Global ETD Search

451	Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension Nasim, Md. Talat, Ogo, T., Ahmed, Mohammed I., Randall, R., Chowdhury, H.M., Snape, K.M., Bradshaw, T.Y., Southgate, L., Lee, G.J., Jackson, I., Lord, G.M., Gibbs, J.S., Wilkins, M.R., Ohta-Ogo, K., Nakamura, K., Girerd, B., Coulet, F., Soubrier, F., Humbert, M., Morrell, N.W., Trembath, R.C., Machado, R.D. January 2011 (has links) Yes / Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease. Bone morphogenetic protein receptors Type II Genetics Cohort studies Female Gene expression regulation Humans Hypertension Pulmonary Male Sequence analysis DNA Signal transduction Smad1 protein Smad8 protein Transcriptional regulation REF 2014
452	BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH Nasim, Md. Talat, Ogo, T., Chowdhury, H.M., Zhao, L., Chen, C-n., Rhodes, C., Trembath, R.C. January 2012 (has links) Yes / Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor beta (TGFbeta) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFbeta-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFbeta-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFbeta-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH. Animals Apoptosis Bone morphogenetic protein receptors Type II Metabolism Cell proliferation Cells Cultured Hypertension Pulmonary Pathology MAP kinase Mice Pulmonary artery Rats Signal transduction Transforming growth factor beta REF 2014
453	Preservation of ancient DNA in thermally damaged archaeological bone Ottoni, C., Koon, Hannah E.C., Collins, M.J., Penkman, K.E.H., Rickards, O., Craig, O.E. January 2009 (has links) No / Evolutionary biologists are increasingly relying on ancient DNA from archaeological animal bones to study processes such as domestication and population dispersals. As many animal bones found on archaeological sites are likely to have been cooked, the potential for DNA preservation must be carefully considered to maximise the chance of amplification success. Here, we assess the preservation of mitochondrial DNA in a medieval cattle bone assemblage from Coppergate, York, UK. These bones have variable degrees of thermal alterations to bone collagen fibrils, indicative of cooking. Our results show that DNA preservation is not reliant on the presence of intact collagen fibrils. In fact, a greater number of template molecules could be extracted from bones with damaged collagen. We conclude that moderate heating of bone may enhance the retention of DNA fragments. Our results also indicate that ancient DNA preservation is highly variable, even within a relatively recent assemblage from contexts conducive to organic preservation, and that diagenetic parameters based on protein diagenesis are not always useful for predicting ancient DNA survival. Animals Ancient DNA Archaeology Bone and bones Cattle Cooking Collagen DNA Fossils History Medieval Polymerase chain reaction Preservation Biological REF 2014
454	Microstructural elucidation of self-emulsifying system: effect of chemical structure Patil, S.S., Venugopal, E., Bhat, S., Mahadik, K.R., Paradkar, Anant R January 2012 (has links) No / PURPOSE: Self-emulsifying systems (SES) emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase. The self-emulsification process plays an important role during formation of emulsion. The objective of current work was to understand and explore the inner structuration of SES through controlled hydration and further to study the influence of additive on the same which ultimately governs performance of final formulation in terms of droplet size. METHODS: Droplet size of final formulations containing structural analogues of ibuprofen was determined. Microstructural properties of intermediate hydrated regimes of SES were investigated using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology. RESULTS: The current work established inverse relationship between droplet size of the formulations containing structural analogues of ibuprofen and their Log P values. Microstructural analysis of intermediate hydrated regimes of the prepared samples showed formation of local lamellar structure. Structural analogues of ibuprofen significantly altered microstructure of lamellae which was well correlated with the droplet size of final formulations. In vitro drug release study showed increase in dissolution rate of lipophillic drugs when formulated as SES. CONCLUSION: The current work emphasizes the fact that tailor-made formulations can be prepared by controlling the properties of intermediate regimes. Analgesics Calorimetry Diffusion Emulsions Ibuprofen Oils Particle size Pharmaceutical vehicles Rheology Scattering Solubility Surface-active agents Water X-Ray diffraction REF 2014 Non-Narcotic Administration & dosage Chemistry Differential scanning Flurbiprofen Analogs & derivatives Ketoprofen Lamellar structure Small angle
455	Probing influence of mesophasic transformation on performance of self-emulsifying system: effect of ion Patil, S.S., Venugopal, E., Bhat, S., Mahadik, K.R., Paradkar, Anant R January 2012 (has links) Self-emulsifying systems are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastrointestinal tract. The process of self-emulsification has remained the center of attraction for most researchers. Controlled hydration of self-emulsifying systems shows formation of an intermediate gel phase which upon rupture forms an emulsion. Current work was undertaken to understand and explore the microstructural properties of intermediate gel phase which are believed to influence the performance (droplet size) of the final formulation. The effect of additives on microstructural properties of intermediate gel phase has also been investigated. Microstructural elucidation of hydrated samples of intermediate regimes was done by using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology. Samples from intermediate regimes showed formation of local lamellar structure which swelled with hydration. In the present work, the effect of addition of salt form of naproxen (sodium and potassium) and naproxen (base) on microstructural properties of intermediate regimes was investigated. Systems containing naproxen salts formed larger droplets whereas naproxen base formed smaller ones. Microstructural properties of intermediate lamellar structures were well correlated with performance of the final formulation. The current studies indicate that by controlling the properties of intermediate regimes optimized formulations with desired performance can be tailor-made. Calorimetry Drug stability Emulsifying agents Emulsions Ions Liquid crystals Naproxen Particle size Rheology Salts Scattering Surface properties Temperature Thermogravimetry Water X-Ray diffraction REF 2014 Differential scanning Chemistry Small angle
456	Stem cell factor/c-Kit signalling in normal and androgenetic alopecia hair follicles Randall, Valerie A., Jenner, Tracey J., Hibberts, Nigel A., De Oliveira, Isabel O., Vafaee, Tayyebeh January 2008 (has links) No / Androgens stimulate many hair follicles to alter hair colour and size via the hair growth cycle; in androgenetic alopecia tiny, pale hairs gradually replace large, pigmented ones. Since stem cell factor (SCF) is important in embryonic melanocyte migration and maintaining adult rodent pigmentation, we investigated SCF/c-Kit signalling in human hair follicles to determine whether this was altered in androgenetic alopecia. Quantitative immunohistochemistry detected three melanocyte-lineage markers and c-Kit in four focus areas: the epidermis, infundibulum, hair bulb (where pigment is formed) and mid-follicle outer root sheath (ORS). Colocalisation confirmed melanocyte c-Kit expression; cultured follicular melanocytes also exhibited c-Kit. Few ORS cells expressed differentiated melanocyte markers or c-Kit, but NKI/beteb antibody, which also recognises early melanocyte-lineage antigens, identified fourfold more cells, confirmed by colocalisation. Occasional similar bulbar cells were seen. Melanocyte distribution, concentration and c-Kit expression were unaltered in balding follicles. Androgenetic alopecia cultured dermal papilla cells secreted less SCF, measured by ELISA, than normal cells. This identifies three types of melanocyte-lineage cells in human follicles. The c-Kit expression by dendritic, pigmenting, bulbar melanocytes and rounded, differentiated, non-pigmenting ORS melanocytes implicate SCF in maintaining pigmentation and migration into regenerating hair bulbs. Less differentiated, c-Kit-independent cells in the mid-follicle ORS stem cell niche and occasionally in the bulb, presumably a local reserve for long scalp hair growth, implicate other factors in activating stem cells. Androgens appear to reduce alopecia hair colour by inhibiting dermal papilla SCF production, impeding bulbar melanocyte pigmentation. These results may facilitate new treatments for hair colour changes in hirsutism, alopecia or greying. Adult Alopecia Metabolism Androgens Pharmacology Cell lineage Cells Cultured Female Hair colour Hair follicle Cytology Humans Immunohistochemistry Male Melanins Melanocytes Chemistry Middle aged Proto-oncogene proteins c-kit Signal transduction Stem cell factor REF 2014
457	Ancient human genome sequence of an extinct Palaeo-Eskimo Rasmussen, M., Li, Y., Lindgreen, S., Pedersen, J.S., Albrechtsen, A., Moltke, I., Metspalu, M., Metspalu, E., Kivisild, T., Gupta, R., Bertalan, M., Nielsen, K., Gilbert, M.T.P., Wang, Y., Raghavan, M., Campos, P.F., Kamp, H.M., Wilson, Andrew S., Gledhill, Andrew R., Tridico, S., Bunce, M., Lorenzen, E.D., Binladen, J., Guo, X., Zhao, J., Zhang, X., Zhang, H., Li, Z., Chen, M., Orlando, L., Kristiansen, K., Bak, M., Tommerup, N., Bendixen, C., Pierre, T.L., Gronnow, B., Meldgaard, M., Andreasen, C., Fedorova, S.A., Osipova, L.P., Higham, T.F.G., Ramsey, C.B., Hansen, T.v.O., Nielsen, F.C., Crawford, M.H., Brunak, S., Sicheritz-Ponten, T., Villems, R., Nielsen, R., Krogh, A., Wang, J., Willerslev, E. January 2010 (has links) No / We report here the genome sequence of an ancient human. Obtained from approximately 4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20x, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit. Cryopreservation Emigration Immigration Extinction Genetics Population Genome Human Genetics Genomics Genotype Greenland Hair History Ancient Humans Inuits Male Phenotype Phylogeny Polymorphism Single nucleotide Sequence analysis DNA Siberia Ethnology REF 2014
458	Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways Sharov, A.A., Mardaryev, Andrei N., Sharova, T.Y., Grachtchouk, M., Atoyan, R., Byers, H.R., Seykora, J.T., Overbeek, P., Dlugosz, A., Botchkarev, Vladimir A. January 2009 (has links) No / Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways. Adult Aged Animals Bone Morphogenetic Proteins Carrier Proteins Cell Transformation Female Hair Follicle Hedgehog Proteins Humans Keratinocytes Male Mice Middle Aged Signal transduction Skin Skin Neoplasms Wnt Proteins REF 2014
459	Human hair follicles contain two forms of ATP-sensitive potassium channels, only one of which is sensitive to minoxidil Shorter, K., Farjo, N.P., Picksley, Stephen M., Randall, Valerie A. January 2008 (has links) No / Hair disorders cause psychological distress but are generally poorly controlled; more effective treatments are required. Despite the long-standing use of minoxidil for balding, its mechanism is unclear; suggestions include action on vasculature or follicle cells. Similar drugs also stimulate hair, implicating ATP-sensitive potassium (K(ATP)) channels. To investigate whether K(ATP) channels are present in human follicles, we used organ culture, molecular biological, and immunohistological approaches. Minoxidil and tolbutamide, a K(ATP) channel blocker, opposed each other's effects on the growing phase (anagen) of scalp follicles cultured in media with and without insulin. Reverse transcriptase-polymerase chain reaction identified K(ATP) channel component gene expression including regulatory sulfonylurea receptors (SUR) SUR1 and SUR2B but not SUR2A and pore-forming subunits (Kir) Kir6.1 and Kir6.2. When hair bulb tissues were examined separately, epithelial matrix expressed SUR1 and Kir6.2, whereas both dermal papilla and sheath exhibited SUR2B and Kir6.1. Immunohistochemistry demonstrated similar protein distributions. Thus, human follicles respond biologically to K(ATP) channel regulators in culture and express genes and proteins for two K(ATP) channels, Kir6.2/SUR1 and Kir6.1/SUR2B; minoxidil only stimulates SUR2 channels. These findings indicate that human follicular dermal papillae contain K(ATP) channels that can respond to minoxidil and that tolbutamide may suppress hair growth clinically; novel drugs designed specifically for these channels could treat hair disorders. ATP-binding cassette transporters Hair follicle Chemistry Humans Immunohistochemistry KATP channels Analysis Drug effects Genetics Minoxidil Pharmacology Organ culture techniques Polymerase chain reaction Potassium channels Inwardly rectifying Receptors Sulfonylurea receptors Tolbutamide Vasodilator agents REF 2014
460	Specialized and independent processing of orientation and shape in visual field maps LO1 and LO2 Silson, E.H., McKeefry, Declan J., Rodgers, J., Gouws, A.D., Hymers, M., Morland, A.B. January 2013 (has links) No / We identified human visual field maps, LO1 and LO2, in object-selective lateral occipital cortex. Using transcranial magnetic stimulation (TMS), we assessed the functions of these maps in the perception of orientation and shape. TMS of LO1 disrupted orientation, but not shape, discrimination, whereas TMS of LO2 disrupted shape, but not orientation, discrimination. This double dissociation suggests that specialized and independent processing of different visual attributes occurs in LO1 and LO2. Adult Brain mapping Methods Female Form perception Physiology Humans Image processing Computer-assisted Magnetic Resonance Imaging Male Middle aged Neurons Orientation Photic stimulation Transcranial magnetic stimulation Visual cortex Visual fields Visual pathways REF 2014

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