraced. Embracing a deliberative foundation for ecological economics raises questions about the compatibility of deeply democratic practice and the normative discourses arguing for a sustainability transition. We highlight three potential mechanisms by which deliberation may contribute to a sustainability transition: preference formation; normative evaluation; and legitimation. We explore each in turn, demonstrating the theoretical possibility that deliberation may be conducive in and of itself to a sustainability transition. We point to a series of challenges facing the “scaling up” of deliberative systems that demand further empirical and theoretical work. These challenges constitute a research agenda for a deeply democratic sustainability transition and can inform the future development of ecological economics and other normative, critical transdisciplines.

BACKGROUND: One of the purported reasons of ineffectiveness of immunotherapy for GBM is the meager immune response in the tumor microenvironment. We have observed that GBM can harbor dense B-cell infiltrate, but their prevalence and function is unknown. Pre-clinical studies have shown that B-cells can act as antigen-presenting cells which can stimulate T-cell proliferation; however, B-cells can also downregulate effector T-cells by secreting immunosuppressive cytokines including IL-10. Our study aims to determine the roles of B-cells in GBM and their association with patient outcomes. METHODS: Multiplexed immunohistochemistry, imaging and quantitation was performed on primary GBM samples obtained between 1/2008-8/2015. Intratumoral CD20(+)B-cells and CD8(+)T-cells infiltrate were enumerated from 3 serial GBM sections. Relevant prognostic clinical and molecular variables were reviewed. We also analyzed the association of MS4A1 gene encoding B-cell antigen CD20 with survival from the TCGA. RESULTS: We observed an average infiltrate of 5.5 CD20(+) cells/mm(2)and 36.7 CD8(+)cells/mm(2)tumor. B-cells were stratified into CD20(low)(12 patients) and CD20(high)groups (36 patients) with 0.24 B-cells/mm(2) cut off. Kaplan-Meier analyses indicated that the CD20(low)group had better overall survival (OS) than the CD20(high)cohort (31.7 versus 18.7 months; p=0.02), while a trend toward improved survival was observed with high CD8(+)T-cell infiltration (p=0.06). Cox proportional hazard demonstrated an association between decreased OS and CD20(high)cohort (HR=2.8, p=0.03), but no significance seen between CD8(+)infiltration and OS (p=0.16). A positive correlation was detected between CD8(+)and CD20(+)density (p CONCLUSIONS: Our results suggest that B-cell infiltrate carries an inverse correlation with survival. We hypothesize that CD20(+)B-cells may be regulatory B-cells, limiting immune activation in GBM. Further studies are underway to understand the role of B-cells in the GBM microenvironment.

Caused by the parasitic nematodes Toxocara canis and cati, toxocariasis in humans can result in covert toxocariasis, ocular toxocariasis, visceral larval migrans, and neurotoxocariasis. A common infection, toxocariasis exposure varies widely within and between countries, with a previous estimate of Toxocara seroprevalence using data from 1988 to 1994 in the United States of approximately 13%. Age, poverty, sex, educational attainment, ethnicity, and region have been associated with Toxocara seroprevalence. In this study, we sought to determine the seroprevalence of and factors associated with Toxocara seropositivity in the United States using data from the National Health and Nutrition Examination Survey from 2011 to 2014 to provide a more recent estimate of Toxocara seroprevalence in the United States. We found an overall Toxocara seroprevalence of 5.1%. Increasing age, male sex, low educational attainment, low income, and immigration status each was associated with Toxocara seropositivity. Mexican Americans had reduced odds of exposure. These findings show that exposure to Toxocara continues in the United States and that several demographic factors influence the risk of exposure.

Background: Second-generation antipsychotic medications have proven effective for individuals with serious mental illness (SMI) but may cause weight gain and other metabolic sequelae. Investigators designed and assessed a 12-month behavioral intervention for overweight/obese patients with SMI called “Lifestyle Balance” (LB), based on the Diabetes Prevention Program (DPP), which was tested at 4 VA sites.

Background: The delivery of mental health care is shifting to one that is patient-centered and recovery-oriented, with the goal of increasing quality of life. These pilot studies test an adjunctive, holistic, behavioral approach to treating serious mental illness (SMI) and medication-associated weight gain; investigators hypothesized that engagement in a greater number of therapeutic lifestyle changes (TLCs) leads to improvement in quality of life, reduction of psychiatric symptoms, and weight loss.

Obesity has been on the rise in the US and worldwide for the last several decades. Obesity has been associated with chronic disease development, such as certain types of cancer, type 2 diabetes, cardiovascular disease, and liver diseases. Previously, we reported that obesity promotes DMBA-induced mammary tumor development using the obese Zucker rat model. The intestinal microbiota is composed of a diverse population of obligate and facultative anaerobic microorganisms, and these organisms carry out a broad range of metabolic activities. Obesity has been linked to changes in the intestinal microbiota, but the composition of the bacterial populations in lean and obese Zucker rats has not been carefully studied. Therefore, the objective of this study was to determine the effects of obesity on the gut microbiota in this model. Lean and obese female Zucker rats (n = 16) were fed an AIN-93G-like diet for 8 weeks. Rats were weighed twice weekly, and fecal samples were collected at the beginning and end of the experiment. 16S rRNA gene sequencing was used to evaluate the composition of the fecal bacterial populations. At the outset of the study, the lean rats exhibited much lower ratios of the Firmicutes to Bacteroidetes phyla than the obese rats, but after 60 days, this ratio in the lean rats exceeded that of the obese. This shift was associated with reductions in the Bacteroidaceae, S24-7 and Paraprevotellaceae families in the lean rats. Obese rats also showed increased levels of the genus Akkermansia at day 60. PCoA plots of beta diversity showed clustering of the different test groups, indicating clear differences in intestinal microbiota populations associated with both the time point of the study and the lean or obese status in the Zucker rat model for obesity.

An experimental and DFT investigation of the mechanism of the coupling of methylisocyanide and C-H activation mediated by the germylene (germanediyl) Ge(Ar(Me6))2 (Ar(Me6) = C6H3-2,6(C6H2-2,4,6-Me3)2) showed that it proceeded by initial MeNC adduct formation followed by an isomerization involving the migratory insertion of the MeNC carbon into the Ge-C ligand bond. Addition of excess MeNC led to sequential insertions of two further MeNC molecules into the Ge-C bond. The insertion of the third MeNC leads to methylisocyanide methyl group C-H activation to afford an azagermacyclopentadienyl species. The X-ray crystal structures of the 1:1 (Ar(Me6))2GeCNMe adduct, the first and final insertion products (Ar(Me6))GeC(NMe)Ar(Me6) and (Ar(Me6))GeC(NHMe)C(NMe)C(Ar(Me6))NMe were obtained. The DFT calculations on the reaction pathways represent the first detailed mechanistic study of isocyanide oligomerization by a p-block element species.

We sequenced and annotated the complete 7,170,504-bp genome of a novel secondary metabolite-producing Streptomyces strain, Streptomyces albus SM254, isolated from copper-rich subsurface fluids at ~220-m depth within the Soudan Iron Mine (Soudan, MN, USA).

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism of microglia dysfunction in RTT, we identified a MeCP2 target gene,SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor ofSNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3) increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31. Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted antioxidants for RTT.

Despite increased frequencies of neutrophils found in autoimmune diseases such as systemic lupus erythematosus (SLE), how they contribute to disease pathogenesis and the mechanisms that affect the accumulation of neutrophils are poorly understood. The aim of this study was to identify factors in autoantibody-mediated autoimmunity that controls the accumulation of spleen resident neutrophils and to determine whether neutrophils contribute to abnormal B cell responses. Increased levels of the cytokine BAFF have been linked to loss of B cell tolerance in autoimmunity, but the cellular source responsible for excess BAFF is unknown. B cell maturation antigen (BCMA) is a receptor for BAFF and is critical for the survival of bone marrow plasma cells. Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting plasma cells in spleens of lupus-prone mice and the reasons for this effect are not understood. Here we analyzed the phenotype, localization and function of neutrophils in spleens of healthy mice and congenic lupus-prone mice, and compared mice sufficient or deficient in BCMA expression. Neutrophils were found to be significantly increased in frequency and activation status in spleens of lupus-prone mice when BCMA was absent. Furthermore, neutrophils localized within T cell zones and enhanced CD4(+) T cell proliferation and IFNγ production through the production of BAFF. Reduced BAFF and IFNγ serum levels, decreased frequencies of IFNγ-producing T cells, germinal center B cells, and autoantibody production after neutrophil depletion indicated the involvement of neutrophils in these autoimmune traits. Thus, we have identified a novel role for BCMA to control excess BAFF production in murine lupus through restraining the accumulation of BAFF-producing neutrophils. Our data suggests that devising therapeutic strategies to reduce neutrophils in autoimmunity may decrease BAFF levels and ameliorate disease.

The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.

Polyomaviruses are nonenveloped viruses with capsids composed primarily of 72 pentamers of the viral VP1 protein, which forms the outer shell of the capsid and binds to cell surface oligosaccharide receptors. Highly conserved VP1 proteins from closely related polyomaviruses recognize different oligosaccharides. To determine whether amino acid changes restricted to the oligosaccharide binding site are sufficient to determine receptor specificity and how changes in receptor usage affect tropism, we studied the primate polyomavirus simian virus 40 (SV40), which uses the ganglioside GM1 as a receptor that mediates cell binding and entry. Here, we used two sequential genetic screens to isolate and characterize viable SV40 mutants with mutations in the VP1 GM1 binding site. Two of these mutants were completely resistant to GM1 neutralization, were no longer stimulated by incorporation of GM1 into cell membranes, and were unable to bind to GM1 on the cell surface. In addition, these mutant viruses displayed an infection defect in monkey cells with high levels of cell surface GM1. Interestingly, one mutant infected cells with low cell surface GM1 more efficiently than wild-type virus, apparently by utilizing a different ganglioside receptor. Our results indicate that a small number of mutations in the GM1 binding site are sufficient to alter ganglioside usage and change tropism, and they suggest that VP1 divergence is driven primarily by a requirement to accommodate specific receptors. In addition, our results suggest that GM1 binding is required for vacuole formation in permissive monkey CV-1 cells. Further study of these mutants will provide new insight into polyomavirus entry, pathogenesis, and evolution.

B cell maturation antigen (BCMA) is a tumor necrosis family receptor (TNFR) member that is predominantly expressed on terminally differentiated B cells and, upon binding to its ligands B cell activator of the TNF family (BAFF) and a proliferation inducing ligand (APRIL), delivers pro-survival cell signals. Thus, BCMA is most known for its functional activity in mediating the survival of plasma cells that maintain long-term humoral immunity. The expression of BCMA has been also linked to a number of cancers, autoimmune disorders, and infectious diseases that suggest additional roles for BCMA activity. Despite the recent advances in our understanding of the roles for the related TNFR members BAFF-R and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), the signaling pathway used by BCMA for mediating plasma cell survival as well as its putative function in certain disease states are not well understood. By examining the expression, regulation, and signaling targets of BCMA we may gain further insight into this receptor and how it operates within cells in both health and disease. This information is important for identifying new therapeutic targets that may be relevant in treating diseases that involve the BAFF/APRIL cytokine network.

This complement cascade team-based learning (TBL) module bridges student understanding of innate and adaptive immune mechanisms to bacterial pathogenesis in relation to human health and disease. The module consists of an advanced preparation assignment that integrates the immune pathways of the complement system during an infection, a Readiness Assurance Test that assesses student competency with the assigned materials, and a group application exercise that applies the complement activation pathways in three clinical cases. The goal of the first case is to describe the biological activities of complement through discussion of a patient with recurrent meningococcal infections; the goal of the second, to explain the initiating events that distinguish the alternative, lectin, and classical pathways in complement activation, as well as the clinical consequences of a patient deficient in these events; and the goal of the third, to identify mechanisms that control complement activation and selectivity for pathogens. Key features of this exercise include discussion and interpretation of results from two laboratory tests, one measuring the efficiency of individual complement components, the other measuring cell surface expression of inhibitory molecules on human cells preventing complement activation. Twelve multiple-choice questions are embedded throughout the exercise. Medical students are to discuss these questions in teams to arrive at an answer. After each case, teams present their answers to the entire class. The instructor can then act as a facilitator, encouraging peer-to-peer clarification of inaccurate or incomplete responses. This TBL reinforces basic principles of the immune system by bridging innate and adaptive immune mechanisms through understanding the complement cascade. The material integrates the immune pathways of the complement system during an infection and the consequences that result from complement deficiencies.

Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for IFN regulatory factor 5 [IRF]5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the IFN-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5/Blimp-1 axis could regulate the expression of these genes. We found that an Irf5 deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2 deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone C57BL/6.Nba2, New Zealand Black, and C57BL/6.Sle123 female mice (as compared with age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Taken together, our observations demonstrate that the IRF5/Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and they suggest an important role for the IRF5/Blimp-1/p202 axis in murine lupus susceptibility.

Murine Aim2 and p202 proteins (encoded by the Aim2 and Ifi202 genes) are members of the IFN-inducible p200 protein family. Both proteins can sense dsDNA in the cytoplasm. However, upon sensing dsDNA, only the Aim2 protein through its pyrin domain can form an inflammasome to activate caspase-1 and induce cell death. Given that the p202 protein has been predicted to inhibit the activation of caspase-1 by the Aim2 protein and that increased levels of the p202 protein in female mice of certain strains are associated with lupus susceptibility, we compared the expression of Aim2 and Ifi202 genes between Aim2-deficient and age-matched wild-type mice. We found that the Aim2 deficiency in immune cells stimulated the expression of Ifi202 gene. The increased levels of the p202 protein in cells were associated with increases in the expression of IFN-β, STAT1, and IFN-inducible genes. Moreover, after knockdown of Aim2 expression in the murine macrophage cell line J774.A1, IFN-β treatment of cells robustly increased STAT1 protein levels (compared with those of control cells), increased the activating phosphorylation of STAT1 on Tyr-701, and stimulated the activity of an IFN-responsive reporter. Notably, the expression of Aim2 in non-lupus-prone (C57BL/6 and B6.Nba2-C) and lupus-prone (B6.Nba2-ABC) splenic cells and in a murine macrophage cell line that overexpressed p202 protein was found to be inversely correlated with Ifi202. Collectively, our observations demonstrate an inverse correlation between Aim2 and p202 expressions. We predict that defects in Aim2 expression within immune cells contribute to increased susceptibility to lupus.

The authors have declared that no competing interests exist. This publication was made possible through support provided to the Global Livestock Collaborative Research Support Program by the Office of Agriculture, Bureau for Economic Growth, Agriculture and Trade, United States Agency for International Development under terms of Grant No. PCE-G-00-98-00036-00. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of the USAID. The funders played no role in the decision to submit the article or in its preparation. Provenance: Commissioned; externally peer reviewed.

Antimicrobial peptides (AMPs) kill or prevent the growth of microbes. AMPs are made by virtually all single and multicellular organisms and are encountered by bacteria in diverse environments, including within a host. Bacteria use sensor-kinase systems to respond to AMPs or damage caused by AMPs. Salmonella enterica deploys at least three different sensor-kinase systems to modify gene expression in the presence of AMPs: PhoP-PhoQ, PmrA-PmrB, and RcsB-RcsC-RcsD. The ydeI gene is regulated by the RcsB-RcsC-RcsD pathway and encodes a 14-kDa predicted oligosaccharide/oligonucleotide binding-fold (OB-fold) protein important for polymyxin B resistance in broth and also for virulence in mice. We report here that ydeI is additionally regulated by the PhoP-PhoQ and PmrA-PmrB sensor-kinase systems, which confer resistance to cationic AMPs by modifying lipopolysaccharide (LPS). ydeI , however, is not important for known LPS modifications. Two independent biochemical methods found that YdeI copurifies with OmpD/NmpC, a member of the trimeric β-barrel outer membrane general porin family. Genetic analysis indicates that ompD contributes to polymyxin B resistance, and both ydeI and ompD are important for resistance to cathelicidin antimicrobial peptide, a mouse AMP produced by multiple cell types and expressed in the gut. YdeI localizes to the periplasm, where it could interact with OmpD. A second predicted periplasmic OB-fold protein, YgiW, and OmpF, another general porin, also contribute to polymyxin B resistance. Collectively, the data suggest that periplasmic OB-fold proteins can interact with porins to increase bacterial resistance to AMPs.

(IF : 5,52); International audience; System A transporters SNAT1 and SNAT2 mediate uptake of neutral alpha-amino acids (e.g. glutamine, alanine, and proline) and are expressed in central neurons. We tested the hypothesis that SNAT2 is required to support neurotransmitter glutamate synthesis by examining spontaneous excitatory activity after inducing or repressing SNAT2 expression for prolonged periods. We stimulated de novo synthesis of SNAT2 mRNA and increased SNAT2 mRNA stability and total SNAT2 protein and functional activity, whereas SNAT1 expression was unaffected. Increased endogenous SNAT2 expression did not affect spontaneous excitatory action-potential frequency over control. Long term glutamine exposure strongly repressed SNAT2 expression but increased excitatory action-potential frequency. Quantal size was not altered following SNAT2 induction or repression. These results suggest that spontaneous glutamatergic transmission in pyramidal neurons does not rely on SNAT2. To our surprise, repression of SNAT2 activity was not limited to System A substrates. Taurine, gamma-aminobutyric acid, and beta-alanine (substrates of the SLC6 gamma-aminobutyric acid transporter family) repressed SNAT2 expression more potently (10x) than did System A substrates; however, the responses to System A substrates were more rapid. Since ATF4 (activating transcription factor 4) and CCAAT/enhancer-binding protein are known to bind to an amino acid response element within the SNAT2 promoter and mediate induction of SNAT2 in peripheral cell lines, we tested whether either factor was similarly induced by amino acid deprivation in neurons. We found that glutamine and taurine repressed the induction of both transcription factors. Our data revealed that SNAT2 expression is constitutively low in neurons under physiological conditions but potently induced, together with the taurine transporter TauT, in response to depletion of neutral amino acids.

Few studies have examined the impact of mentoring (developing a special relationship with a nonparental adult) on educational achievement and attainment in the general population. In addition, prior research has yet to clarify the extent to which mentoring relationships reduce inequality by enabling disadvantaged youths to compensate for the lack of social resources or to promote inequality by serving as a complementary resource for advantaged youths. The results of a nationally representative sample of youths show (1) a powerful net influence of mentors on the educational success of youths and (2) how social background and parental, peer, and personal resources condition the formation and effectiveness of mentoring relationships. The findings uncover an interesting paradox—that informal mentors may simultaneously represent compensatory and complementary resources. Youths with many resources are more likely than are other young people to have mentors, but those with few resources are likely to benefit more from having a mentor—particularly a teacher mentor—in their lives.

The DONuT experiment collected data in 1997 and published first results in 2000 based on four observed ντ charged-current (CC) interactions. The final analysis of the data collected in the experiment is presented in this paper, based on 3.6×1017 protons on target using the 800 GeV Tevatron beam at Fermilab. The number of observed ντ CC events is 9 with an estimated background of 1.5 events, from a total of 578 observed neutrino interactions. We calculate the ντ CC cross section as a function of one parameter. Assuming Ds mesons are the sole source for ντ, the energy-independent part of the total CC cross section can be parametrized as σconst(ντ )=2.51n1.52×10-40cm2GeV-1 for n 4, where n is the parameter controlling the longitudinal part of the Ds differential cross section of the form dσ/dxF (1-|xF|)n. The analysis could not distinguish between ντ and ν̄τ. The value of n obtained from Pythia simulations, n=6.1, gives an estimated value of σconst(ντ)=(0.39±0.13±0.13) ×10-38cm2GeV-1. © 2008 The American Physical Society.

Family predictors of tobacco and alcohol use were studied in random samples of school-going Black, Coloured, and White adolescents (total N=1,800) in the Cape Town Metropolitan Area. The subjects ranged in age from 14 to 17 years, with a mean age of 15.95 years. Logistic regression analysis of the data showed invariance across the three racial groups in terms of the specific family variables that were predictive, as well as their direction and magnitude of association with substance use. Essentially, higher rates of substance use for all three groups were predicted by parental behavioural control, parental monitoring/knowledge and limit setting, marital relations and family stress. The findings extend the work on South African adolescent substance use by providing a view into the proximal (family) socialising forces that are related to substance use. The findings also extend the broader work on identifying specialised effects of dimensions of socialization on adolescent functioning. The discussion section includes commentary on the cultural invariance found when measuring socialising forces at this level of generality.Journal of Child and Adolescent Mental Health 2006, 18(1): 7–15

From conception to death, helping relationships promote positive development and enable people to surmount challenges in their lives. Is it the case that the negative consequences of a genetic propensity for risky behaviors can be attenuated by helping relationships (a G × E)? But is it also the case that people with such a genetic propensity are less likely to have helping relationships compared to people without such a propensity (a rGE)? We illustrate this complex pattern of gene–environment interplay by drawing on the National Longitudinal Study of Adolescent Health and a combinatoric analytic strategy. We focus on a gene associated with dopamine receptor type 2 (DRD2 TaqIA), student–mentor relationships, and educational continuation beyond secondary school. Results reveal that, for both white and black males, DRD2 A1+ (A1A1 and A1A2 genotypes) is associated with a decreased likelihood of school continuation compared to their counterparts with DRD2 A1–; mentors who are teachers compensate for this negative association (a G × E); and youth with DRD2 A1+ are less likely to have a mentor who is a teacher than their counterparts with DRD2 A1– (a rGE).

The Galaxy Evolution Explorer, a NASA small explorer mission, is performing the first all-sky, deep imaging and spectroscopic surveys in the space ultraviolet. The prime goal of GALEX is to study star formation in galaxies and its evolution with time. Now in its fourth year of operations the emphasis of the mission is changing from completing the primary science goals set at launch to servicing the astronomical community with a guest investigator program that uses 50% or more of the available observing time. We outline here mission operations, describe some of the challenges the GALEX team has surmounted, and some of the changes needed to accomplish the goals of the extended mission.

Recent advances in the development of lab-on-a-chip devices have been rapid and broad ranging. In general however these devices, while containing micro- or even nano-scale components, rely heavily on macroscale infrastructure (e.g. microscopes, chip readers and power sources) to perform much of the actual product detection and subsequent analysis. As such to enable the next generation of portable lab-on-chip devices, techniques for simply and cheaply integrating on-chip analysis functionalities will be required. In this work we present our work directed towards the development of a new concept in rapid on-chip imaging which we refer to as “optofluidic microscopy (OFM)”. Here we present an overview of the imaging theory, fabrication procedure and operational details of the initial prototype. Preliminary experimental results of this on-chip optical imager are also reported. A significant advantage of the technique is that through proper spatial scaling, sub-wavelength resolution can be achieved without bulk optics.