Identification of new alleles and the determination of alleles and genotypes frequencies at the CYP2D6 gene in Emiratis

CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20-25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls.     

Sediment oxygen demand and benthic foraminiferal faunas in the Arabian Gulf: A test of the method on a siliciclastic substrate

In this study, we investigated the relationship between environmental parameters (water and sediment) and benthic foraminiferal assemblages found in nearshore siliciclastic sediment in the Arabian Gulf. Nearshore marine water and sediment samples were collected from a beach on the Gulf of Bahrain located south of Al Khobar, Saudi Arabia. The water samples were analyzed for biochemical oxygen demand (BOD₅) and other chemical analyses. The sediment samples were tested for sediment oxygen demand (SOD) and heavy metal analysis. Results showed the BOD₅ levels were below the detection limit (<1 ppm), while the mean SOD value was 0.97 ± 0.08 g/m²·day. The water and sediments were unpolluted and free of eutrophic enrichment, while the sediment was anoxic. The two most common genera in the benthic foraminiferal assemblage, Ammonia and Elphidium, are typical of shallow water sandy substrates. This is the first reported comparison between SOD and benthic foraminiferal assemblages.     

Comparing the osteogenic potential of schneiderian membrane and dental pulp mesenchymal stem cells: an in vitro study

Cell and Tissue Banking - Mesenchymal stem cells, being characterized by high self-renewal capacity and multi-lineage differentiation potential, are widely used in regenerative medicine especially...     

Combined ESR/U-series chronology of Acheulian hominid-bearing layers at Trinchera Galería site,Atapuerca, Spain

The Sierra de Atapuerca, northern Spain, is known from many prehistoric and palaeontological sites documenting human prehistory in Europe. Three major sites, Gran Dolina, Galería and Sima del Elefante, range in age from the oldest hominin of Western Europe dated to 1.1 to 1.3 Ma (millions of years ago) at Sima del Elefante to c.a. 0.2 Ma on the top of the Galería archaeological sequence. Recently, a chronology based on luminescence methods (Thermoluminescence [TL] and Infrared Stimulated Luminescence [IRSL]) applied to cave sediments was published for the Gran Dolina and Galería sites. The authors proposed for Galería an age of 450 ka (thousands of years ago) for the units lower GIII and GII, suggesting that the human occupation there is younger than the hominid remains of Sima de los Huesos (>530 ka) around 1 km away.     

Cement flow during impaction allografting: a finite element analysis

Cement intrusion into cancellous or impacted bone is not well understood. We adopted an engineering mechanics approach to predict the effect of surgical variables on the cement intrusion into impacted cancellous bone, used for the revision of failed total hip replacement with the impaction allografting technique. Specifically, a three-dimensional finite element model was used to determine the effects of cement viscosity, the magnitude and duration of pressurization, and the distribution of the porosity along the femur on cement intrusion. The overall averaged mean intrusion depth difference between the finite element model prediction and the cadaveric measurements was 1.1mm. The depth of penetration increased with higher pressurization pressure, duration of pressurization, and earlier stem insertion (lower viscosity), but maintained a similar profile. The distribution of the porosity along the femur determined the intrusion profile. Cement viscosity, the applied pressure or the duration of the pressurization can be adjusted to limit the cement volume injected into the medullary canal and therefore prevent the cement from reaching the endosteal surface.     

lazaro encodes a lipid phosphate phosphohydrolase that regulates phosphatidylinositol turnover during Drosophila phototransduction

An essential step in Drosophila phototransduction is the hydrolysis of phosphatidylinositol 4,5 bisphosphate PI(4,5)P2 by phospholipase Cbeta (PLCbeta) to generate a second messenger that opens the light-activated channels TRP and TRPL. Although the identity of this messenger remains unknown, recent evidence has implicated diacylglycerol kinase (DGK), encoded by rdgA, as a key enzyme that regulates its levels, mediating both amplification and response termination. In this study, we demonstrate that lazaro (laza) encodes a lipid phosphate phosphohydrolase (LPP) that functions during phototransduction. We demonstrate that the synergistic activity of laza and rdgA regulates response termination during phototransduction. Analysis of retinal phospholipids revealed a reduction in phosphatidic acid (PA) levels and an associated reduction in phosphatidylinositol (PI) levels. Together our results demonstrate the contribution of PI depletion to the rdgA phenotype and provide evidence that depletion of PI and its metabolites might be a key signal for TRP channel activation in vivo.     

A model-free feature-based bi-planar RSA method for kinematic analysis of total knee arthroplasty

Fluoroscopic imaging is commonly used for assessing relative motions of orthopaedic implants. One limiting factor to in vivo model-based roentgen stereophotogrammetric analysis of total knee arthroplasty is the need for 3D models of the implants.The 3D models of the implant components must be reverse-engineered, if not provided by the company, which makes this method impractical for a clinical study involving many types or sizes of implants. This study introduces a novel feature-based methodology that registers the features at the implant-bone or implant-cement interface of the components that have elementary shapes. These features include pegs with hemispherical heads, and straight, circular or curved edges located on flat faces of the box of the femoral component or the stem geometry of the tibial component. Software was developed to allow easy registration of these features through a graphical user interface. The accuracy and precision of registration for multiple flexion angles from 0 to 120 deg was determined with reference to registered poses of the implants through experiments on bone replica models and also on a cadaver specimen implanted with total knee prostheses. When compared to an equivalent bi-planar model-based registration, the results were comparable: The mean accuracy of this feature-based method was 1.45 deg and 1.03 mm (in comparison to 0.95 deg and 1.32 mm for the model-based approach), and the mean precision was 0.57 deg and 0.26 mm (in comparison to 0.42 deg and 0.44 mm for the model-based approach).The methodology and the developed software can easily accommodate different design of implants with various fixation features. This method can facilitate in vivo kinematic analysis of total knee arthroplasty by eliminating the need for 3D models of the implant components.     

A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance

ABSTRACT: BACKGROUND: We have previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. METHODS: We have used whole exome sequencing on two affected members of the index family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. RESULTS: Here we report the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently implicated in Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. This is the first missense homozygous disease-causing mutation reported in KIF7, which might account for the unique presentation. CONCLUSIONS: The phenotype of our patients partially overlap with those previously associated with KIF7 mutations. In addition, our results expand the clinical spectrum associated with KIF7 mutations to multiple epiphyseal dysplasia.     

Xylanase XYL1p from Scytalidium acidophilum: Site-directed mutagenesis and acidophilic adaptation

The role of residues Asp60, Tyr35 and Glu141 in the pH-dependent activity of xylanase XYL1p from Scytalidium acidophilum was investigated by site-directed mutagenesis. These amino acids are highly conserved among the acidophilic family 11 xylanases and located near the catalytic site. XYL1p and its single mutants D60N, Y35W and E141A and three combined mutants DN/YW, DN/EA and YW/EA were over-expressed in Pichia pastoris and purified. Xylanase activities at different pH’s and temperatures were determined. All mutations increased the pH optimum by 0.5–1.5 pH units. All mutants have lower specific activities except the E141A mutant that exhibited a 50% increase in specific activity at pH 4.0 and had an overall catalytic efficiency higher than the wild-type enzyme. Thermal unfolding experiments show that both the wild-type and E141A mutant proteins have a T_m maximum at pH 3.5, the E141A mutant being slightly less stable than the wild-type enzyme. These mutations confirm the importance of these amino acids in the pH adaptation. Mutant E141A with its enhanced specific activity at pH 4.0 and improved overall catalytic efficiency is of possible interest for biotechnological applications.