Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene.

BACKGROUND: Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. METHODS: Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. RESULTS: We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. CONCLUSIONS: These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.     

Controlling room temperature ferromagnetism and band gap in ZnO nanostructured thin films by varying angle of implantation

The defects in the host lattice play a major role in tuning the surface roughness, optical band gap and the room temperature ferromagnetism (RTFM) of ZnO thin films. Herein, we report a novel approach to tailor the band gap and RTFM of a ZnO nanostructure by varying the angle of implantation of 60 keV N ions keeping the ion fluence of 1 × 10¹⁶ ions per cm² and the beam size of 3 mm constant. The implantation was performed by changing the thin films'' orientations at 30°, 60° and 90° with respect to the incident beams. Remarkably, an enhancement of ∼6 times in RTFM, tuning in band gap from 3.27 to 3.21 eV and ∼60% reduction in surface roughness were noticed when the ion implantation was done at 60° to the normal. This novel technique may be suitable for tuning the physical properties of nanostructures for their application in the spintronics, semiconductor and solar cell industries.

The defects in the host lattice play a major role in tuning the surface roughness, optical band gap and the room temperature ferromagnetism of ZnO thin films.     

Gastric cancer in Malaysia: the need for early diagnosis

Gastric cancer is an important cause of death among patients with malignancies in Malaysia. Survival of patients with gastric cancer is dependent on the stage at which diagnosis is made. We report our experience in dealing with gastric cancer in a major Ministry of Health Hospitals in Malaysia. A retrospective review of two hundred and fifty consecutive histologically proven gastric adenocarcinoma at Hospital Ipoh for the period January 1988 to 1998 was performed. The study confirms that gastric cancer is a disease of the elderly and has a male preponderance. It is also identifies the Chinese and Indians to be at increased risk of gastric cancer when compared to the Malays. The most striking finding in this study was the very late stage of disease at time of presentation. Eighty-two percent of the patients presented with stage IV disease and curative surgery was offered only to a 16% of them. In a substantial number of patients not even a palliative procedure was offered. Early detection is the key to improving survival in gastric cancer patients. There is an urgent need for clinicians to change their approach to the management of the disease. Patients with dyspeptic symptoms should be investigated early rather then wait for classical symptoms of gastric cancer.     

The Impact of Glycosylation on the Pharmacokinetics of a TNFR2:Fc Fusion Protein Expressed in Glycoengineered Pichia Pastoris

Purpose

P. pastoris has previously been genetically engineered to generate strains that are capable of producing mammalian-like glycoforms. Our objective was to investigate the correlation between sialic acid content and pharmacokinetic properties of recombinant TNFR2:Fc fusion proteins generated in glycoengineered P. pastoris strains.

Methods

TNFR2:Fc fusion proteins were generated with varying degrees of sialic acid content. The pharmacokinetic properties of these proteins were assessed by intravenous and subcutaneous routes of administration in rats. The binding of these variants to FcRn were also evaluated for possible correlations between in vitro binding and in vivo PK.

Results

The pharmacokinetic profiles of recombinant TNFR2:Fc produced in P. pastoris demonstrated a direct positive correlation between the extent of glycoprotein sialylation and in vivo pharmacokinetic properties. Furthermore, recombinant TNFR2:Fc produced in glycoengineered Pichia, with a similar sialic acid content to CHO-produced etanercept, demonstrated similar in vivo pharmacokinetic properties to the commercial material. In vitro surface plasmon resonance FcRn binding at pH6.0 showed an inverse relationship between sialic acid content and receptor binding affinity, with the higher affinity binders having poorer in vivo PK profiles.

Conclusions

Sialic acid content is a critical attribute for modulating the pharmacokinetics of recombinant TNFR2:Fc produced in glycoengineered P. pastoris.     

Matrix metalloproteinases (MMP-8, MMP-9) and the tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) in patients with fungal keratitis

PURPOSE: To study the infiltrating cells and quantify the levels of matrix metalloproteinases (MMP-8, MMP-9) and tissue inhibitor of metalloproteinases (TIMP-1, TIMP-2) in the cornea, tear, and serum of patients with fungal keratitis. METHODS: Experimental study. Infected corneal tissue from 4 patients with fungal keratitis (group 1) scheduled to undergo therapeutic keratoplasty accounted for the histopathologic and cytospin smear analysis. Ten patients with fungal keratitis from group 2 served for the quantification of MMPs and TIMPs. Five patients with keratoconus undergoing penetrating keratoplasty and 5 cadaver corneas were chosen as controls for group 2. Corneal buttons obtained during keratoplasty, 15 to 20 microL of tears collected using the capillary flow method, and 3 mL of blood was obtained from patients with fungal keratitis and patients with keratoconus. Corneal button sections from group 1 were stained with hematoxylin and eosin and Grocott methenamine silver nitrate for the histopathologic studies and Giemsa staining for the cytospin smear analysis. Enzyme-linked immunosorbent assay was used for the quantification of total MMP-8, MMP-9, TIMP-1, and TIMP-2 in the corneal homogenates, tear, and serum samples of group 2. RESULTS: Corneal sections from group 1 revealed dense fungal filaments and a large proportion (91.4% +/- 38%) of polymorphonuclear leukocytes (PMNs). Significant elevation in the levels of MMP-8 and MMP-9 (P < 0.05) in the fungal keratitis corneas was observed in group 2 compared with the cadaver and keratoconus corneas. The ratio of MMP/TIMP was also higher in the fungal keratitis corneas. CONCLUSIONS: Infiltrating PMNs in the cornea of patients with fungal keratitis contributed to the increased activities of MMP-8 and MMP-9, thereby enhancing tissue destruction and derangement.     

A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent

By convention, presentation of major histocompatibility complex (MHC) class I-restricted epitopes involves processing by cytosolic proteasomes, whereas MHC class II-restricted epitopes are generated by endosomal proteases. Here, we show that two MHC class II-restricted epitopes within influenza virus were generated by a proteasome- and TAP-dependent pathway that was accessed by exogenous virus in dendritic cells (DCs) but not cell types with less permeable endosomes. Both epitopes were presented by recycling MHC class II molecules. Challenging mice with influenza or vaccinia viruses demonstrated that a substantial portion of the MHC class II-restricted response was directed against proteasome-dependent epitopes. By complementing endosomal activities, this pathway broadens the array of MHC class II-restricted epitopes available for CD4(+) T cell activation.