Regulation of interleukin-21 receptor expression and its signal transduction by WSB-2

Interleukin-21 (IL-21) is a pleiotropic cytokine that regulates T-cell, B-cell, NK-cell, and myeloid-cell functions. IL-21 binds with its cognate receptor complex, which consists of the IL-21 receptor (IL-21R) and the common gamma chain (γc) receptor subunit. We identified novel IL-21R-binding molecule, WD-40 repeats containing SOCS-box-2, WSB-2. WSB-2 associated with the membrane-proximal intracytoplasmic region of IL-21R, including box1 and box2. Overexpression study of WSB-2 showed the reduction of IL-21R expression and IL-21-induced signal transduction. On the other hand, small interfering RNA for WSB-2 enhanced the expression level of IL-21R and IL-21-induced STAT3 activation, indicating that WSB-2 negatively controls the receptor expression. This report provides the first evidence that WSB-2 is a regulator of IL-21R expression and IL-21-induced signal transduction.     

Impaired IL-7 signaling may explain a case of atypical JAK3-SCID

Janus kinase 3-severe combined immunodeficiency (JAK3-SCID) is an autosomal recessive immunodeficiency disease caused by various mutations in the JAK3 gene. Typical JAK3-SCID is characterized by a phenotype in which B cells are present but T and NK cells are not, the T^?B⁺NK^? phenotype, and by impaired signaling through cytokine receptors that use the common gamma chain (γc) subunit. An atypical JAK3-SCID case carrying a single glutamate to glycine substitution mutation (E481G) in the JH3 domain of one JAK3 allele, and a deletion mutation (del482-596) in the JH3 and JH2 domains of the other allele was reported previously. Although this patient had CD4⁺ T cells and NK cells unlike typical cases, the CD4⁺ T cells were functionally impaired. We report here that the JAK3-E481G mutant transduced IL-2-, IL-4-, IL-15-, and IL-21-induced signals as efficiently as wild-type JAK3. However, this mutant failed to respond to IL-7 by phosphorylating JAK1, JAK3, or STAT5. The other mutant JAK3, JAK3-del482-596, was non-functional. Thus, an impaired IL-7 signal may cause SCID and compromise T-cell differentiation, even if the IL-15 signal is preserved and supports NK-cell development, as in this patient.     

Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta).

Adipose tissue deposition is highly responsive to estrogen; ovariectomy increases adipose deposition, and estrogen replacement reverses this. Estrogen receptor alpha (ERalpha) plays a major role in adipose tissue. ERalpha knockout (alphaERKO) mice show an increase in adipose tissue of over a 100 % compared to wild-type mice. However, alphaERKO mice undergo a 10-fold increase in 17beta-estradiol (E2), and persistent or even increased signaling through ERbeta could be a factor in obesity of alphaERKO mice. To test the hypothesis that ERbeta plays a role in adipose tissue, adult female alphaERKO mice were ovariectomized or sham-ovariectomized and fed a phytoestrogen-free diet. Ovariectomized mice were treated with vehicle or E2, and bodyweights and food consumption were measured. Mice were killed after 28 days and inguinal and parametrial fat pads collected. Sham-ovariectomized alphaERKO mice had increased body weight, ovariectomized alphaERKO mice showed a 6 % decrease, and E2 replacement restored body weight to sham levels. Fat pads of ovariectomized alphaERKO mice showed 45 % and 16 % decreases in weight and adipocyte circumference, respectively, compared to sham-ovariectomized or E2-replaced ovariectomized alphaERKO mice. Ovariectomized alphaERKO mice showed a trend towards decreased feed consumption that did not reach significance. Blood glucose levels were lower both before and after glucose injection in ovariectomized compared to sham alphaERKO mice, and E2 treatment reversed this. Insulin levels following glucose challenge were lower in ovariectomized compared to sham-ovariectomized alphaERKO mice, indicating that ovariectomy ameliorated the glucose intolerance and insulin resistance in alphaERKO mice. Immunohistochemical analysis revealed strong staining for ERbeta in adipose tissue. These observations indicate that removing E2/ERbeta signaling in alphaERKO mice by ovariectomy decreases body and fat-pad weights and adipocyte size, while improving insulin and glucose metabolism. ERbeta mediated effects on adipose tissue are opposite those of ERalpha, although E2 effects on adipose tissue are predominately through ERalpha.     

Molecular modeling,synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole,indazole, benzothiazole and thiazole

A new series of heterocyclic molecules bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broath dilution method, molecules were found to be highly active (MIC value 50–3.1?µg/mL) against different human pathogens, namely B. cerus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was observed during determination of FIC where molecules were used in combination with reference drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination – varying concentration of test compounds and ½ MIC of reference drugs or varying concentration of reference drugs and ½ MIC of test compounds, was reduced up to ¹/₄ or ¹/₃₂ of the original value, indicating thereby the combination was 4–32 times more potent than the test molecule. The molecules also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results positively indicated towards the development of lead antibacterials using the combination approach.     

Synthesis and Characterization of Functionalized Metal-organic Frameworks

Metal-organic frameworks have attracted extraordinary amounts of research attention, as they are attractive candidates for numerous industrial and technological applications. Their signature property is their ultrahigh porosity, which however imparts a series of challenges when it comes to both constructing them and working with them. Securing desired MOF chemical and physical functionality by linker/node assembly into a highly porous framework of choice can pose difficulties, as less porous and more thermodynamically stable congeners (e.g., other crystalline polymorphs, catenated analogues) are often preferentially obtained by conventional synthesis methods. Once the desired product is obtained, its characterization often requires specialized techniques that address complications potentially arising from, for example, guest-molecule loss or preferential orientation of microcrystallites. Finally, accessing the large voids inside the MOFs for use in applications that involve gases can be problematic, as frameworks may be subject to collapse during removal of solvent molecules (remnants of solvothermal synthesis). In this paper, we describe synthesis and characterization methods routinely utilized in our lab either to solve or circumvent these issues. The methods include solvent-assisted linker exchange, powder X-ray diffraction in capillaries, and materials activation (cavity evacuation) by supercritical CO₂ drying. Finally, we provide a protocol for determining a suitable pressure region for applying the Brunauer-Emmett-Teller analysis to nitrogen isotherms, so as to estimate surface area of MOFs with good accuracy.     

Giving the silent majority a stronger voice? Initiatives to empower Muslim women as part of the UK's ‘War on Terror’

Abstract

This article provides a gendered analysis of the ‘War on Terror’ in the UK context. Specifically it looks at initiatives to empower Muslim women, which were part of New Labour's Preventing Violent Extremism (PVE) agenda, the impetus for which stemmed from the idea that, as ‘the silent majority’, women need to be given a ‘stronger voice’. Based on analysis of qualitative interviews, this article situates these initiatives within a broader policy landscape of debates on multiculturalism, community cohesion and Britishness. It explores interviewees' understandings of Muslim women's silence in relation to those suggested by policy discourse, considering the ways in which the state's attempt to ‘give voice’ worked in practice. I argue that the operation of such initiatives continued to constrain Muslim women's voices, restricting ‘voice’ to a narrow range of speakers speaking about a narrow range of issues.     

Phylogenetic diversity and biotechnological potentials of marine bacteria from continental slope of eastern Arabian Sea

Marine environments are substantially untapped source for the isolation of bacteria with the capacity to produce various extracellular hydrolytic enzymes, which have important ecological roles and promising biotechnological applications. Hydrolases constitute a class of enzymes widely distributed in nature from bacteria to higher eukaryotes. Marine microbial communities are highly diverse and have evolved during extended evolutionary processes of physiological adaptations under the influence of a variety of ecological conditions and selection pressures. A number of marine hydrolases have been described, including amylases, lipases and proteases, which are being used extensively for biotechnological applications. The present study was carried out to isolate marine bacteria from continental slope sediments of the eastern Arabian Sea and explore their biotechnological potential. Among the 119 isolates screened, producers of amylases (15%), caseinases (40%), cellulases (40%), gelatinases (60%), lipases (26%), ligninases (33%), phytase (11%) and Malachite Green dye degraders (16%) were detected. Phylogenetic analysis based on 16S rRNA gene sequencing showed that predominant marine sediment bacteria possessing more than four enzymatic activities belonged to the phyla Firmicutes and Proteobacteria, was assigned to the genera Bacillus, Planococcus, Staphylococcus, Chryseomicrobium, Exiguobacterium and Halomonas. Biodegradation of the dye Malachite Green using the liquid decolorization assay showed that both the individual cultures (Bacillus vietnamensis, Planococcus maritimus and Bacillus pumilus) and their consortium were able to decolorize more than 70% of dye within 24?h of incubation. This is the first report on diversity and extracellular hydrolytic enzymatic activities and bioremediation properties of bacteria from continental slope sediment of eastern Arabian Sea.