The importance of arginine mutation for the evolutionary structure and function of phenylalanine hydroxylase gene

Phenylalanine hydroxylase (PAH) gene mutations were investigated in 23 (46 alleles) unrelated phenylketonuria (PKU) patients in Cukurova region. First, all exons of PAH gene were screened by denaturing high performance liquid chromatography (DHPLC), and then, the suspicious samples were analyzed by direct sequencing technique. Consequently, the following results were obtained: IVS10-11g-->a splicing mutation in 27/46 (58.7%), R261Q mutation in 7/46 (15.2%) and E178G, R243X, R243Q, P281L, Y386C, R408W mutations, each found in the frequency of 2/46 (4.3%). In many countries, Arginine mutations have the highest frequency among PAH gene mutations in PKU patients. Although, CpG dinucleotids are effective in mutations resulting in arginine changes, this finding originated from the studies on the causes of mutations rather than the studies on the importance of arginine amino acid. In our analyses, we have detected that a majority of mutations causing a change in arginine and other amino acids concentrated in exon 7 comprising the catalytic domain (residues 143-410) of PAH gene. Several studies has emphasized the role of arginine amino acid; with the following outcomes; arginine repetition is significant for RNA binding proteins, and for histon proteins in eukaryotic gene expression, and also arginine repetition occurring in the structure of signal recognition particle's (SRPs) as a consequence of post-translational processes is very important in terms of gene expression. Therefore, the role of arginine amino acid in PAH gene is rather remarkable in that it shows the role of amino acids in the protein/RNA interaction that has started in the evolutionary process and is still preserved and maintained in the motif formation of active domain structure due to its strong binding properties. Thus, such properties imply that both arginine amino acid and exon 7 is of great significance with regards to the structure and function of the PheOH enzyme.     

Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species

New 2-substituted-phenyl-1H-benzimidazole-5-carboxylic acids (35, 38), ethyl-5-carboxylate (36), -5-carboxamides (37, 39),-5-carboxaldehyde (42), -5-chloro (40), -5-trifluoromethyl (41), and -5-carbonitriles (44-53, 55-67), -6-carbonitrile (54) were prepared and evaluated in vitro against Candida species. The cyano substituted compounds 53, 57, 58 and 61 exhibited the greatest activity with MIC values of 3.12 microg/mL, values similar to that of fluconazole.     

The effect of attachment type and implant number on satisfaction and quality of life of mandibular implant-retained overdenture wearers

doi: 10.1111/j.1741‐2358.2011.00531.x The effect of attachment type and implant number on satisfaction and quality of life of mandibular implant‐retained overdenture wearers Objective: The aim of this study was to compare the quality of life and patient satisfaction outcomes of two attachment systems in mandibular overdentures with different numbers of supporting implants. Materials and methods: Sixty‐two edentulous patients with either splinted or single attachments in mandibular implant overdentures with different numbers of supporting interforaminal implants were investigated for patient satisfaction and quality of life in this retrospective study. Comparisons between groups were perceived by the Mann–Whitney U test. Relations among the parameters were investigated by Spearman’s rho correlation analysis. The results were evaluated statistically at a significance level of p < 0.05. Results: No statistically significant association is found between visual analogue scales scores and attachment type as well as implant number (p > 0.05), whereas Oral Health Impact Profile (OHIP)‐14 total scores for patients with 4‐implant‐supported bars were significantly lower than all the other attachment types (p < 0.05). Additionally, a negative (rate = 32.2%), statistically significant association between period of edentulism and total OHIP‐14 scores was detected (p < 0.05). Conclusions: A mandibular implant‐retained overdenture supported with four implants and bar attachments shows the highest ‘quality of life’ score and patient satisfaction is not influenced by the number of implants or attachment type.     

Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols including natural products

(2-Bromo-3,4-dimethoxyphenyl) (3,4-dimethoxyphenyl)methanone (10) and its derivatives with Br, one dibromide and isomeric three tribromides, were synthesized. Demethylation of these compounds afforded a series of new bromophenols. Inhibition of human cytosolic carbonic anhydrase II (hCA II) isozyme by these new bromophenols and naturally occurring 3,4,6-tribromo-5-(2,5-dibromo-3,4-dihydroxybenzyl)benzene-1,2-diol (3), and 5,5'-methylenebis(3,4,6-tribromo-benzene-1,2-diol) (4) was investigated. The synthesized compounds showed carbonic anhydrase inhibitory capacities with IC(50) values in the range of 0.7-372 μM against hCA II. Some bromophenols investigated here showed effective hCA II inhibitory activity and might be used as leads for generating novel carbonic anhydrase inhibitors which are valuable drug candidates for the treatment of glaucoma, epilepsy, gastric and duodenal ulcers, neurological disorders, or osteoporosis.     

The mitochondrial T1095C mutation increases gentamicin-mediated apoptosis

We have previously reported a heteroplasmic mtDNA mutation (T1095C) in the 12SrRNA gene of an Italian family with features of maternally-inherited parkinsonism, antibiotic-mediated deafness and peripheral neuropathy. In the present study, we demonstrate that a transmitochondrial cybrid line derived from the proband of this family shows selective depletion of mitochondrial glutathione and decreases in the activity of complex II/III. Moreover, when exposed to an aminoglycoside antibiotic these cells responded with a ten-fold increase in the number of apoptotic cells compared to controls. These results support a pathogenic role for the T1095C mutation and indicate that the mutation increases the risk for aminoglycoside-induced toxicity.     

The Germinal Center Kinase TNIK Is Required for Canonical NF-κB and JNK Signaling in B-Cells by the EBV Oncoprotein LMP1 and the CD40 Receptor

The tumor necrosis factor-receptor-associated factor 2 (TRAF2)- and Nck-interacting kinase (TNIK) is a ubiquitously expressed member of the germinal center kinase family. The TNIK functions in hematopoietic cells and the role of TNIK-TRAF interaction remain largely unknown. By functional proteomics we identified TNIK as interaction partner of the latent membrane protein 1 (LMP1) signalosome in primary human B-cells infected with the Epstein-Barr tumor virus (EBV). RNAi-mediated knockdown proved a critical role for TNIK in canonical NF-κB and c-Jun N-terminal kinase (JNK) activation by the major EBV oncoprotein LMP1 and its cellular counterpart, the B-cell co-stimulatory receptor CD40. Accordingly, TNIK is mandatory for proliferation and survival of EBV-transformed B-cells. TNIK forms an activation-induced complex with the critical signaling mediators TRAF6, TAK1/TAB2, and IKKβ, and mediates signalosome formation at LMP1. TNIK directly binds TRAF6, which bridges TNIK's interaction with the C-terminus of LMP1. Separate TNIK domains are involved in NF-κB and JNK signaling, the N-terminal TNIK kinase domain being essential for IKKβ/NF-κB and the C-terminus for JNK activation. We therefore suggest that TNIK orchestrates the bifurcation of both pathways at the level of the TRAF6-TAK1/TAB2-IKK complex. Our data establish TNIK as a novel key player in TRAF6-dependent JNK and NF-κB signaling and a transducer of activating and transforming signals in human B-cells.