Intronic miR-6741-3p targets the oncogene SRSF3: Implications for oral squamous cell carcinoma pathogenesis.

Epigenetic silencing through methylation is one of the major mechanisms for downregulation of tumor suppressor miRNAs in various malignancies. The aim of this study was to identify novel tumor suppressor miRNAs which are silenced by DNA hypermethylation and investigate the role of at least one of these in oral squamous cell carcinoma (OSCC) pathogenesis. We treated cells from an OSCC cell line SCC131 with 5-Azacytidine, a DNA methyltransferase inhibitor, to reactivate tumor suppressor miRNA genes silenced/downregulated due to DNA methylation. At 5-day post-treatment, total RNA was isolated from the 5-Azacytidine and vehicle control-treated cells. The expression of 2,459 mature miRNAs was analysed between 5-Azacytidine and control-treated OSCC cells by the microRNA microarray analysis. Of the 50 miRNAs which were found to be upregulated following 5-Azacytidine treatment, we decided to work with miR-6741-3p in details for further analysis, as it showed a mean fold expression of >4.0. The results of qRT-PCR, Western blotting, and dual-luciferase reporter assay indicated that miR-6741-3p directly targets the oncogene SRSF3 at the translational level only. The tumor-suppressive role of miR-6741-3p was established by various in vitro assays and in vivo study in NU/J athymic nude mice. Our results revealed that miR-6741-3p plays a tumor-suppressive role in OSCC pathogenesis, in part, by directly regulating SRSF3. Based on our observations, we propose that miR-6741-3p may serve as a potential biological target in tumor diagnostics, prognostic evaluation, and treatment of OSCC and perhaps other malignancies.

Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.

Our understanding of genetic and phenotypic heterogeneity associated with the clinical spectrum of rare diseases continues to expand. Thorough phenotypic descriptions and model organism functional studies are valuable tools in dissecting the biology of the disease process. Kinesin genes are well known to be associated with specific disease phenotypes and a subset of kinesin genes, including KIF21A, have been associated with more than one disease. Here we report two patients with KIF21A variants identified by exome sequencing; one with biallelic variants, supporting a novel KIF21A related syndrome with recessive inheritance and the second report of this condition, and another with a heterozygous de novo variant allele representing a phenotypic expansion of the condition described to date. We provide detailed phenotypic information on both families, including a novel neuropathology finding of neuroaxonal dystrophy associated with biallelic variants in KIF21A. Additionally, we studied the dominant variant in Saccharomyces cerevisiae to assess variant pathogenicity and found that this variant appears to impair protein function. KIF21A associated disease has mounting evidence for phenotypic heterogeneity; further patients and study of an allelic series are required to define the phenotypic spectrum and further explore the molecular etiology for each of these conditions.

Heteroleptic Cu(I) bis-diimine complexes as sensitizers in dye-sensitized solar cells (DSSCs): on some factors affecting intramolecular charge transfer.

A set of eight heteroleptic bis-diimine copper dye complexes with two different ancillary ligands (functionalised 2,9-dimethyl-1,10-phenanthroline (dmp) and functionalised 6,6'-diphenyl-2,2'-bipyridine (dpbpy)) are investigated for their potential use as sensitizers in dye-sensitized solar cells (DSSCs), using first principles density functional theory (DFT) and time dependent DFT (TDDFT). A detailed analysis of the structural properties, projected density of electronic states and Kohn-Sham energy levels, and optical absorption spectra in the UV-visible region reveals that substituting the thiophene group in the ancillary ligand, and enhancing conjugation in the anchoring ligand, lead to increase in the light harvesting efficiency (LHE). However, a natural transition orbital (NTO) analysis, shows that the nature of charge transfer depends mainly on the nature of the parent ancillary group and is not significantly affected by the structural modifications. Importantly, the lower energy excitations lead to favourable mixed metal to ligand charge transfer (MLCT) and ligand to ligand charge transfer (LLCT), as well as good electron injection. The best charge transfer directionality is found in the dmp-based dyes, particularly thiophene substituted dyes, thus making these the more effective sensitizers in DSSCs.

Spatial inter-centromeric interactions facilitated the emergence of evolutionary new centromeres.

Centromeres of Candida albicans form on unique and different DNA sequences but a closely related species, Candida tropicalis, possesses homogenized inverted repeat (HIR)-associated centromeres. To investigate the mechanism of centromere type transition, we improved the fragmented genome assembly and constructed a chromosome-level genome assembly of C. tropicalis by employing PacBio sequencing, chromosome conformation capture sequencing (3C-seq), chromoblot, and genetic analysis of engineered aneuploid strains. Further, we analyzed the 3D genome organization using 3C-seq data, which revealed spatial proximity among the centromeres as well as telomeres of seven chromosomes in C. tropicalis. Intriguingly, we observed evidence of inter-centromeric translocations in the common ancestor of C. albicans and C. tropicalis. Identification of putative centromeres in closely related Candida sojae, Candida viswanathii and Candida parapsilosis indicates loss of ancestral HIR-associated centromeres and establishment of evolutionary new centromeres (ENCs) in C. albicans. We propose that spatial proximity of the homologous centromere DNA sequences facilitated karyotype rearrangements and centromere type transitions in human pathogenic yeasts of the CUG-Ser1 clade.

Effect of Helicobacter pylori infection on fibrinogen level in elderly patients with ischaemic heart disease.

BACKGROUND: Fibrinogen is an important risk factor for ischaemic heart disease (IHD) (1) and an elevated fibrinogen level has been reported in younger patients infected with Helicobacter pylori (H pylori) infection (2, 3). However, the effect of Helicobacter pylori infection on fibrinogen level in elderly population with IHD is not known. Also in particular the effect on fibrinogen with eradication of Helicobacter pylori has not been previously reported. The aim of this study was to investigate the influence of H pylori on fibrinogen levels in elderly patients with IHD and to assess the effect of eradication therapy on fibrinogen levels. PATIENTS AND METHODS: Forty patients over the age of 65 years presenting with symptomatic IHD and an age-matched control group of 21 patients were studied. The 14-C urea breath test was used for detecting H pylori infection. Patients found to be H pylori positive were treated with omeprazole 40 mg daily and amoxicillin 500 mg three times daily for 14 days. Fibrinogen concentration was measured at the beginning of treatment and repeated at 4 weeks after completion of treatment along with the urea breath test in those tested positive for H pylori and fibrinogen level was repeated at 6 weeks in the H pylori negative patients. RESULTS: The prevalence of H pylori infection was 19/40 (47.5%) in the IHD group and 9/21 (42.8%) in the control group. The median serum fibrinogen level was 4.34 g/l (3.73-6.04 i.q. range) in H Pylori positive patients and 4.86 g/l (3.58-6.11 i.q. range) in H Pylori negative patients in both the IHD and age-matched control group, with no significant difference between the two groups, p = 0.78 (Mann-Whitney test). In the IHD group 27/40 (67.5%) had a fibrinogen level >4.0 g/l compared to 11/21 (52.3%) in the control group. The median fibrinogen level decreased significantly from 5.75g/l (i.q. range 4.39-6.71) to 4.41 g/l (i.q. range 3.80-6.06) after eradication treatment of H pylori in patients with raised fibrinogen levels (p < 0.01). CONCLUSION: The presence of H Pylori infection did not correlate with the presence of IHD, and the fibrinogen level was not raised in the IHD group. However, in elderly patients with H pylori infection, eradication therapy lowered fibrinogen levels in those with elevated (>4.0 g/l) fibrinogen level.