Profibrogenic role of IL-15 through IL-15 receptor alpha-mediated trans-presentation in the carbon tetrachloride-induced liver fibrosis model.

Background: Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Rα), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis. Methods: We induced liver fibrosis in Il15-/- , Il15ra-/- and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl4). Liver fibrosis was evaluated by Sirius red and Mason's trichrome staining and α-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry. Results: Both Il15-/- and Il15ra-/- mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. Il15ra-/- mice showed further reduction in collagen deposition compared to Il15-/- mice. However, Col1a1 and Col1a3 genes were similarly induced in the fibrotic livers of wildtype, Il15-/- and Il15ra-/- mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, Il15-/- and Il15ra-/- mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45+ immune cells and CD68+ macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice. Conclusion: Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15Rα.

Insight into the roles of hematite iron oxide nanoparticles on microalgae growth, urban wastewater treatment and bioproducts generation: Gompertz simulation, nutrient mass balance and gene expression.

In this study, the effect of α-Fe2O3 nanoparticles spiking in urban wastewater (UWW) on growth rate, wastewater treatment ability and bioproducts generation of C. vulgaris and Spirulina was investigated and compared with pure cultivation system. The biomass concentration of C. vulgaris and Spirulina improved by 20 % and 39 % at 10 and 15 mg/L α-Fe2O3, respectively while the both microalgae growth pattern fitted better with Gompertz simulation after treatment with α-Fe2O3. The nutrients mass balance revealed that 1 g of treated C. vulgaris and Spirulina could uptake more COD, TN and TP in comparison to the untreated cells. The lipid generation increased remarkably (C. vulgaris: 45 % and Spirulina: 72 %) after α-Fe2O3 treatment. While, the addition of α-Fe2O3 showed no significant impact on the protein and carbohydrate productivity. Overall, this study evangelize the role of nanoparticles on promoting microalgae applications as a sustainable approach for UWW treatment and promising feedstock for biofuel production.

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition.

Background: Following SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic. Methods: The study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA. Results: The frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD-CD27-) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups. Conclusions: The antibody responses to the spike protein, but not the anti-RBD B cell responses diverge between convalescent males and females who develop PCC. Our findings also suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens.

IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation.

We previously reported that NOD.Scid mice lacking interleukin-15 (IL-15), or IL-15 receptor alpha-chain, develop T-acute lymphoblastic leukemia (T-ALL). To understand the mechanisms by which IL-15 signaling controls T-ALL development, we studied the thymocyte developmental events in IL-15-deficient Scid mice from NOD and C57BL/6 genetic backgrounds. Both kinds of mice develop T-ALL characterized by circulating TCR-negative cells expressing CD4, CD8 or both. Analyses of thymocytes in NOD.Scid.Il15-/- mice prior to T-ALL development revealed discernible changes within the CD4-CD8- double-negative (DN) thymocyte developmental stages and increased frequencies of CD4+CD8+ double-positive cells with a high proportion of TCR-negative CD4+ and CD8+ cells. The DN cells also showed elevated expressions of CXCR4 and CD117, molecules implicated in the expansion of DN thymocytes. T-ALL cell lines and primary leukemic cells from IL-15-deficient NOD.Scid and C57BL/6.Scid mice displayed increased NOTCH1 activation that was inhibited by NOTCH1 inhibitors and blockers of the PI3K/AKT pathway. Primary leukemic cells from NOD.Scid.Il15-/- mice survived and expanded when cultured with MS5 thymic stromal cells expressing Delta-like ligand 4 and supplemented with IL-7 and FLT3 ligand. These findings suggest that IL-15 signaling in the thymus controls T-ALL development from aberrant thymocytes with an impaired DNA repair capacity and increased NOTCH1 activation.

The effect of transcranial direct current stimulation (tDCS) on cerebellum in reduction of the symptoms of obsessive-compulsive disorder.

Obsessive-Compulsive Disorder (OCD) is one disabling psychiatric condition.  Investigations reported the effectiveness of trans-cranial direct current stimulation (tDCS) in regulating orbito-fronto-striato-pallido-thalamic network activity in OCD patients. In these patients, hypo- or hyper-activity of different brain areas including orbitofrontal cortex (OFC), pre-supplementary motor area (pre-SMA), cingulate gyrus, putamen, thalamus, parietal cortex and cerebellum have been reported.The purpose of this study is determination the efficacy of three different tDCS protocols and finding the best one to mitigate OCD symptoms.This study was a quasi-experimental research with pre-test-post-test and a one-month follow-up. Of the patients that referred to Brain and Cognitive Clinic in Tehran, 40 OCD subjects were randomly selected and assigned into four groups (three experimental groups and one control group). Of the mentioned patients, those who scored 16 or above on the Yale-Brown obsessive-compulsive scale were chosen. tDCS was delivered over a period of 5 days at an intensity of 2 mA for 15 minutes twice a day. In the three intervention groups, tDCS was delivered in one of the following electrode montages: (i) anode over the right cerebellum (O2) and cathode over the supplementary motor area (pre-SMA; c3/c4); (ii) anode over O2 and cathode over the left OFC (FP1); or (iii) anode over O2 and cathode over the left cerebellum (O1). The control group received sham stimulation (anode over O2 and cathode over the left FP1). Analysis of covariance (ANCOVA) was used to evaluate the results.The results showed that two of the tDCS protocols reduced OCD symptoms (P < 0.001). Data also revealed that the effect of the anodal stimulation of the O2 led to better outputs as compared to O1..

Effect of Hydroalcoholic Extract of Rosmarinus officinalis L. Leaf on Anxiety in Mice.

In today's stressful world, psychopathy (especially anxiety) is receiving increased importance. Most of the drugs used to treat this disease have several side effects. Medicinal plants derived from natural products have fewer side effects and can be used in the treatment of this disease. The aim of this study was to evaluate the effect of the hydroalcoholic extract of Rosmarinus officinalis L. on anxiety in mice. In this experimental study, 50 male mice were randomly divided into 5 groups. To evaluate anxiety, the Elevated Plus Maze test was performed. The control group received normal saline, the positive control group received diazepam (1 mg/kg) as intraperitoneal injection, and the experimental groups received doses of 100, 200, and 400 mg/kg body weight of rosemary extract. The data were analyzed using SPSS 15 and ANOVA statistical tests. The results show that rosemary extract dose-dependently increases the mice spending time and the entries number of mice in plus maze open arms (indicating less stress). This effect at a dose of 400 mg/kg was similar to diazepam, which, in comparison to the control group, was statistically significant (P < .01), while the evaluation of locomotor activity in treated groups, compared with the control groups, showed no significant difference (P > .05). On the other hand, the rosemary extract, similar to the standard drug diazepam, showed an anti-anxiety effect. This effect is probably due to the presence of flavonoids in this plant and their antioxidant property.

Genome-wide association study and meta-analysis of intraocular pressure.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10(-8)). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

The association of primary open-angle glaucoma with mortality: a meta-analysis of observational studies.

OBJECTIVE: To conduct a meta-analysis to estimate the relationship between primary open-angle glaucoma (POAG) and mortality. METHODS: A systematic search of the PubMed, Embase, and Web of Science databases yielded 9 cohort studies with relative risk (RR) estimates for all-cause mortality. The studies were critically reviewed by an expert in the field. The data were extracted and analyzed in a pooled analysis by the random-effects model. Meta-regression to assess for heterogeneity by several covariates and subgroup analysis on cardiovascular mortality were performed. RESULTS: A significant risk was not detected in the final pooled analysis (RR, 1.13; 95% confidence interval [CI], 0.97-1.31) for all-cause mortality. A meta-regression across mean follow-up time, age, and sex was not significant. A meta-regression across diabetes status in 3 of the 9 studies did not demonstrate significant results (P = .94). Subgroup analysis on cardiovascular mortality from 4 of the 9 studies was marginally significant (RR, 1.20; 95% CI, 1.00-1.43; P = .05), but insignificant after removal of a study in which POAG was ascertained by self and proxy report (RR, 1.12; 95% CI, 0.87-1.46). CONCLUSION: This meta-analysis does not demonstrate an association between POAG and all-cause or cardiovascular mortality.

Macular ischemia associated with imatinib mesylate therapy for chronic myeloid leukemia.

PURPOSE: Imatinib mesylate (Gleevec, East Hanover, NJ) is a drug approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) or Kit-positive gastrointestinal stromal tumors. A case of ischemic maculopathy associated with imatinib mesylate therapy is reported. METHODS: A 62-year-old woman with a 16-year history of CML was treated with imatinib mesylate, initially at a daily dose of 400 mg that was decreased to 300 mg due to systemic side effects. Several weeks after beginning imatinib mesylate therapy, she developed blurred vision (greater in the left eye than in the right eye). RESULTS: Fundus examination of both eyes revealed retinal telangiectasia with intraretinal hemorrhages and perifoveal retinal telangiectasia. Fluorescein angiography showed macular ischemia (greater in the left eye than in the right eye). Late perifoveal leakage was present surrounding the macular ischemic zone. Visual acuity was reduced to 20/30 in the right eye and 20/100 in the left eye, which did not improve over 10 months of follow-up. CONCLUSION: Imatinib mesylate may be associated with ischemic maculopathy that can severely compromise vision. It may be necessary for patients receiving this therapy to be monitored for associated visual symptoms and funduscopic abnormalities.