Dietary docosahexaenoic acid supplementation inhibits acute pulmonary transcriptional and autoantibody responses to a single crystalline silica exposure in lupus-prone mice.

Introduction: Workplace exposure to respirable crystalline silica (cSiO2) has been epidemiologically linked to lupus. Consistent with this, repeated subchronic intranasal cSiO2 instillation in lupus-prone NZBWF1 mice induces inflammation-/autoimmune-related gene expression, ectopic lymphoid tissue (ELT), autoantibody (AAb) production in the lung within 5 to 13 wk followed systemic AAb increases and accelerated onset and progression of glomerulonephritis within 13 to 17 wk. Interestingly, dietary docosahexaenoic acid (DHA) supplementation suppresses these pathologic effects, but the underlying molecular mechanisms remain unclear. Methods: This study aimed to test the hypothesis that dietary DHA supplementation impacts acute transcriptional and autoantibody responses in the lungs of female NZBWF1 mice 1 and 4 wk after a single high-dose cSiO2 challenge. Groups of mice were initially fed a control (Con) diet or a DHA-containing diet (10 g/kg). Cohorts of Con- and DHA-fed were subjected to a single intranasal instillation of 2.5 mg cSiO2 in a saline vehicle (Veh), while a Con-fed cohort was instilled with Veh only. At 1 and 4 wk post-instillation (PI), we compared cSiO2's effects on innate-/autoimmune-related gene expression and autoantibody (AAb) in lavage fluid/lungs of Con- and DHA-fed mice and related these findings to inflammatory cell profiles, histopathology, cell death, and cytokine/chemokine production. Results: DHA partially alleviated cSiO2-induced alterations in total immune cell and lymphocyte counts in lung lavage fluid. cSiO2-triggered dead cell accumulation and levels of inflammation-associated cytokines and IFN-stimulated chemokines were more pronounced in Con-fed mice than DHA-fed mice. Targeted multiplex transcriptome analysis revealed substantial upregulation of genes associated with autoimmune pathways in Con-fed mice in response to cSiO2 that were suppressed in DHA-fed mice. Pathway analysis indicated that DHA inhibited cSiO2 induction of proinflammatory and IFN-regulated gene networks, affecting key upstream regulators (e.g., TNFα, IL-1ß, IFNAR, and IFNγ). Finally, cSiO2-triggered AAb responses were suppressed in DHA-fed mice. Discussion: Taken together, DHA mitigated cSiO2-induced upregulation of pathways associated with proinflammatory and IFN-regulated gene responses within 1 wk and reduced AAb responses by 4 wk. These findings suggest that the acute short-term model employed here holds substantial promise for efficient elucidation of the molecular mechanisms through which omega-3 PUFAs exert protective effects against cSiO2-induced autoimmunity.

Awareness data on cervical cancer among females of rural and urban areas of Haryana, India.

A cross-sectional study was done to assess the degree of current awareness and behaviors about cervical cancer among females in urban and rural areas of North India. This survey was conducted on one thousand females (500 rural and 500 urban). A well-structured questionnaire was designed to collect information about participants' knowledge on cancer of cervix uteri such as age, height and weight measurements, marital status, menstrual status, personal hygiene, age at menarche, sexual history, pregnancy and abortion history, use of contraceptive pills for birth-control, smoking, alcohol consumption, and other relevant information. The data was collected by conducting face-to-face interviews after obtaining the verbal consent of the participants. The data has the potential to reduce disease burden by spreading awareness about symptoms and risk factors of cervical cancer as well as implementation of effective early screening strategies.

Chemical technology principles for selective bioconjugation of proteins and antibodies.

Proteins are multifunctional large organic compounds that constitute an essential component of a living system. Hence, control over their bioconjugation impacts science at the chemistry-biology-medicine interface. A chemical toolbox for their precision engineering can boost healthcare and open a gateway for directed or precision therapeutics. Such a chemical toolbox remained elusive for a long time due to the complexity presented by the large pool of functional groups. The precise single-site modification of a protein requires a method to address a combination of selectivity attributes. This review focuses on guiding principles that can segregate them to simplify the task for a chemical method. Such a disintegration systematically employs a multi-step chemical transformation to deconvolute the selectivity challenges. It constitutes a disintegrate (DIN) theory that offers additional control parameters for tuning precision in protein bioconjugation. This review outlines the selectivity hurdles faced by chemical methods. It elaborates on the developments in the perspective of DIN theory to demonstrate simultaneous regulation of reactivity, chemoselectivity, site-selectivity, modularity, residue specificity, and protein specificity. It discusses the progress of such methods to construct protein and antibody conjugates for biologics, including antibody-fluorophore and antibody-drug conjugates (AFCs and ADCs). It also briefs how this knowledge can assist in developing small molecule-based covalent inhibitors. In the process, it highlights an opportunity for hypothesis-driven routes to accelerate discoveries of selective methods and establish new targetome in the precision engineering of proteins and antibodies.

Differential localization of dengue virus protease affects cell homeostasis and triggers to thrombocytopenia.

Thrombocytopenia is one of the symptoms of many virus infections which is the "hallmark" in the case of dengue virus. In this study, we show the differential localization of existing two forms of dengue virus protease, i.e., NS2BNS3 to the nucleus and NS3 to the nucleus and mitochondria. We also report a nuclear transcription factor, erythroid differentiation regulatory factor 1 (EDRF1), as the substrate for this protease. EDRF1 regulates the expression and activity of GATA1, which in turn controls spectrin synthesis. Both GATA1 and spectrins are required for platelet formation. On the other hand, we found that the mitochondrial activities will be damaged by NS3 localization which cleaves GrpEL1, a co-chaperone of mitochondrial Hsp70. Levels of both EDRF1 and GrpEL1 were found to deteriorate in dengue virus-infected clinical samples. Hence, we conclude that NS2BNS3-mediated EDRF1 cleavage and the NS3-led mitochondrial dysfunction account for thrombocytopenia.

Lipidome modulation by dietary omega-3 polyunsaturated fatty acid supplementation or selective soluble epoxide hydrolase inhibition suppresses rough LPS-accelerated glomerulonephritis in lupus-prone mice.

Introduction: Lipopolysaccharide (LPS)-accelerated autoimmune glomerulonephritis (GN) in NZBWF1 mice is a preclinical model potentially applicable for investigating lipidome-modulating interventions against lupus. LPS can be expressed as one of two chemotypes: smooth LPS (S-LPS) or rough LPS (R-LPS) which is devoid of O-antigen polysaccharide sidechain. Since these chemotypes differentially affect toll-like receptor 4 (TLR4)-mediated immune cell responses, these differences may influence GN induction. Methods: We initially compared the effects of subchronic intraperitoneal (i.p.) injection for 5 wk with 1) Salmonella S-LPS, 2) Salmonella R-LPS, or 3) saline vehicle (VEH) (Study 1) in female NZBWF1 mice. Based on the efficacy of R-LPS in inducing GN, we next used it to compare the impact of two lipidome-modulating interventions, ω-3 polyunsaturated fatty acid (PUFA) supplementation and soluble epoxide hydrolase (sEH) inhibition, on GN (Study 2). Specifically, effects of consuming ω-3 docosahexaenoic acid (DHA) (10 g/kg diet) and/or the sEH inhibitor 1-(4-trifluoro-methoxy-phenyl)-3-(1-propionylpiperidin-4-yl) urea (TPPU) (22.5 mg/kg diet ≈ 3 mg/kg/day) on R-LPS triggering were compared. Results: In Study 1, R-LPS induced robust elevations in blood urea nitrogen, proteinuria, and hematuria that were not evident in VEH- or S-LPS-treated mice. R-LPS-treated mice further exhibited kidney histopathology including robust hypertrophy, hyperplasia, thickened membranes, lymphocytic accumulation containing B and T cells, and glomerular IgG deposition consistent with GN that was not evident in VEH- or SLPS-treated groups. R-LPS but not S-LPS induced spleen enlargement with lymphoid hyperplasia and inflammatory cell recruitment in the liver. In Study 2, resultant blood fatty acid profiles and epoxy fatty acid concentrations reflected the anticipated DHA- and TPPU-mediated lipidome changes, respectively. The relative rank order of R-LPS-induced GN severity among groups fed experimental diets based on proteinuria, hematuria, histopathologic scoring, and glomerular IgG deposition was: VEH/CON< R-LPS/DHA ≈ R-LPS/TPPU<<< R-LPS/TPPU+DHA ≈ R-LPS/CON. In contrast, these interventions had modest-to- negligible effects on R-LPS-induced splenomegaly, plasma antibody responses, liver inflammation, and inflammation-associated kidney gene expression. Discussion: We show for the first time that absence of O-antigenic polysaccharide in R-LPS is critical to accelerated GN in lupus-prone mice. Furthermore, intervention by lipidome modulation through DHA feeding or sEH inhibition suppressed R-LPS-induced GN; however, these ameliorative effects were greatly diminished upon combining the treatments.

Disintegrate (DIN) Theory Enabling Precision Engineering of Proteins.

The chemical toolbox for the selective modification of proteins has witnessed immense interest in the past few years. The rapid growth of biologics and the need for precision therapeutics have fuelled this growth further. However, the broad spectrum of selectivity parameters creates a roadblock to the field's growth. Additionally, bond formation and dissociation are significantly redefined during the translation from small molecules to proteins. Understanding these principles and developing theories to deconvolute the multidimensional attributes could accelerate the area. This outlook presents a disintegrate (DIN) theory for systematically disintegrating the selectivity challenges through reversible chemical reactions. An irreversible step concludes the reaction sequence to render an integrated solution for precise protein bioconjugation. In this perspective, we highlight the key advancements, unsolved challenges, and potential opportunities.

Feasibility and Acceptability of a Remote Stepped Care Mental Health Programme for Adolescents during the COVID-19 Pandemic in India.

Remote mental health services were rapidly deployed during the COVID-19 pandemic, yet there is relatively little contemporaneous evidence on their feasibility and acceptability. This study assessed the feasibility and acceptability of a stepped care mental health programme delivered remotely by lay counsellors to adolescents in New Delhi, India, during a period of 'lockdown'. The programme consisted of a brief problem-solving intervention ("Step 1") followed by a tailored behavioural module ("Step 2") for non-responders. We enrolled 34 participants (M age = 16.4 years) with a self-identified need for psychological support. Feasibility and acceptability were assessed through quantitative process indicators and qualitative interviews (n = 17 adolescents; n = 5 counsellors). Thirty-one (91%) adolescents started Step 1 and 16 (52%) completed the planned Step 1 protocol. Twelve (75%) of the Step 1 completers were non-responsive. Eight (67%) non-responsive cases started Step 2, all of whom met response criteria when reassessed at 12 weeks post-enrolment. Adolescents favoured voice-only sessions over video-calls due to privacy concerns and difficulties accessing suitable devices. Counsellors noted challenges of completing remote sessions within the allotted time while recognising the importance of supervision for developing competence in new ways of working. Both adolescents and counsellors discussed the importance of working collaboratively and flexibly to fit around individual preferences and circumstances. Disentangling pandemic-specific barriers from more routine challenges to remote delivery should be a focus of future research.

Respiratory illness virus infections with special emphasis on COVID-19.

Viruses that emerge pose challenges for treatment options as their uniqueness would not know completely. Hence, many viruses are causing high morbidity and mortality for a long time. Despite large diversity, viruses share common characteristics for infection. At least 12 different respiratory-borne viruses are reported belonging to various virus taxonomic families. Many of these viruses multiply and cause damage to the upper and lower respiratory tracts. The description of these viruses in comparison with each other concerning their epidemiology, molecular characteristics, disease manifestations, diagnosis and treatment is lacking. Such information helps diagnose, differentiate, and formulate the control measures faster. The leading cause of acute illness worldwide is acute respiratory infections (ARIs) and are responsible for nearly 4 million deaths every year, mostly in young children and infants. Lower respiratory tract infections are the fourth most common cause of death globally, after non-infectious chronic conditions. This review aims to present the characteristics of different viruses causing respiratory infections, highlighting the uniqueness of SARS-CoV-2. We expect this review to help understand the similarities and differences among the closely related viruses causing respiratory infections and formulate specific preventive or control measures.

Exogenous administration of hydrogen sulfide alleviates homocysteine induced inflammation in ARPE-19 cells.

Plasma homocysteine (Hcy) is an independent risk factor for Age related macular degeneration (AMD) and an inducer of inflammation. Homocysteine catabolism releases hydrogen sulfide (H2S). H2S has controversial effects on inflammation. In this study we have analysed the endogenous and exogenous H2S in modulating inflammation using adult retinal pigment epithelial (ARPE-19) cells as an in vitro model for AMD. ARPE-19 cells were treated with various concentrations of Hcy (15, 30 and 50 µM) for 3 h. Expression of Hcy transulfuration genes (CBS, CSE) by qPCR and western blot. H2S levels were measured using Free Radical Analyzer System (WPI, USA). The inflammatory markers (IL-6 and IL-8) were evaluated using real-time PCR and ELISA. Hcy exposure increased CBS protein expression, hydrogen sulfide levels and pro-inflammatory cytokines, modulating CBS by silencing did not alter H2S levels, but inhibition of CSE with PAG inhibited H2S production and decreased cytokine (IL-6 and IL-8) levels. On the contrary exogenous supply of hydrogen sulfide with NaHS and by compound 1c showed anti-inflammatory effects even in the presence of Hcy. This study shows that exogenous delivery of H2S decreases inflammation in retinal pigment epithelial cells on exposure to Hcy in ARPE-19 cells.

Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus.

Workplace exposure to respirable crystalline silica dust (cSiO2) has been etiologically linked to the development of lupus and other human autoimmune diseases. Lupus triggering can be recapitulated in female NZBWF1 mice by four weekly intranasal instillations with 1 mg cSiO2. This elicits inflammatory/autoimmune gene expression and ectopic lymphoid structure (ELS) development in the lung within 1 week, ultimately driving early onset of systemic autoimmunity and glomerulonephritis. Intriguingly, dietary supplementation with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA) found in fish oil, beginning 2 week prior to cSiO2 challenge, prevented inflammation and autoimmune flaring in this novel model. However, it is not yet known how ω-3 PUFA intervention influences established autoimmunity in this murine model of toxicant-triggered lupus. Here we tested the hypothesis that DHA intervention after cSiO2-initiated intrapulmonary autoimmunity will suppress lupus progression in the NZBWF1 mouse. Six-week old NZWBF1 female mice were fed purified isocaloric diet for 2 weeks and then intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 consecutive weeks. One week after the final instillation, which marks onset of ELS formation, mice were fed diets supplemented with 0, 4, or 10 g/kg DHA. One cohort of mice (n = 8/group) was terminated 13 weeks after the last cSiO2 instillation and assessed for autoimmune hallmarks. A second cohort of mice (n = 8/group) remained on experimental diets and was monitored for proteinuria and moribund criteria to ascertain progression of glomerulonephritis and survival, respectively. DHA consumption dose-dependently increased ω-3 PUFA content in the plasma, lung, and kidney at the expense of the ω-6 PUFA arachidonic acid. Dietary intervention with high but not low DHA after cSiO2 treatment suppressed or delayed: (i) recruitment of T cells and B cells to the lung, (ii) development of pulmonary ELS, (iii) elevation of a wide spectrum of plasma autoantibodies associated with lupus and other autoimmune diseases, (iv) initiation and progression of glomerulonephritis, and (v) onset of the moribund state. Taken together, these preclinical findings suggest that DHA supplementation at a human caloric equivalent of 5 g/d was an effective therapeutic regimen for slowing progression of established autoimmunity triggered by the environmental toxicant cSiO2.

Rapid Induction of Pulmonary Inflammation, Autoimmune Gene Expression, and Ectopic Lymphoid Neogenesis Following Acute Silica Exposure in Lupus-Prone Mice.

Occupational exposure to crystalline silica (cSiO2) is etiologically associated with systemic lupus erythematosus (lupus) and other autoimmune diseases. cSiO2's autoimmune effects in humans can be mimicked chronically in female lupus-prone NZBWF1 mice following repeated exposure to the particle. However, the immediate and short-term effects of cSiO2 in this widely used model of autoimmune disease are not well-understood. In the present study, we tested the hypothesis that a single acute cSiO2 dose triggers early presentation of cellular, histopathological, transcriptomic, and protein biomarkers of inflammation and autoimmunity in lupus-prone mice. Eight-week old female NZBWF1 mice were intranasally instilled once with 2.5 mg cSiO2 or saline vehicle and necropsied at 1, 7, 14, 21, and 28 d post-instillation (PI). Analyses of bronchoalveolar lavage fluid (BALF) and lung tissue revealed that by 7 d PI, acute cSiO2 exposure persistently provoked: (i) robust recruitment of macrophages, neutrophils, and lymphocytes into the alveoli, (ii) cell death as reflected by increased protein, double-stranded DNA, and lactate dehydrogenase activity, (iii) elevated secretion of the cytokines IL-1α, IL-1ß, IL-18, TNF-α, IL-6, MCP-1, and B cell activation factor (BAFF), and (iv) upregulation of genes associated with chemokines, proinflammatory cytokines, lymphocyte activation, and type I interferon signaling. The appearance of these endpoints was subsequently followed by the emergence in the lung of organized CD3+ T cells (14 d PI) and CD45R+ B cells (21 d PI) that were indicative of ectopic lymphoid structure (ELS) development. Taken together, acute cSiO2 exposure triggered a rapid onset of autoimmune disease pathogenesis that was heralded in the lung by unresolved inflammation and cell death, proinflammatory cytokine production, chemokine-driven recruitment of leukocytes, an interferon response signature, B and T cell activation, and ELS neogenesis. This short-term murine model provides valuable new insight into potential early mechanisms of cSiO2-induced lupus flaring and, furthermore, offers a rapid venue for evaluating interventions against respirable particle-triggered inflammation and autoimmunity.

An Examination of Downward Drift as an Explanation of the Relationship Between Childhood Maltreatment and Residence in Unhealthy Neighborhoods in Adulthood: The Role of Psychiatric Symptoms.

This study sought to determine whether downward drift explains relationships among childhood maltreatment, psychiatric disorders, and residence in unhealthy neighborhoods. Using data from a prospective cohort design study, individuals with court substantiated cases of child abuse and/neglect (ages 0-11 during the years 1967-1971) and matched controls were followed up in adulthood. Mental health symptoms and neighborhood disadvantage were measured in young (Mage  = 29) and middle adulthood (Mage  = 40). Physical disorder and social cohesion were also measured in middle adulthood. Childhood maltreatment increased risk for more symptoms of depression, anxiety, and illicit drug use in young adulthood and depression and anxiety in middle adulthood. Childhood maltreatment negatively impacted neighborhood residence in young and middle adulthood, increasing a person's risk of living in neighborhoods with higher levels of physical disorder and economic disadvantage, and lower levels of social cohesion. Neighborhood disadvantage in young adulthood did not increase risk for psychiatric symptoms in middle adulthood. With one exception, neighborhood disadvantage earlier in life, not psychiatric symptoms, helped explain the relationship between childhood maltreatment and living in unhealthy neighborhoods. The negative impact of childhood maltreatment was evident earlier in life and continued into middle adulthood.

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study.

Trans-cranial magnetic stimulation (TMS) can noninvasively modulate specific brain regions to dissipate symptoms in treatment-resistant schizophrenia (TRS). Citing impaired resting state connectivity between cerebellum and prefrontal cortex in schizophrenia, we aimed to study the effect of intermittent theta burst stimulation (iTBS) targeting midline cerebellum in TRS subjects on a randomized rater blinded placebo control study design. In this study, 36 patients were randomly allocated (using block randomization method) to active and sham iTBS groups. They were scheduled to receive ten iTBS sessions, two per day (total of 1200 pulses) for 5 days in a week. The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Schizophrenia Cognition Rating Scale (SCoRS), Simpson-Angus Extrapyramidal Side Effects Scale (SAS), and Clinical Global Impression (CGI) were assessed at baseline, after last session, and at 2 weeks post-rTMS. Thirty patients (16 and 14 in active and sham groups) completed the study. Intention to treat analysis (ITT) using mixed (growth curve) model analysis was conducted. No significant group (active vs sham) × time (pretreatment-end of 10th session-end of 2 weeks post iTBS) interaction was found for any of the variable. No major side effects were reported. Our study fails to show a significant effect of intensive cerebellar iTBS (iCiTBS) on schizophrenia psychopathology, cognitive functions, and global improvement, compared with sham stimulation, in treatment resistant cases. However, we conclude that it is safe and well tolerated. Trials using better localization technique with large sample, longer duration, and better dosing protocols are needed.

Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis.

Airway exposure of lupus-prone NZBWF1 mice to crystalline silica (cSiO2), a known trigger of human autoimmune disease, elicits sterile inflammation and alveolar macrophage death in the lung that, in turn, induces early autoimmune onset and accelerates lupus progression to fatal glomerulonephritis. Dietary supplementation with docosahexaenoic acid (DHA), a marine ω-3 polyunsaturated fatty acid (PUFA), markedly ameliorates cSiO2-triggered pulmonary, systemic, and renal manifestations of lupus. Here, we tested the hypothesis that DHA influences both cSiO2-induced death and efferocytotic clearance of resultant cell corpses using three murine macrophage models: (i) primary alveolar macrophages (AM) isolated from NZBWF1 mice; (ii) self-renewing AM-like Max Planck Institute (MPI) cells isolated from fetuses of C57BL/6 mice, and (iii) RAW 264.7 murine macrophages, a virus-transformed cell line derived from BALB/c mice stably transfected with the inflammasome adaptor protein ASC (RAW-ASC). Incubation with cSiO2 at 25 and 50 µg/ml for 6 h was found to dose-dependently induce cell death (p < 0.05) in all three models as determined by both acridine orange/propidium iodide staining and release of lactate dehydrogenase into cell culture supernatant. Pre-incubation with DHA at a physiologically relevant concentration (25 µM) significantly reduced cSiO2-induced death (p < 0.05) in all three models. Cell death induction by cSiO2 alone and its suppression by DHA were primarily associated with caspase-3/7 activation, suggestive of apoptosis, in AM, MPI, and RAW-ASC cells. Fluorescence microscopy revealed that all three macrophage models were similarly capable of efferocytosing RAW-ASC target cell corpses. Furthermore, MPI effector cells could likewise engulf RAW-ASC target cell corpses elicited by treatment with staurosporine (apoptosis), LPS, and nigericin (pyroptosis), or cSiO2. Pre-incubation of RAW-ASC target cells with 25 µM DHA prior to death induced by these agents significantly enhanced their efferocytosis (p < 0.05) by MPI effector cells. In contrast, pre-incubating MPI effector cells with DHA did not affect engulfment of RAW-ASC target cells pre-incubated with vehicle. Taken together, these findings indicate that DHA at a physiologically relevant concentration was capable of attenuating macrophage death and could potentiate efferocytosis, with the net effect of reducing accumulation of cell corpses capable of eliciting autoimmunity.

Omega-3 fatty acid intake suppresses induction of diverse autoantibody repertoire by crystalline silica in lupus-prone mice.

Inhalation of crystalline silica (cSiO2) in the workplace is etiologically linked to lupus and other autoimmune diseases. Exposing lupus-prone NZBWF1 mice to respirable cSiO2 unleashes a vicious cycle of inflammation and cell death in the lung that triggers interferon-regulated gene expression, ectopic lymphoid structure (ELS) development, elevation of local and systemic autoantibodies (AAbs), and glomerulonephritis. However, cSiO2-induced inflammation and onset of autoimmunity can be prevented by inclusion of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) into the diet of these mice. Since cSiO2 both causes cell death and interferes with efferocytosis, secondary necrosis of residual cell corpses might provide a rich and varied autoantigen (AAg) source in the lung. While it is known that the particle induces anti-nuclear and anti-dsDNA AAbs in NZBWF1 mice, the full extent of the cSiO2-induced AAb response relative to specificity and isotype is not yet understood. The purpose of this study was to test the hypotheses that cSiO2 exposure induces a wide spectrum of AAbs in the pulmonary and systemic compartments, and that dietary DHA intervention prevents these changes. Archived tissue fluid samples were obtained from a prior study in which NZBWF1 mice were fed purified isocaloric diets containing no DHA (control) or DHA corresponding calorically to human doses of 2 and 5 g/day. Mice were intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 weeks, then groups euthanized 1, 5, 9, or 13 weeks post-instillation (PI) of the last cSiO2 dose. Bronchoalveolar lavage fluid (BALF) and plasma from each time point were subjected to AAb profiling using a microarray containing 122 AAgs. cSiO2 triggered robust IgG and IgM AAb responses against lupus-associated AAgs, including DNA, histones, ribonucleoprotein, Smith antigen, Ro/SSA, La/SSB, and complement as early as 1 week PI in BALF and 5 weeks PI in plasma, peaking at 9 and 13 weeks PI, respectively. Importantly, cSiO2 also induced AAbs to AAgs associated with rheumatoid arthritis (collagen II, fibrinogen IV, fibrinogen S, fibronectin, and vimentin), Sjögren's syndrome (α-fodrin), systemic sclerosis (topoisomerase I), vasculitis (MPO and PR3), myositis (Mi-2, TIF1-γ, MDA5), autoimmune hepatitis (LC-1), and celiac disease (TTG). cSiO2 elicited comparable but more modest IgA AAb responses in BALF and plasma. cSiO2-induced AAb production was strongly associated with time dependent inflammatory/autoimmune gene expression, ELS development, and glomerulonephritis. AAb responses were dose-dependently suppressed by DHA supplementation and negatively correlated with the ω-3 index, an erythrocyte biomarker of ω-3 content in tissue phospholipids. Taken together, these findings suggest that cSiO2 exposure elicits a diverse multi-isotype repertoire of AAbs, many of which have been reported in individuals with lupus and other autoimmune diseases. Furthermore, induction of this broad AAb spectrum could be impeded by increasing ω-3 tissue content via dietary DHA supplementation.

Carbonyl Sulfide (COS) Donor Induced Protein Persulfidation Protects against Oxidative Stress.

The emergence of hydrogen sulfide (H2 S) as an important signalling molecule in redox biology with therapeutic potential has triggered interest in generating this molecule within cells. One strategy that has been proposed is to use carbonyl sulfide (COS) as a surrogate for hydrogen sulfide. Small molecules that generate COS have been shown to produce hydrogen sulfide in the presence of carbonic anhydrase, a widely prevalent enzyme. However, other studies have indicated that COS may have biological effects which are distinct from H2 S. Thus, it would be useful to develop tools to compare (and contrast) effects of COS and H2 S. Here we report enzyme-activated COS donors that are capable of inducing protein persulfidation, which is symptomatic of generation of hydrogen sulfide. The COS donors are also capable of mitigating stress induced by elevated reactive oxygen species. Together, our data suggests that the effects of COS parallel that of hydrogen sulfide, laying the foundation for further development of these donors as possible therapeutic agents.

Internal Consistency and Convergent Validity of the Personality Assessment Inventory English and European-Spanish Version with English/Spanish Bilinguals.

Practitioners have few personality inventory options when assessing Spanish-speakers, despite professional guidelines that encourage them to administer measures that are validated with their populations of interest. To build on research in this area, we examined the internal consistency and convergent validity of the Personality Assessment Inventory (PAI) and the Personality Assessment Inventory European-Spanish (PAIE-S) version among bilingual Latin American Spanish-speakers (final n = 53). For the PAI, 72.72% of scales and 35.48% of subscales had alphas above .70. For the PAIE-S, 50.00% of scales and 25.81% of scales met this alpha. Participants tended to score lowest on the PAI Alcohol Problems scale (T = 47.19) and the PAIE-S Warmth scale (T = 45.49). On average, participants scored highest on the PAI's Paranoia-Hypervigilance scale (T = 61.15) and the PAIE-S's Paranoia scale (T = 57.64). We identified 10 scales and subscales on which participants were significantly more likely (p < .00094) to score higher on one measure than the other. Participants more often scored higher on the PAI than the PAIE-S. All parallel scales and subscales converged at p < .00094 with the exception of the Antisocial Features-Egocentricity scale. Taken together, findings suggest taking caution when administering these measures to Latin American bilingual Spanish-speakers.

Docosahexaenoic Acid Consumption Impedes Early Interferon- and Chemokine-Related Gene Expression While Suppressing Silica-Triggered Flaring of Murine Lupus.

Exposure of lupus-prone female NZBWF1 mice to respirable crystalline silica (cSiO2), a known human autoimmune trigger, initiates loss of tolerance, rapid progression of autoimmunity, and early onset of glomerulonephritis. We have previously demonstrated that dietary supplementation with the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) suppresses autoimmune pathogenesis and nephritis in this unique model of lupus flaring. In this report, we utilized tissues from prior studies to test the hypothesis that DHA consumption interferes with upregulation of critical genes associated with cSiO2-triggered murine lupus. A NanoString nCounter platform targeting 770 immune-related genes was used to assess the effects cSiO2 on mRNA signatures over time in female NZBWF1 mice consuming control (CON) diets compared to mice fed diets containing DHA at an amount calorically equivalent to human consumption of 2 g per day (DHA low) or 5 g per day (DHA high). Experimental groups of mice were sacrificed: (1) 1 d after a single intranasal instillation of 1 mg cSiO2 or vehicle, (2) 1 d after four weekly single instillations of vehicle or 1 mg cSiO2, and (3) 1, 5, 9, and 13 weeks after four weekly single instillations of vehicle or 1 mg cSiO2. Genes associated with inflammation as well as innate and adaptive immunity were markedly upregulated in lungs of CON-fed mice 1 d after four weekly cSiO2 doses but were significantly suppressed in mice fed DHA high diets. Importantly, mRNA signatures in lungs of cSiO2-treated CON-fed mice over 13 weeks reflected progressive amplification of interferon (IFN)- and chemokine-related gene pathways. While these responses in the DHA low group were suppressed primarily at week 5, significant downregulation was observed at weeks 1, 5, 9, and 13 in mice fed the DHA high diet. At week 13, cSiO2 treatment of CON-fed mice affected 214 genes in kidney tissue associated with inflammation, innate/adaptive immunity, IFN, chemokines, and antigen processing, mostly by upregulation; however, feeding DHA dose-dependently suppressed these responses. Taken together, dietary DHA intake in lupus-prone mice impeded cSiO2-triggered mRNA signatures known to be involved in ectopic lymphoid tissue neogenesis, systemic autoimmunity, and glomerulonephritis.

Internal consistency and convergent validity of the Personality Assessment Inventory English and European-Spanish version with English/Spanish bilinguals

Practitioners have few personality inventory options when assessing Spanish-speakers, despite professional guidelines that encourage them to administer measures that are validated with their populations of interest. To build on research in this area, we examined the internal consistency and convergent validity of the Personality Assessment Inventory (PAI) and the Personality Assessment Inventory European-Spanish (PAIE-S) version among bilingual Latin American Spanish-speakers (final n = 53). For the PAI, 72.72% of scales and 35.48% of subscales had alphas above .70. For the PAIE-S, 50.00% of scales and 25.81% of scales met this alpha. Participants tended to score lowest on the PAI Alcohol Problems scale (T = 47.19) and the PAIE-S Warmth scale (T = 45.49). On average, participants scored highest on the PAI's Paranoia-Hypervigilance scale (T = 61.15) and the PAIE-S's Paranoia scale (T = 57.64). We identified 10 scales and subscales on which participants were significantly more likely (p < .00094) to score higher on one measure than the other. Participants more often scored higher on the PAI than the PAIE-S. All parallel scales and subscales converged at p < .00094 with the exception of the Antisocial Features-Egocentricity scale. Taken together, findings suggest taking caution when administering these measures to Latin American bilingual Spanish-speakers

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