Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations

Primary microcephaly is an autosomal recessive disorder characterized by smaller than normal brain size and mental retardation. It is genetically heterogeneous with seven loci: MCPH1-MCPH7. We have previously reported genetic analysis of 35 families, including the identification of the MCPH7 gene STIL. Of the 35 families, three families showed linkage to the MCPH2 locus. Recent whole-exome sequencing studies have shown that the WDR62 gene, located in the MCPH2 candidate region, is mutated in patients with severe brain malformations. We therefore sequenced the WDR62 gene in our MCPH2 families and identified two novel homozygous protein truncating mutations in two families. Affected individuals in the two families had pachygyria, microlissencephaly, band heterotopias, gyral thickening, and dysplastic cortex. Using immunofluorescence study, we showed that, as with other MCPH proteins, WDR62 localizes to centrosomes in A549, HepG2, and HaCaT cells. In addition, WDR62 was also localized to nucleoli. Bioinformatics analysis predicted two overlapping nuclear localization signals and multiple WD-40 repeats in WDR62. Two other groups have also recently identified WDR62 mutations in MCPH2 families. Our results therefore add further evidence that WDR62 is the MCPH2 gene. The present findings will be helpful in genetic diagnosis of patients linked to the MCPH2 locus.

Effect of rolling temperature and reduction in thickness on microstructure and mechanical properties of ZM21 magnesium alloy and its subsequent annealing treatment

In this present paper, the effects of non-isothermal rolling temperature and reduction in thickness followed by annealing on microstructure and mechanical properties of ZM21 magnesium alloy were investigated. The alloy rolled at four different temperatures 250 degrees C, 300 degrees C, 350 degrees C and 400 degrees C with reductions of 25%, 50% and 75%. Non-isothermal rolling resulted in grain refinement, introduction of shear bands and twins in the matrix alloy. Partial to full recrystallization was observed when the rolling temperature was above recrystallization temperature. Rolling and subsequent annealing resulted in strain-free equiaxed grains and complete disappearance of shear bands and twins. Maximum ultimate strength (345 MPa) with good ductility (14%) observed in the sample rolled at 250 degrees C with 75% reduction in thickness followed by short annealing. Recrystallization during warm/hot rolling was sluggish, but post-roll treatment gives distinct views about dynamic and static recrystallization. (C) 2011 Elsevier B.V. All rights reserved.

The influence of Zr layer thickness on contact deformation and fracture in a ZrN-Zr multilayer coating

In order to understand the influence of ductile metal interlayer on the overall deformation behavior of metal/nitride multilayer, different configurations of metal and nitride layers were deposited and tested under indentation loading. To provide insight into the trends in deformation with multilayer spacings, an FEM model with elastic-perfect plastic metal layers alternate with an elastic nitride on top of an elastic-plastic substrate. The strong strain mismatch between the metal and nitride layers significantly alters the stress field under contact loading leading to micro-cracking in the nitride, large tensile stresses immediately below the contact, and a transition from columnar sliding in thin metal films to a more uniform bending and microcracking in thicker coatings.

A Simple Charge Model for Symmetric Double-Gate MOSFETs Adapted to Gate-Oxide-Thickness Asymmetry

Surface-potential-based compact charge models for symmetric double-gate metal-oxide-semiconductor field-effect transistors (SDG-MOSFETs) are based on the fundamental assumption of having equal oxide thicknesses for both gates. However, for practical devices, there will always be some amount of asymmetry between the gate oxide thicknesses due to process variations and uncertainties, which can affect device performance significantly. In this paper, we propose a simple surface-potential-based charge model, which is applicable for tied double-gate MOSFETs having same gate work function but could have any difference in gate oxide thickness. The proposed model utilizes the unique so-far-unexplored quasi-linear relationship between the surface potentials along the channel. In this model, the terminal charges could be computed by basic arithmetic operations from the surface potentials and applied biases, and thus, it could be implemented in any circuit simulator very easily and extendable to short-channel devices. We also propose a simple physics-based perturbation technique by which the surface potentials of an asymmetric device could be obtained just by solving the input voltage equation of SDG devices for small asymmetry cases. The proposed model, which shows excellent agreement with numerical and TCAD simulations, is implemented in a professional circuit simulator through the Verilog-A interface and demonstrated for a 101-stage ring oscillator simulation. It is also shown that the proposed model preserves the source/drain symmetry, which is essential for RF circuit design.

Inclusion of body doping in compact models for fully-depleted common double gate MOSFET adapted to gate-oxide thickness asymmetry

Since it is difficult to find the analytical solution of the governing Poisson equation for double gate MOSFETs with the body doping term included, the majority of the compact models are developed for undoped-body devices for which the analytical solution is available. Proposed is a simple technique to included a body doping term in such surface potential based common double gate MOSFET models also by taking into account any differences between the gate oxide thickness. The proposed technique is validated against TCAD simulation and found to be accurate as long as the channel is fully depleted.

Effect of Thickness on The Optical Properties Change in Bi/As2S3 Bilayer Thin Films

Bilayer thin films of Bi/As2S3 were prepared from Bi and As2S3 by thermal evaporation technique under high vacuum. We have prepared three bilayer films of 905nm, 910nm and 915nm thickness with with As2S3 as bottom layer (900nm) and Bi as top layer (5,10,15 nm). We have compared the optical changes due to the thickness variation of Bi layer on As2S3 film. The changes were characterized by FTIR and XPS techniques.

Effect of thickness variation of hole injection and hole blocking layers on the performance of fluorescent green organic light emitting diodes

In this paper we present the effect of thickness variation of hole injection and hole blocking layers on the performance of fluorescent green organic light emitting diodes (OLEDs). A number of OLED devices have been fabricated with combinations of hole injecting and hole blocking layers of varying thicknesses. Even though hole blocking and hole injection layers have opposite functions, yet there is a particular combination of their thicknesses when they function in conjunction and luminous efficiency and power efficiency are maximized. The optimum thickness of CuPc (Copper(II) phthalocyanine) layer, used as hole injection layer and BCP (2,9 dimethyl-4,7-diphenyl-1,10-phenanthroline) used as hole blocking layer were found to be 18 nm and 10 nm respectively. It is with this delicate adjustment of thicknesses, charge balancing is achieved and luminous efficiency and power efficiency were optimized. The maximum luminous efficiency of 3.82 cd/A at a current density of 24.45 mA/cm(2) and maximum power efficiency of 2.61 lm/W at a current density of 5.3 mA/cm(2) were achieved. We obtained luminance of 5993 cd/m(2) when current density was 140 mA/cm(2). The EL spectra was obtained for the LEDs and found that it has a peaking at 524 nm of wavelength. (C) 2012 Elsevier B.V. All rights reserved.

Influence of GaN underlayer thickness on structural, electrical and optical properties of InN films grown by PAMBE

We present an extensive study on the structural, electrical and optical properties of InN thin films grown on c-Al2O3, GaN(130 nm)/Al2O3, GaN(200 nm)/Al2O3 and GaN(4 mu m)/Al2O3 by using plasma-assisted molecular beam epitaxy. The high resolution X-ray diffraction study reveals better crystalline quality for the film grown on GaN(4 mu m)/Al2O3 as compared to others. The electronic and optical properties seem to be greatly influenced by the structural quality of the films, as can be evidenced from Hall measurement and optical absorption spectroscopy. Kane's k.p model was used to describe the dependence of optical absorption edge of InN films on carrier concentration by considering the non-parabolic dispersion relation for carrier in the conduction band. Room temperature Raman spectra for the InN films grown on GaN show the signature of residual tensile stress in contrast to the compressive stress observed for the films grown directly on c-Al2O3. (C) 2012 Elsevier B.V. All rights reserved.

Improvement in Bone Properties by Using Risedronate Adsorbed Hydroxyapatite Novel Nanoparticle Based Formulation in a Rat Model of Osteoporosis

A superior drug formulation capable of achieving efficient osteogenesis is in imperative demand for the treatment of osteoporosis. In the present study we investigated the potential of using novel risedronate-hydroxyapatite (HA) nanoparticle based formulation in an animal model of established osteoporosis. Nanoparticles of HA loaded with risedronate (NHLR) of various sizes (80-130 nm) were generated for bone targeted drug delivery. Three months after ovariectomy, 36 ovariectomized (OVX) rats were divided into 6 equal groups and treated with various doses of NHLR (500,350 and 250 mu g/kg intravenous single dose) and sodium risedronate (500 mu g/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. One month after drug administration, the left tibia and femur were tested for bone mechanical properties and histology, respectively. In the right femur, bone density was measured by method based on Archimedes principle and bone porosity analyses were performed using X-ray imaging. NHLR (250 mu g/kg) showed a significant increase in bone density and reduced bone porosity when compared with OVX control. Moreover, NHLR (250 mu g/kg) significantly increased bone mechanical properties and bone quality when compared with OVX control. The results strongly suggest that the NHLR, which is a novel nanoparticle based formulation, has a therapeutic advantage over risedronate sodium monotherapy for the treatment of osteoporosis in a rat model of postmenopausal osteoporosis.

Nonquasi-static charge model for common double-gate MOSFETs adapted to gate oxide thickness asymmetry

With the unique quasi-linear relationship between the surface potentials along the channel, recently we have proposed a quasi-static terminal charge model for common double-gate MOSFETs, which might have asymmetric gate oxide thickness. In this brief, we extend this concept to develop the nonquasi-static (NQS) charge model for the same by solving the governing continuity equations. The proposed NQS model shows good agreement against TCAD simulations and appears to be useful for efficient circuit simulation.

Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: pivotal role of the redox regulator forkhead O1

In this study we determined the molecular mechanisms of how homocysteine differentially affects receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) synthesis in the bone. The results showed that oxidative stress induced by homocysteine deranges insulin-sensitive FOXO1 and MAP kinase signaling cascades to decrease OPG and increase RANKL synthesis in osteoblast cultures. We observed that downregulation of insulin/FOXO1 and p38 MAP kinase signaling mechanisms due to phosphorylation of protein phosphatase 2 A (PP2A) was the key event that inhibited OPG synthesis in homocysteine-treated osteoblast cultures. siRNA knockdown experiments confirmed that FOXO1 is integral to OPG and p38 synthesis. Conversely homocysteine increased RANKL synthesis in osteoblasts through c-Jun/JNK MAP kinase signaling mechanisms independent of FOXO1. In the rat bone milieu, high-methionine diet-induced hyperhomocysteinemia lowered FOXO1 and OPG expression and increased synthesis of proresorptive and inflammatory cytokines such as RANKL, M-CSF, IL-1 alpha, IL-1 beta, G-CSF, GM-CSF, MIP-1 alpha, IFN-gamma, IL-17, and TNF-alpha. Such pathophysiological conditions were exacerbated by ovariectomy. Lowering the serum homocysteine level by a simultaneous supplementation with N-acetylcysteine improved OPG and FOXO1 expression and partially antagonized RANKL and proresorptive cytokine synthesis in the bone milieu. These results emphasize that hyperhomocysteinemia alters the redox regulatory mechanism in the osteoblast by activating PP2A and deranging FOXO1 and MAPK signaling cascades, eventually shifting the OPG:RANKL ratio toward increased osteoclast activity and decreased bone quality (C) 2013 Elsevier Inc. All rights reserved.

Scaffolds for bone tissue engineering: role of surface patterning on osteoblast response

The fabrication of tissue engineering scaffolds necessitates amalgamation of a multitude of attributes including a desirable porosity to encourage vascular invasion, desired surface chemistry for controlled deposition of calcium phosphate-based mineral as well as ability to support attachment, proliferation, and differentiation of lineage specific progenitor cells. Scaffold fabrication often includes additional surface treatments to bring about desired changes in the surface chemistry. In this perspective, this review documents the important natural and synthetic scaffolds fabricated for bone tissue engineering applications in tandem with the surface treatment techniques to maneuver the biocompatibility of engineered scaffolds. This review begins with a discussion on the fundamental concepts related to biocompatibility as well as the characteristics of the biological micro-environment. The primary focus is to discuss the effects of surface micro/nano patterning on the modulation of bone cell response. Apart from reviewing a host of experimental studies reporting the functionality of osteoblast-like bone cells and stem cells on surface modified or textured bioceramic/biopolymer scaffolds, theoretical insights to predict cell behavior on a scaffold with different topographical features are also briefly analyzed.

Elastic thickness structure of the Andaman subduction zone: Implications for convergence of the Ninetyeast Ridge

We use the Bouguer coherence (Morlet isostatic response function) technique to compute the spatial variation of effective elastic thickness (T-e) of the Andaman subduction zone. The recovered T-e map resolves regional-scale features that correlate well with known surface structures of the subducting Indian plate and the overriding Burma plate. The major structure on the India plate, the Ninetyeast Ridge (NER), exhibits a weak mechanical strength, which is consistent with the expected signature of an oceanic ridge of hotspot origin. However, a markedly low strength (0< T-e <3 km) in that region, where the NER is close to the Andaman trench (north of 10 N), receives our main attention in this study. The subduction geometry derived from the Bouguer gravity forward modeling suggests that the NER has indented beneath the Andaman arc. We infer that the bending stresses of the viscous plate, which were reinforced within the subducting oceanic plate as a result of the partial subduction of the NER buoyant load, have reduced the lithospheric strength. The correlation, T-e < T-s (seismogenic thickness) reveals that the upper crust is actively deforming beneath the frontal arc Andaman region. The occurrence of normal-fault earthquakes in the frontal arc, low Te zone, is indicative of structural heterogeneities within the subducting plate. The fact that the NER along with its buoyant root is subducting under the Andaman region is inhibiting the subduction processes, as suggested by the changes in trench line, interrupted back-arc volcanism, variation in seismicity mechanism, slow subduction, etc. The low T-e and thinned crustal structure of the Andaman back-arc basin are attributed to a thermomechanically weakened lithosphere. The present study reveals that the ongoing back-arc spreading and strike-slip motion along the West Andaman Fault coupled with the ridge subduction exerts an important control on the frequency and magnitude of seismicity in the Andaman region. (C) 2013 Elsevier Ltd. All rights reserved.

Methionine down-regulates TLR4/MyD88/NF-kappa B signalling in osteoclast precursors to reduce bone loss during osteoporosis

Background and PurposeStudies have demonstrated that a moderate intake of amino acids is associated with development of bone health. Methionine, a sulphur-containing essential amino acid, has been largely implicated for improving cartilage formation, however its physiological significance on bone integrity and functionality have not been elucidated. We investigated whether methionine can prevent osteoporotic bone loss. Experimental ApproachThe anti-resorptive effect of methionine, (250mgkg(-1) body wt administered in drinking water for 10 weeks), was evaluated in ovariectomized (OVX) rats by monitoring changes in bone turnover, formation of osteoclasts from blood-derived mononuclear cells and changes in the synthesis of pro-osteoclastogenic cytokines. Key resultsMethionine improved bone density and significantly decreased the degree of osteoclast development from blood mononuclear cells in OVX rats, as indicated by decreased production of osteoclast markers tartarate resistant acid phosphatase b (TRAP5b) and MIP-1. siRNA-mediated knockdown of myeloid differentiation primary response 88 MyD88], a signalling molecule in the toll-like receptor (TLR) signalling cascade, abolished the synthesis of both TRAP5b and MIP-1 in developing osteoclasts. Methionine supplementation disrupted osteoclast development by inhibiting TLR-4/MyD88/NF-B pathway. Conclusions and ImplicationsTLR-4/MyD88/NF-B signalling pathway is integral for osteoclast development and this is down-regulated in osteoporotic system on methionine treatment. Methionine treatment could be beneficial for the treatment of postmenopausal osteoporosis.

Reach task-associated excitatory overdrive of motor cortical neurons following infusion with ALS-CSF

Converging evidence from transgenic animal models of amyotrophic lateral sclerosis (ALS) and human studies suggest alterations in excitability of the motor neurons in ALS. Specifically, in studies on human subjects with ALS the motor cortex was reported to be hyperexcitable. The present study was designed to test the hypothesis that infusion of cerebrospinal fluid from patients with sporadic ALS (ALS-CSF) into the rat brain ventricle can induce hyperexcitability and structural changes in the motor cortex leading to motor dysfunction. A robust model of sporadic ALS was developed experimentally by infusing ALS-CSF into the rat ventricle. The effects of ALS-CSF at the single neuron level were examined by recording extracellular single unit activity from the motor cortex while rats were performing a reach to grasp task. We observed an increase in the firing rate of the neurons of the motor cortex in rats infused with ALS-CSF compared to control groups. This was associated with impairment in a specific component of reach with alterations in the morphological characteristics of the motor cortex. It is likely that the increased cortical excitability observed in the present study could be the result of changes in the intrinsic properties of motor cortical neurons, a dysfunctional inhibitory mechanism and/or an underlying structural change culminating in a behavioral deficit.