Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish family with severe combined immunodeficiency disorder

Protein tyrosine kinases (PTKs) play an important role in T cell development and activation. In vitro and in vivo defects, resulting in variable deficiencies in thymic development and in T cell antigen receptor (TCR) signal transduction, in PTKs have been shown. ZAP70, one of those PTKs, is a 70-kDa tyrosine phosphoprotein and associates with the ζ chain and undergoes tyrosine phosphorylation following TCR stimulation. It is expressed in T and natural killer (NK) cells. Several mutations were shown to lead to an autosomal recessive form of severe combined immunodeficiency disease (SCID).     

Alpha7 Helix Plays an Important Role in the Conformational Stability of PTP1B

Abstract

The C-terminus of Protein Tyrosine Phosphatase 1B (PTP1B) includes an α-helix (α7), which forms an allosteric binding site 20 Å away from the active site. This helix is specific to PTP1B and its truncation decreases the catalytic activity significantly. Here, molecular dynamics (MD) simulations in the presence and absence of α7 were performed to investigate the role played by α7. The highly mobile α7 was found to maintain its contacts with loop 11 (L11)- α3 helix throughout the simulations. The interactions of Tyr152 on L11, Tyr176, Thr177 on the catalytically important WPD loop and Ser190 on α3 are important for the conformational stability and the concerted motions of the regions surrounding the WPD loop. In the absence of α7, L11 and WPD loop move away from their crystal structure conformations, resulting in the loss of the interactions in this region, and a decrease in the residue displacement correlations in the vicinity of WPD loop. Therefore, we suggest that one of the functionally important roles of α7 may be to limit the L11 and α3 motions, and, facilitate the WPD loop motions. Truncation of α7 in PTP1B is found to affect distant regions as well, such as the substrate recognition site and the phosphate binding-loop (P-loop), changing the conformations of these regions significantly. Our results show that the PTP1B specific α7 is important for the conformation and dynamics of the WPD loop, and also may play a role in ligand binding.     

A Pilot Study on Neopterin Levels and Tryptophan Degradation in Zinc-Exposed Galvanization Workers

Hot-dip galvanization is a zinc-coating process to protect the metal items from corrosion. Zinc oxide nanoaerosol fume rising from hot metal bath surface in nano dimensions contains the greatest risk for workers in galvanization process. In the present study, it was evaluated whether inhalation of zinc causes any alteration in cellular immunity and tryptophan degradation by measuring neopterin, tryptophan, kynurenine, and zinc levels in 63 male galvanization workers and 23 male office personnel as controls. Serum and urinary zinc levels were found as 14.90?±?0.90 and 102?±?4.7 μg/dL in workers while 12.87?±?1.45 and 75?±?4.2 μg/dL in controls, respectively (both, p?<?0.05). Similarly, the mean urinary neopterin levels and serum neopterin and kynurenine levels were found to be statistically higher in galvanization workers than the controls (all, p?<?0.05). Significant correlations were found between urinary neopterin levels and kynurenine to tryptophan ratio or serum zinc levels. The results indicated cellular immune activation by occupational zinc exposure. It was estimated that neopterin, in parallel with kynurenine pathway, could reflect occupational exposure to zinc nanoaerosols and might be useful in early diagnosis of immune alterations due to nano-scale exposures.     

Support for Kurdish language rights in Turkey: the roles of ethnic group,group identifications,contact, and intergroup perceptions

The question of Kurdish language rights has been a central issue in the Turkish–Kurdish conflict. The current study examined endorsement of Kurdish language rights in relation to intergroup factors (i.e. group identifications, cross-group friendships, perceived discrimination, and perceived out-group beliefs about state unity) among self-identified Turkish and Kurdish participants. The results indicate that Turks were much less in favour of these rights than the Kurds. In addition, for the Turks, higher national and ethnic identification were associated with lower support for Kurdish language rights, while cross-group friendship, perceived discrimination of Kurds and the belief that Kurds endorse national unity were associated with more support for rights. For the Kurdish participants, stronger national identification seems to undermine the mobilizing meaning that Kurdish group identification has for language rights support. Furthermore, friendship with Turks can undermine the support for rights because it strengthens national identification and reduces ethnic identification.     

Kinetic and in silico studies of hydroxy-based inhibitors of carbonic anhydrase isoforms I and II

A series of hydroxy and phenolic compounds have been assayed for the inhibition of two physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II. The investigated molecules showed inhibition constants in the range of 1.07–4003 and 0.09–31.5?μM at the hCA I and hCA II enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are compared using three different scoring algorithms, namely Glide/SP, Glide/XP and Glide/IFD. In addition, different ADME (absorption, distribution, metabolism and excretion) analysis was performed. All the examined compounds were found within the acceptable range of pharmacokinetic profiles.     

8-Br-cADPR, a TRPM2 ion channel antagonist,inhibits renal ischemia–reperfusion injury

The transient receptor potential melastatin-2 (TRPM2) channel belongs to the transient receptor potential channel superfamily and is a cation channel permeable to Na⁺ and Ca ²⁺. The TRPM2 ion channel is expressed in the kidney and can be activated by various molecules such as hydrogen peroxide, calcium, and cyclic adenosine diphosphate (ADP)-ribose (cADPR) that are produced during acute kidney injury. In this study, we investigated the role of 8-bromo-cyclic ADP-ribose (8-Br-cADPR; a cADPR antagonist) in renal ischemia–reperfusion injury using biochemical and histopathological parameters. CD38, cADPR, tumor necrosis factor-α, interleukin-1β, and myeloperoxidase (inflammatory markers), urea and creatinine, hydrogen peroxide (oxidant), and catalase (antioxidant enzyme) levels that increase with ischemia–reperfusion injury decreased in the groups treated with 8-Br-cADPR. In addition, renin levels were elevated in the groups treated with 8-Br-cADPR. Histopathological examination revealed that 8-Br-cADPR reduced renal damage and the expression of caspase-3 and TRPM2. Our results suggest that the inhibition of TRPM2 ion channel may be a new treatment modality for ischemic acute kidney injury.     

Distribution of N-cadherin in human cerebral cortex during prenatal development

An important subgroup of adhesion molecules is the superfamily of cadherins, which takes part in cell recognition and differentiation during development. To our knowledge only one study describing N-cadherin expression in developing human brain has been performed so far. Our aim is to identify N-cadherin expression to establish a relationship between its expression and function in human cerebral cortex during prenatal development. In the present study, localization and intensity of N-cadherin was investigated in developing cerebral cortex. Fetuses from spontaneous abortions (n=13) were obtained from first, second, and third trimesters. Western blot analysis revealed three bands and the third trimester samples showed the strongest bands for N-cadherin. Cell processes, axon bundles, and some of the developing neurons revealed immunoreactivity for N-cadherin throughout pregnancy. The immunoreactivity increased in the developing neocortex and expanded from the ventricular layer toward the marginal zone as development progressed. Moreover, the immunoreactivity was strong in vascular endothelium during all three trimesters. We conclude that N-cadherin is dynamically related to the organization of cerebral cortex layers during prenatal development. The dynamic expression pattern implicates N-cadherin as a potential regulator of cell migration, axon extension and fasciculation, the establishment of synaptic contacts, and neurovascular angiogenesis in the developing human cerebral cortex.     

Gastroprotective and Antioxidant Effects of Lobaria pulmonaria and Its Metabolite Rhizonyl Alcohol on Indomethacin‐Induced Gastric Ulcer

Two lichen metabolites, rhizonaldehyde ( 1 ) and rhizonyl alcohol ( 2 ), were isolated from the acetone extract of Lobaria pulmonaria by chromatographic methods, and their chemical structures were determined by UV/VIS, IR, and 1D‐ and 2D‐NMR spectroscopic methods. The gastroprotective and in vivo antioxidant activities of extracts of L. pulmonaria and its metabolites, 1 and 2 , were investigated in indomethacin‐induced ulcer models in rats. The gastric lesions were significantly reduced by acetone, hexane, and CHCl₃ extracts, with 75.3–41.5% inhibition. Rhizonyl alcohol ( 2 ) significantly reduced the gastric lesions with an inhibition rate of 84.6–42.8%, whereas rhizonaldehyde ( 1 ) significantly increased the gastric lesions. Antioxidant parameters and myeloperoxidase activities were also evaluated in the gastric tissues of the rats. Indomethacin caused oxidative stress, which resulted in lipid peroxidation in gastric tissues by decreasing the levels of the antioxidants as compared to healthy rat tissues. In contrast to indomethacin, all extracts and rhizonyl alcohol ( 2 ) caused a significant decrease in lipid peroxidation levels and an increase in antioxidant parameters, superoxide dismutase, glutathione peroxidase, and glutathione‐S‐transferase, and reduced glutathione in gastric tissues. The administration of rhizonyl alcohol ( 2 ) also resulted in a decrease in gastric myeloperoxidase activity increased by indomethacin. The gastroprotective effect of rhizonyl alcohol ( 2 ) can be attributed to its antioxidant properties and its suppressing effect on neutrophil infiltration into gastric tissues.