排序方式: 共有136条查询结果,搜索用时 5 毫秒
81.
82.
Basel-Vanagaite L Zevit N Har Zahav A Guo L Parathath S Pasmanik-Chor M McIntyre AD Wang J Albin-Kaplanski A Hartman C Marom D Zeharia A Badir A Shoerman O Simon AJ Rechavi G Shohat M Hegele RA Fisher EA Shamir R 《American journal of human genetics》2012,90(1):49-60
The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation. 相似文献
83.
Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes
Iain R. Thompson Samantha M. Mirczuk Lorna Smith Andrew J. Lessey Bigboy Simbi Andrew Sunters Gary F. Baxter Victoria J. Lipscomb Imelda M. McGonnell Caroline P. Wheeler-Jones Abir Mukherjee Mark S. Roberson Craig A. McArdle Robert C. Fowkes 《Cell and tissue research》2014,355(2):425-436
The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders. 相似文献
84.
Brown ML Bonomi L Ungerleider N Zina J Kimura F Mukherjee A Sidis Y Schneyer A 《Obesity (Silver Spring, Md.)》2011,19(10):1940-1949
Transforming growth factor-β superfamily ligands, including activin and myostatin, modulate body composition, islet function, and glucose homeostasis. Their bioactivity is controlled by the antagonists follistatin (FST) and FST like-3 (FSTL3). The hypothesis tested was that FST and FSTL3 have distinct roles in regulating body composition, glucose homeostasis, and islet function through regulation of activin and myostatin bioactivity. Three genetic mutant mouse lines were created. FSTL3 knockout (FSTL3 KO), a mouse line producing only the FST288 isoform (FST288-only) and a double mutant (2xM) in which the lines were crossed. FST288-only males were lighter that wild-type (WT) littermates while FSTL3 KO and 2xM males had reduced perigonadal fat pad weights. However, only 2xM mice had increased whole body fat mass and decreased lean mass by quantitative nuclear magnetic resonance (qNMR). Fasting glucose levels in FSTL3 WT and KO mice were lower than FST mice in younger animals but were higher in older mice. Serum insulin and pancreatic insulin content in 2xM mice was significantly elevated over other genotypes. Nevertheless, 2xM mice were relatively insulin resistant and glucose intolerant compared to FST288-only and WT mice. Fractional islet area and proportion of β-cells/islet were increased in FSTL3 KO and 2xM, but not FST288-only mice. Despite their larger size, islets from FSTL3 KO and 2xM mice were not functionally enhanced compared to WT mice. These results demonstrate that body composition and glucose homeostasis are differentially regulated by FST and FSTL3 and that their combined loss is associated with increased fat mass and insulin resistance despite elevated insulin production. 相似文献
85.
Meriam Ben Halima Amani Kallel Abir Baara Safa Ben Wafi Haifa Sanhagi Hedia Slimane 《Biomarkers》2013,18(8):787-792
AbstractContext: Variations in the fat mass and obesity-associated gene (FTO) has been associated with obesity in many populations, but the results are conflicting.Objective: The aim of this study was to evaluate the effect of the rs9939609 polymorphism in the FTO gene on obesity risk and plasma leptin, adiponectin, insulin and lipid concentrations in Tunisians.Materials and methods: Four hundred and ninety-four subjects with obesity and 334 non-obese participated in this study. The rs9939609 (T/A) genotype was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.Results: Significant differences in genotype frequencies were observed between cases and controls. In the separate analysis by gender, the association between the AA genotype and obesity was statistically significant in women but not in men. After stratification by obesity class this association remains only with obesity class III.Discussion: Our study is in agreement with studies on Caucasian, Portuguese and Cebu Filipino populations where a gender-specific association was found between rs9939609 polymorphism and obesity. It is also in agreement with studies on Mexican, Spanish and European populations, where an association was found with obesity class III.Conclusion: The rs9939609 polymorphism of FTO gene is associated with obesity, especially obesity class III in women. 相似文献
86.
The gas phase proton affinities PA and basicities GB for a series of para-substituted acetophenones weak bases (B) p.X???C6H4CO*CH3 with X?=?H, F, Cl, Br, I, Me, CF3, CN, NO2, OCH3, NH2, CH2OH, N(CH3)2, OH, $ {\text{NH}}_3^{+} $ , … have been calculated at 298.15 K at the density functional theory DFT/B3LYP level with a 6-311++G (2d,2p) basis set. Conformational results lead to only one stable planar conformer for both unprotonated compounds and their O*-protonated forms. Satisfactory accuracy and computational efficiency could be reached if the computed PAs are scaled by a factor 0.983. Protonation at more than one site is discussed and the carbonyl oxygen atom is found to be the preferential protonated site rather than the substituent X. The calculated gas phase PAs show a good agreement with the experimental available data. The electron-donating/electron-withdrawing nature of the substituents has an enormous influence upon the thermochemical and structural properties. The influence of environment on the proton affinity has been studied by means of SCRF solvent effect computations using PCM solvation model for two solvents: water and SO2CI2. Confrontation between computed and experimental pK(B) values exhibits better agreement in aqueous solution than in organic solvent. 相似文献
87.
Ghosh Amrita Igamberdiev Abir U. Debnath Samir C. 《Plant Cell, Tissue and Organ Culture》2021,146(2):269-284
Plant Cell, Tissue and Organ Culture (PCTOC) - Blueberry (Vaccinium spp. L.) plants exhibit high potential of regeneration via adventitious shoot formation on a semi-solid medium followed by shoot... 相似文献
88.
Abir Mondal Soumyadeep Mukherjee Waseem Dar Shailja Singh Soumya Pati 《生物化学与生物物理学报:疾病的分子基础》2021,1867(10):166185
Autism Spectrum Disorder (ASD) is a common group of neurodevelopmental disorders which causes significant alterations in social and communication skills along with repetitive behavior and limited interests. The physiological understanding of ASD is ambiguous. Several reports suggested that environmental, genetic and epigenetic changes, neuroinflammation, mitochondrial dysfunction and metabolic alterations orchestrate the pathological outcomes of ASD. A recent report from Saudi Arabia found a mutation in X-chromosomal housekeeping glucose 6-phosphate dehydrogenase (G6PD) gene in two male ASD patients. Although, the involvement of G6PD-deficiency in the pathogenesis of ASD is poorly understood. Several reports suggested that G6PD deficiency impedes cellular detoxification of reactive oxygen species (ROS), which may result in neuronal damage and neuroinflammation. A deficiency of G6PD in newborn children may play a fundamental role in the pathogenesis of ASD. In this review, we will discuss the implications of G6PD deficiency in pathogenesis, male biasness and theranostics in ASD patients. 相似文献
89.
Veeraraghavan N Ganguly A Chen JH Bevilacqua PC Hammes-Schiffer S Golden BL 《Biochemistry》2011,50(13):2672-2682
The hepatitis delta virus (HDV) ribozyme uses both metal ion and nucleobase catalysis in its cleavage mechanism. A reverse G·U wobble was observed in a recent crystal structure of the precleaved state. This unusual base pair positions a Mg(2+) ion to participate in catalysis. Herein, we used molecular dynamics (MD) and X-ray crystallography to characterize the conformation and metal binding characteristics of this base pair in product and precleaved forms. Beginning with a crystal structure of the product form, we observed formation of the reverse G·U wobble during MD trajectories. We also demonstrated that this base pair is compatible with the diffraction data for the product-bound state. During MD trajectories of the product form, Na(+) ions interacted with the reverse G·U wobble in the RNA active site, and a Mg(2+) ion, introduced in certain trajectories, remained bound at this site. Beginning with a crystal structure of the precleaved form, the reverse G·U wobble with bound Mg(2+) remained intact during MD simulations. When we removed Mg(2+) from the starting precleaved structure, Na(+) ions interacted with the reverse G·U wobble. In support of the computational results, we observed competition between Na(+) and Mg(2+) in the precleaved ribozyme crystallographically. Nonlinear Poisson-Boltzmann calculations revealed a negatively charged patch near the reverse G·U wobble. This anionic pocket likely serves to bind metal ions and to help shift the pK(a) of the catalytic nucleobase, C75. Thus, the reverse G·U wobble motif serves to organize two catalytic elements, a metal ion and catalytic nucleobase, within the active site of the HDV ribozyme. 相似文献
90.
Respiration of barley protoplasts before and after illumination 总被引:1,自引:0,他引:1
Abir U. Igamberdiev Guoquing Zhou Gunilla Malmberg Per Gardeström 《Physiologia plantarum》1997,99(1):15-22
Respiratory O2 consumption was investigated in dark-adapted barley (Hordeum vulgare L. cv. Gunilla) protoplasts and after illumination for 10 min at high and very low CO2 in the presence of respiratory and photorespiratory inhibitors. In dark-adapted protoplasts no difference was observed between inhibitor treatments in high and very low CO2. The respiratory rate increased somewhat after illumination and a difference in responce to inhibitors was in some cases observed between high and very low CO2. Thus, the operation of the mitochondrial electron transport chain is affected following a period of active photosynthesis. In all situations tested, oligomycin inhibited respiratiory O2 uptake indicating that respiration of mitochondria in protoplasts is not strictly ADP limited. Antimycin A inhibited respiration more in dark-adapted protoplasts than after illumination whereas SHAM gave the opposite response. Rotenone inhibited respiration both in dark-adapted protoplasts (about 30%) and after illumination where the inhibition was much greater in very low CO2 (50%) than in high CO2 (10%). After illumination in very low CO2. SHAM + rotenone inhibited respiration almost completely (70%). Photorespiratory inhibitors had very small effect on O2 consumption in darkness. After illumination the effect of aminoacetonitrile (AAN) was also very low whereas α-hydroxypyridine-2-methane sulphonate (HPMS) in photorespiratory conditions inhibited O2 uptake much stronger (35%). The addition of glyoxylate enhanced respiration in the presence of HPMS up to the control level suggesting that alternative pathways of glyoxylate conversion might be operating. The differences in inhibitor responses may reflect fine mechanisms for the regulation of energetic balance in the plant cell which consists of switching from electron transport coupled to ATP production to non-coupled transport. Photorespiratory flux is also very flexible, and the suppression of glycine decarboxylation can induce bypass reactions of glyoxylate metabolism. 相似文献