DISC1 gene polymorphisms and the risk of schizophrenia in an Iranian population: A preliminary study

Background: Schizophrenia, schizoaffective disorder, and bipolar illness are common psychological disorders with high heritability and variable phenotypes. The disrupted in schizophrenia 1 ( DISC1) gene, on chromosome 1q42, has an essential role in neurite outgrowth and cell signaling. The purpose of this study was to investigate the association of three single-nucleotide polymorphisms (SNPs; rs6675281, rs2255340, and rs2738864) with schizophrenia disorder. These three SNPs were chosen as they had been used in most of the previous studies. Methods: In a case-control study of Iranian population for the first time 778 blood samples were collected including, 402 schizophrenic patients and 376 healthy controls. Genomic DNA was extracted from peripheral blood using DNA extraction kit (BioFlux Co). The genotypes of rs6675281, rs2255340, and rs2738864 were detected by nested allele-specific multiplex polymersae chain reaction (PCR). Results: Our data revealed that the three SNPs are significantly associated with schizophrenia (rs2255349 C>T: confidence interval (CI), 2.115 to 3.268; P = 0.0000 OR: 2.629; rs2738864 C>T: CI, 1.538 to 2.339; P = 0.0000 OR: 1.897; rs6675281 C>T: CI, 2.788 to 4.662; P = 0.0009241 OR: 3.605). Through applying the expectation-maximization (EM) algorithm, we calculated the haplotype frequency, and finally performed haplotype analysis with Bonferroni correction and data preprocessing methods and the results showed rs66875281 to have the highest association. Discussion: Our findings primarily showed that DISC1 gene polymorphisms contribute to schizophrenia risk and have a significant association with this disorder among Iranian population. The strategy was found to be easy, rapid, specific, and consistent for the co-occurring detection of the DISC1 polymorphisms. We could finally confirm that the polymorphisms are related to schizophrenia studied in Iranian population.     

Adsorption and immobilisation of human insulin on graphene monoxide,silicon carbide and boron nitride nanosheets investigated by molecular dynamics simulation

The adsorption and immobilisation of human insulin onto the bio-compatible nanosheets including graphene monoxide, silicon carbide and boron nitride nanosheets were studied by molecular dynamics simulation at the temperature of 310 K. After equilibration, heating and 100 ns production molecular dynamic runs, it was found that the insulin was adsorbed and immobilised onto the considered surfaces in a native folded state. The structural parameters, including root-mean-square deviation and fluctuation, surface accessible solvent area, radius of gyration (R_g) and the distance between the centre of the mass of immobilised protein and the surface of the considered nanosheets, were measured, analysed and discussed. The energetics of the studied systems such as the interaction energy between protein and nanosheet was also measured and addressed. The discussions were centred on the structural and energetic parameters of the protein and nanosheets, including charge density, hydrophobicity, hydrophilicity and residue polarity. The results also showed that the active site of C-termini of chain B played an important role in the adsorption process and this could be helpful in the protection of insulin in its smart delivery and release applications.     

Untargeted mutagenesis induced by UV in the lacI gene of Escherichia coli

Summary Using a nonselective method, we have estimated the proportion of untargeted mutations in the lacI gene of E. coli by transferring either irradiated or unirradiated F pro lac plasmids from an excision deficient donor to an excision deficient pro lac deleted recipient that had been irradiated and allowed to induce recA dependent functions for 30 min. We find that about 10 percent of the mutations induced by either 3.5 Jm^-2 or 7 Jm^-2 UV are untargeted.     

New mutations affecting induced mutagenesis in yeast

Previously isolated mutations in baker's yeast, Saccharomyces cerevisiae, that impair induced mutagenesis were all identified with the aid of tests that either exclusively or predominantly detect base-pair substitutions. To avoid this bias, we have screened 11 366 potentially mutant clones for UV-induced reversion of the frameshift allele, his4–38, and have identified 10 mutants that give much reduced yields of revertants. Complementation and recombination tests show that 6 of these carry mutations at the previously known REV1, REV1 and REV3 loci, while the remaining 4 define 3 new genes, REV4 (2 mutations), REV5 and REV6. The rev4 mutations are readily suppressed in many genetic backgrounds and, like the rev5 mutation, impart only a limited deficiency for induced mutagenesis: it is likely, therefore that the REV4⁺ and REV5⁺ gene functions are only remotely concerned with this process. The rev6 mutants have a more general deficiency, however, as well as marked sensitivity to UV and an increased spontaneous mutation rate, properties that suggest the REV6 gene is directly involved in mutation induction. The REV5 gene is located about 1 cM proximal to CYC1 on chromosome X.     

Fine Structure Mapping in Yeast with Sunlamp Radiation

The X-ray mapping procedure of Manney and Mortimer (1964) is the most widely applicable and convenient method for fine structure analysis in yeast, but suffers the disadvantage that suitable X-ray machines or gamma ray sources are very expensive. Although many other recombinogens are known, none gives a linear dose-response like X-rays and few are as convenient or give as reproducible results. Experiments with Saccharomyces cerevisiae reported in this paper show, however, that the near-ultraviolet radiation emitted by fluorescent sunlamps gives linear dose-response relations, as reproducible results as ionizing radiations, and map distances which correlate highly with those obtained by using (60)Co gamma rays. It is suggested that this convenient recombinogen may be a suitable low-cost substitute for ionizing radiations in fine structure mapping.     

Soluble Sema4D cleaved from osteoclast precursors by TACE suppresses osteoblastogenesis

Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti-coupling factors. Amongst formally known anti-coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane-bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1-MMP are all expressed on the surface of RANKL-primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1-MMP. When TACE and MT1-MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti-TACE-mAb inhibited sSema4D release from osteoclast precursors by ~90%. Supernatant collected from osteoclast precursors (OC-sup) suppressed osteoblastogenesis from MC3T3-E1 cells, as measured by alkaline phosphatase activity, but OC-sup harvested from the osteoclast precursors treated with anti-TACE-mAb restored osteoblastogenesis activity in a manner that compensates for diminished sSema4D. Finally, systemic administration of anti-TACE-mAb downregulated the generation of sSema4D in the mouse model of critical-sized bone defect, whereas local injection of recombinant sSema4D to anti-TACE-mAb-treated defect upregulated local osteoblastogenesis. Therefore, a novel pathway is proposed whereby TACE-mediated shedding of Sema4D expressed on the osteoclast precursors generates functionally active sSema4D to suppress osteoblastogenesis.     

Morphological parameters affecting false lumen thrombosis following type B aortic dissection: a systematic study based on simulations of idealized models

Type B aortic dissection (TBAD) carries a high risk of complications, particularly with a partially thrombosed or patent false lumen (FL). Therefore, uncovering the risk factors leading to FL thrombosis is crucial to identify high-risk patients. Although studies have shown that morphological parameters of the dissected aorta are related to FL thrombosis, often conflicting results have been reported. We show that recent models of thrombus evolution in combination with sensitivity analysis methods can provide valuable insights into how combinations of morphological parameters affect the prospect of FL thrombosis. Based on clinical data, an idealized geometry of a TBAD is generated and parameterized. After implementing the thrombus model in computational fluid dynamics simulations, a global sensitivity analysis for selected morphological parameters is performed. We then introduce dimensionless morphological parameters to scale the results to individual patients. The sensitivity analysis demonstrates that the most sensitive parameters influencing FL thrombosis are the FL diameter and the size and location of intimal tears. A higher risk of partial thrombosis is observed when the FL diameter is larger than the true lumen diameter. Reducing the ratio of the distal to proximal tear size increases the risk of FL patency. In summary, these parameters play a dominant role in classifying morphologies into patent, partially thrombosed, and fully thrombosed FL. In this study, we point out the predictive role of morphological parameters for FL thrombosis in TBAD and show that the results are in good agreement with available clinical studies.

     

PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy

Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD-1) plays an important role in subsiding immune responses and promoting self-tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells. PD-1 is considered as an immune checkpoint and protects against autoimmune responses through both induction of apoptosis in antigen-specific T cells and inhibiting apoptosis in regulatory T cells. Several clinical trials exerting PD-1 monoclonal antibodies as well as other immune-checkpoint blockades have had prosperous outcomes and opened new horizons in tumor immunotherapy. Nonetheless, a bulk of patients have failed to respond to these newly emerging immune-based approach and the survival rate was not satisfying. Additional strategies, especially combination therapies, has been initiated and been further promising. Attempts to identify novel and well-suited predictive biomarkers are also sensed. In this review, the promotion of cancer immunotherapy targeting PD-1 immunoinhibitory pathway is discussed.