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231.
RK Koenekoop H Wang J Majewski X Wang I Lopez H Ren Y Chen Y Li GA Fishman M Genead J Schwartzentruber N Solanki EI Traboulsi J Cheng CV Logan M McKibbin BE Hayward DA Parry CA Johnson M Nageeb;Finding of Rare Disease Genes 《Nature genetics》2012,44(9):1035-1039
Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. 相似文献
232.
Steinbusch LK Schwenk RW Ouwens DM Diamant M Glatz JF Luiken JJ 《Cellular and molecular life sciences : CMLS》2011,68(15):2525-2538
Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose
transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored
in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well
as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly
affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized
at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate
uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences
in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved
in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both
GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking
components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development
of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy. 相似文献
233.
234.
Oleksiewicz U Liloglou T Field JK Xinarianos G 《Cellular and molecular life sciences : CMLS》2011,68(23):3869-3883
Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry,
functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase
and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions
including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection
against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple
cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was
reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested
tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various
pathological conditions and potential clinical utility. 相似文献
235.
MicroRNAs (miRNAs) are short ~21-nt non-coding RNA molecules that have been shown to regulate a number of biological processes.
Previous reports have shown that overexpression of miR-128 in glioma cells inhibited cell proliferation. Literature also suggests
that miR-128 negatively regulates prostate cancer cell invasion. Here, we show that overexpression of hsa-miR-128, a brain-enriched
microRNA, induces apoptosis in HEK293T cells as elucidated by apoptosis assay, cell cycle changes, loss of mitochondrial membrane
potential and multicaspase assay. By in silico analysis, we identified a putative target site within the 3′ untranslated region
(UTR) of Bax, a proapoptotic member of the apoptosis pathway. We found that ectopic expression of hsa-miR-128 suppressed a
luciferase reporter containing the Bax-3′ UTR and reduced the levels of Bax in HEK293T cells. Taken together, our study demonstrates
that overexpression of hsa-miR-128 not only induces apoptosis in HEK293T cells but also is an endogenous regulator of Bax
protein. 相似文献
236.
A population of the dwarf bear-poppy ( Arctomecon humilis Coville, Papaveraceae) at Red Bluff, Washington County, Utah, was monitored twice annually between 1987 and 2002. This is a narrowly endemic, gypsophilous species that has been formally listed as endangered since 1979. During the 16 years of observation, density of this species has fluctuated between 3 and 1336 individuals on the 0.07-ha monitoring plot. Moderate to large recruitments of seedlings occurred in 1992, 1995, and 2001. Seedling recruitments from a large, long-lived seed bank are triggered by abundant precipitation during the February-April period. At least 5.0 cm of rainfall is required during that interval to produce any seedlings. Seedlings experienced considerable mortality in the 1st few months of life in all observed cases. The average seedling initiated in the very large recruitment event of 1992 survived for only 2.6 years. Seedlings in that cohort that were alive 1 year after germination had an average longevity of 4.6 years. None of the seedlings that emerged in 1992 were still alive in October 2002. Mortality in this species was poorly correlated with fluctuations in precipitation or temperature. No epidemics of parasites or herbivores were observed. Mortality in the species appears to be caused by a variety of factors acting over a cohort's lifetime. 相似文献
237.
Restoring coal mined land to pre-mining shrub cover, density, height, community composition, and diversity to renew wildlife habitat quality is a priority for reclamation specialists. Long-term shrub reestablishment success on reclaimed mined land in Wyoming and suitability of these lands for wildlife habitat are unknown. Fourteen reclaimed study sites, 10 yr old or older, were selected on 8 mines in Wyoming to evaluate shrub reestablishment and wildlife habitat value for antelope ( Antilocapra americana ) and sage grouse ( Centrocercus urophasianus ). Five sites were categorized as fourwing saltbush ( Atriplex canescens ) sites and 9 as fourwing saltbush/big sagebrush ( A. canescens/Artemisia tridentata spp. wyomingensis ) sites. Published data describing antelope and sage grouse-preferred habitat requirements in sagebrush-grassland steppe ecosystems were used to evaluate shrub community value of sampled sites for wildlife habitat. Mean shrub canopy cover, density, and height for fourwing saltbush sites were 5.8%, 0.23 m -2 , and 41.6 cm, respectively, compared to 5.6%, 0.61 m -2 , and 31.1 cm for fourwing saltbush/big sagebrush sites. Two fourwing saltbush and 4 fourwing saltbush/big sagebrush sites provided sufficient cover for antelope, while 2 fourwing saltbush and 4 fourwing saltbush/big sagebrush sites were adequate for sage grouse. Only 1 fourwing saltbush/big sagebrush site provided high enough shrub densities for sage grouse. One fourwing saltbush and 7 fourwing saltbush/big sagebrush sites provided ample shrub heights for antelope, while 1 fourwing saltbush and 8 fourwing saltbush/big sagebrush sites were sufficient for sage grouse. One fourwing saltbush and 1 fourwing saltbush/big sagebrush site provided enough grass, forb, and shrub composition for antelope, while no site in either reclamation type was satisfactory for sage grouse. Shrub diversity was 3 times higher for fourwing saltbush/big sagebrush sites (0.984) than for fourwing saltbush sites (0.328). Individually, sites seeded with multiple shrub species had higher canopy cover, density, and diversity compared with single-species shrub seedings. Achieving premining shrub cover, density, height, community composition, and diversity within existing bond-release time frames is unrealistic, considering that some native shrublands require 30-60 yr to reach maturity. 相似文献
238.
The male epiprocts of 2 closely related western Nearctic species, Sweltsa fidelis (Banks) and S. revelstoka (Jewett), were examined using SEM. The males of these 2 species have been historically distinguished by epiproct measurements. The ratio of the length of the base to greatest width versus total epiproct length ranges from 0.49 μm to 0.67 μm ( ̄ x = 0.56) in S. fidelis and 0.55 μm to 0.69 μm ( ̄ x = 0.60) in S. revelstoka . Similarities in measurement suggest that the location of the greatest epiproct width is not a reliable and consistent character for distinguishing males of these 2 species. 相似文献
239.
Becker-Heck A Zohn IE Okabe N Pollock A Lenhart KB Sullivan-Brown J McSheene J Loges NT Olbrich H Haeffner K Fliegauf M Horvath J Reinhardt R Nielsen KG Marthin JK Baktai G Anderson KV Geisler R Niswander L Omran H Burdine RD 《Nature genetics》2011,43(1):79-84
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD. 相似文献
240.
Wright FA Strug LJ Doshi VK Commander CW Blackman SM Sun L Berthiaume Y Cutler D Cojocaru A Collaco JM Corey M Dorfman R Goddard K Green D Kent JW Lange EM Lee S Li W Luo J Mayhew GM Naughton KM Pace RG Paré P Rommens JM Sandford A Stonebraker JR Sun W Taylor C Vanscoy LL Zou F Blangero J Zielenski J O'Neal WK Drumm ML Durie PR Knowles MR Cutting GR 《Nature genetics》2011,43(6):539-546
A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder. 相似文献