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111.
Agamy O Ben Zeev B Lev D Marcus B Fine D Su D Narkis G Ofir R Hoffmann C Leshinsky-Silver E Flusser H Sivan S Söll D Lerman-Sagie T Birk OS 《American journal of human genetics》2010,87(4):538-544
The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans. 相似文献
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113.
Background
Online Consumer Health websites are a major source of information for patients worldwide. We focus on another modality, online physician advice. We aim to evaluate and compare the freely available online expert physicians’ advice in different countries, its scope and the type of content provided.Setting
Using automated methods for information retrieval and analysis, we compared consumer health portals from the US, Canada, the UK and Israel (WebMD,NetDoctor,AskTheDoctor and BeOK). The evaluated content was generated between 2002 and 2011.Results
We analyzed the different sites, looking at the distribution of questions in the various health topics, answer lengths and content type. Answers could be categorized into longer broad-educational answers versus shorter patient-specific ones, with different physicians having personal preferences as to answer type. The Israeli website BeOK, providing 10 times the number of answers than in the other three health portals, supplied answers that are shorter on average than in the other websites. Response times in these sites may be rapid with 32% of the WebMD answers and 64% of the BeOK answers provided in less than 24 hours. The voluntary contribution model used by BeOK and WebMD enables generation of large numbers of physician expert answers at low cost, providing 50,000 and 3,500 answers per year, respectively.Conclusions
Unlike health information in online databases or advice and support in patient-forums, online physician advice provides qualified specialists’ responses directly relevant to the questions asked. Our analysis showed that high numbers of expert answers could be generated in a timely fashion using a voluntary model. The length of answers varied significantly between the internet sites. Longer answers were associated with educational content while short answers were associated with patient-specific content. Standard site-specific guidelines for expert answers will allow for more desirable content (educational content) or better throughput (patient-specific content). 相似文献114.
Polycomb Group (PcG) proteins form an epigenetic "memory system", conserved in both plants and animals, controlling global gene expression during development via histone modifications. The role of PcG proteins in plants was primarily explored in Arabidopsis thaliana, where PcG regulation of developmental processes was demonstrated throughout the plant life cycle. Our knowledge about the PcG machinery in terrestrial plants other than Arabidopsis began to accumulate only in recent years. In this review we summarize recent emerging data on the evolution and diversification of PcG mechanisms in various phyla, from early-diverging plants, including members of the Chlorophyte algae, through bryophytes and flowering plants. We describe the compositions of the PcG gene families, their so-far studied expression profiles, and finally summarize commonalities vs. differences among PcG functions across the various species. This article is part of a Special Issue entitled: Epigenetic control of cellular and developmental processes in plants. 相似文献
115.
Mordechai S Gradstein L Pasanen A Ofir R El Amour K Levy J Belfair N Lifshitz T Joshua S Narkis G Elbedour K Myllyharju J Birk OS 《American journal of human genetics》2011,(3):438-445
Autosomal-recessive high-grade axial myopia was diagnosed in Bedouin Israeli consanguineous kindred. Some affected individuals also had variable expressivity of early-onset cataracts, peripheral vitreo-retinal degeneration, and secondary sight loss due to severe retinal detachments. Through genome-wide linkage analysis, the disease-associated gene was mapped to ~1.7 Mb on chromosome 3q28 (the maximum LOD score was 11.5 at θ = 0 for marker D3S1314). Sequencing of the entire coding regions and intron-exon boundaries of the six genes within the defined locus identified a single mutation (c.1523G>T) in exon 10 of LEPREL1, encoding prolyl 3-hydroxylase 2 (P3H2), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagens. The mutation affects a glycine that is conserved within P3H isozymes. Analysis of wild-type and p.Gly508Val (c.1523G>T) mutant recombinant P3H2 polypeptides expressed in insect cells showed that the mutation led to complete inactivation of P3H2. 相似文献
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117.
Ohad Ilovich Hana Billauer Sharon Dotan Eyal Mishani 《Bioorganic & medicinal chemistry》2010,18(2):612-620
In a continued effort to find a suitable PET tracer for visualization of angiogenic processes, we explored the 3,4-diarylmaleimide family, known to have high affinity and selectivity towards the VEGFR-TKs. One previously reported agent and three new halogen-containing 3,4-diarylmaleimide derivatives were synthesized. The four maleimide derivatives were evaluated for their affinity and selectivity towards the VEGFRs and exhibited promising results. An automated carbon-11 radiolabeling route with a total synthesis time of 50 min successfully labeled the lead compound, resulting in 1.55 ± 0.15 GBq of tracer with a radiochemical yield of 20 ± 2%, 96% radiochemical purity and a SA of 111 ± 22 GBq/μmol (EOB, n = 5). The tracer possessed high stability in in vitro blood stability tests and specific VEGFR-TK binding profiles in intact cell binding experiments. Tracer lipophilicity was evaluated in an n-octanol/phosphate buffer system giving a Log D7.4 of 1.99 ± 0.04. For the in vivo experiments, two animal models were used. The first was a U87 glioma tumor model, frequently reported in the literature and the second, a newly developed 293/KDR tumor model. Both models were validated for VEGFR-2 expression and used in in vivo biodistribution studies. These studies revealed low accumulation and rapid washout of the tracer from tumor tissue. High accumulation of activity in the liver prompted us to examine the tracer’s in vitro stability to liver microsomes, revealing low resistance to P450 metabolism. In spite of encouraging in vitro results, the labeled lead tracer failed to accumulate in VEGFR-2 overexpressing tumors. It is possible that poor resistance to P450 metabolism reduces tracer’s circulation leading to low tumor accumulation. 相似文献
118.
Bank EM Ben-Harush K Wiesel-Motiuk N Barkan R Feinstein N Lotan O Medalia O Gruenbaum Y 《Molecular biology of the cell》2011,22(15):2716-2728
Mutations in the human LMNA gene underlie many laminopathic diseases, including Emery-Dreifuss muscular dystrophy (EDMD); however, a mechanistic link between the effect of mutations on lamin filament assembly and disease phenotypes has not been established. We studied the ΔK46 Caenorhabditis elegans lamin mutant, corresponding to EDMD-linked ΔK32 in human lamins A and C. Cryo-electron tomography of lamin ΔK46 filaments in vitro revealed alterations in the lateral assembly of dimeric head-to-tail polymers, which causes abnormal organization of tetrameric protofilaments. Green fluorescent protein (GFP):ΔK46 lamin expressed in C. elegans was found in nuclear aggregates in postembryonic stages along with LEM-2. GFP:ΔK46 also caused mislocalization of emerin away from the nuclear periphery, consistent with a decreased ability of purified emerin to associate with lamin ΔK46 filaments in vitro. GFP:ΔK46 animals had motility defects and muscle structure abnormalities. These results show that changes in lamin filament structure can translate into disease-like phenotypes via altering the localization of nuclear lamina proteins, and suggest a model for how the ΔK32 lamin mutation may cause EDMD in humans. 相似文献
119.
D Clarke D Harati J Martin J Rowley J Keller M McCaman M Carrion O Karnieli R Maziarz R Perry S Oh J Stanton 《Cytotherapy》2012,14(9):1032-1040
Abstract The concept of particulates, while common to many in the pharmaceutical and blood transfusion disciplines, represents a distinct challenge in the field of cellular therapy. With newly discovered products advancing through clinical trials, the focus has shifted to ensuring products are manufactured in a reliable and safe manner. Given the unique manufacturing processes and resulting products (i.e. the cell being the active ingredient of the product), the way in which particulates are viewed and subsequently tested needs to be reviewed. No specific test or method for particulates will apply to all products, and guidance documents will be generated over time as more cell therapy products are approved. The details of the processes, testing methods used and acceptance criteria established for particulates will play a major role in generating the guidance documents. This will ultimately allow for the manufacture and administration of safe and effective products without thwarting advancement of the cellular therapy field. The intent of this review is to bring awareness to the topic of particulates with respect to cell therapy, and encourage a more open dialog and exchange of examples within the industry. We have reviewed the concept of particulates, where they originate and how they are introduced to cell therapy products, and the current methods available for their detection. We have also reviewed the relevance of current guidance documents and present potential strategies to move forward and address and control unwanted contaminating particulates in cell therapy products. 相似文献
120.
Nuclear pore complexes (NPCs) are the sole passage through the nuclear envelope, connecting the cytoplasm to the nucleoplasm. These gigantic molecular machines, over 100 MDa in molecular weight, allow free diffusion of small molecules and ions while mediating selective energy-dependent nucleocytoplasmic transport of large macromolecules. Here, we applied cryo-electron tomography to human fibroblast cells, reconstructing their nuclear envelopes without applying any purification steps. From these reconstructions, we extracted subtomograms containing individual NPCs and utilized in silico subtomogram averaging procedures to determine the structure of the mammalian pore complex at a resolution of ~6.6?nm. Beyond revealing the canonical features of the human NPC, our analysis identified inner lateral channels and fusing bridge-like structures, suggesting alternative routes of peripheral nuclear passage. Finally, we concluded from our structural analysis that the human NPC is structurally distinct from that of lower eukaryotes in terms of dimension and organization but resembles its amphibian (frog) counterpart. 相似文献