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排序方式: 共有137条查询结果,搜索用时 203 毫秒
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Organisms used as model genomics systems are maintained as isogenic strains, yet evidence of sequence differences between independently maintained wild-type stocks has been substantiated by whole-genome resequencing data and strain-specific phenotypes. Sequence differences may arise from replication errors, transposon mobilization, meiotic gene conversion, or environmental or chemical assault on the genome. Low frequency alleles or mutations with modest effects on phenotypes can contribute to natural variation, and it has proven possible for such sequences to become fixed by adapted evolutionary enrichment and identified by resequencing. Our objective was to identify and analyze single locus genetic defects leading to RNAi resistance in isogenic strains of Caenorhabditis elegans. In so doing, we uncovered a mutation that arose de novo in an existing strain, which initially frustrated our phenotypic analysis. We also report experimental, environmental, and genetic conditions that can complicate phenotypic analysis of RNAi pathway defects. These observations highlight the potential for unanticipated mutations, coupled with genetic and environmental phenomena, to enhance or suppress the effects of known mutations and cause variation between wild-type strains. 相似文献
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4.
TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine
Yang Emma Li Yichang Wang Ximing Du Tizhong Zhang Hoi Yin Mak Sarah E. Hancock Holly McEwen Elvis Pandzic Renee M. Whan Yvette Celine Aw Ivan E. Lukmantara Yiqiong Yuan Xiuju Dong Anthony Don Nigel Turner Shiqian Qi Hongyuan Yang 《The Journal of cell biology》2021,220(6)
TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection. 相似文献
5.
Swee Tin Aw Michael John Todd Nadine Lehnen Grace Elizabeth Aw Konrad Peter Weber Thomas Eggert Gabor Michael Halmagyi 《PloS one》2013,8(12)
Background
Vestibular reflexes, evoked by human electrical (galvanic) vestibular stimulation (EVS), are utilized to assess vestibular function and investigate its pathways. Our study aimed to investigate the electrically-evoked vestibulo-ocular reflex (eVOR) output after bilateral and unilateral vestibular deafferentations to determine the characteristics for interpreting unilateral lesions such as vestibular schwannomas.Methods
EVOR was recorded with dual-search coils as binocular three-dimensional eye movements evoked by bipolar 100 ms-step at EVS intensities of [0.9, 2.5, 5.0, 7.5, 10.0]mA and unipolar 100 ms-step at 5 mA EVS intensity. Five bilateral vestibular deafferented (BVD), 12 unilateral vestibular deafferented (UVD), four unilateral vestibular schwannoma (UVS) patients and 17 healthy subjects were tested with bipolar EVS, and five UVDs with unipolar EVS.Results
After BVD, bipolar EVS elicited no eVOR. After UVD, bipolar EVS of one functioning ear elicited bidirectional, excitatory eVOR to cathodal EVS with 9 ms latency and inhibitory eVOR to anodal EVS, opposite in direction, at half the amplitude with 12 ms latency, exhibiting an excitatory-inhibitory asymmetry. The eVOR patterns from UVS were consistent with responses from UVD confirming the vestibular loss on the lesion side. Unexpectedly, unipolar EVS of the UVD ear, instead of absent response, evoked one-third the bipolar eVOR while unipolar EVS of the functioning ear evoked half the bipolar response.Conclusions
The bidirectional eVOR evoked by bipolar EVS from UVD with an excitatory-inhibitory asymmetry and the 3 ms latency difference between normal and lesion side may be useful for detecting vestibular lesions such as UVS. We suggest that current spread could account for the small eVOR to 5 mA unipolar EVS of the UVD ear. 相似文献6.
Carlisle R Rhoads CA Aw TY Harrison L 《American journal of physiology. Cell physiology》2002,283(6):C1675-C1686
Human umbilical vein endothelial cells (HUVECs) are an endothelial model of replicative senescence. Oxidative stress, possibly due to dysfunctional mitochondria, is believed to play a key role in replicative senescence and atherosclerosis, an age-related vascular disease. In this study, we determined the effect of cell division on genomic instability, mitochondrial function, and redox status in HUVECs that were able to replicate for approximately 60 cumulative population doublings (CPD). After 20 CPD, the nuclear genome deteriorated and the protein content of the cell population increased. This indicated an increase in cell size, which was accompanied by an increase in oxygen consumption, ATP production, and mitochondrial genome copy number and approximately 10% increase in mitochondrial mass. The antioxidant capacity increased, as seen by an increase in reduced glutathione, glutathione peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase. However, by CPD 52, the latter two enzymes decreased, as well as the ratio of mitochondrial-to-nuclear genome copies, the mitochondrial mass, and the oxygen consumption per milligram of protein. Our results signify that HUVECs maintain a highly reducing (GSH) environment as they replicate despite genomic instability and loss of mitochondrial function. 相似文献
7.
Dietary oxidants like lipid hydroperoxides (LOOH) can perturb cellular glutathione/glutathione disulphide (GSH/GSSG) status and disrupt mucosal turnover. This study examines the effect of LOOH on GSH/GSSG balance and phase transitions in the human colon cancer CaCo-2 cell. LOOH at 1 or 5 micro m were noncytotoxic, but disrupted cellular GSH/GSSG and stimulated proliferative activity at 6 h that paralleled increases in ornithine decarboxylase activity, thymidine incorporation, expression of cyclin D1/cyclin-dependent kinase 4, phosphorylation of retinoblastoma protein, and cell progression from G0/G1 to S. At 24 h, LOOH-induced sustained GSH/GSSG imbalance mediated growth arrest at G0/G1 that correlated with suppression of proliferative activity and enhanced oxidative DNA damage. LOOH-induced cell transitions were effectively blocked by N-acetylcysteine. Collectively, the study shows that subtoxic LOOH levels induce CaCo-2 GSH/GSSG imbalance that elicits time-dependent cell proliferation followed by growth arrest. These results provide insights into the mechanism of hydroperoxide-induced disruption of mucosal turnover with implications for understanding oxidant-mediated genesis of gut pathology. 相似文献
8.
Current status of antisense DNA methods in behavioral studies 总被引:4,自引:0,他引:4
The antisense DNA method has been used successfully to block the expression
of specific genes in vivo in neuronal systems. An increasing number of
studies in the last few years have shown that antisense DNA administered
directly into the brain can modify various kinds of behaviors. These
findings strongly suggest that the antisense DNA method can be used as a
powerful tool to study causal relationships between molecular processes in
the brain and behavior. In this article we review the current status of the
antisense method in behavioral studies and discuss its potentials and
problems by focusing on the following four aspects; (i) optimal application
paradigms of antisense DNA methods in behavioral studies; (ii) efficiencies
of different administration methods of antisense DNA used in behavioral
studies; (iii) determination of specificity of behavioral effects of
antisense DNA; and (iv) discrepancies between antisense DNA effects on
behaviors and those on protein levels of the targeted gene.
相似文献
9.
Tak Yee Aw 《Free radical research》1998,28(6):637-646
It has long been recognized that hydroperoxides are agents of cytotoxicity. However, in recent years, it is increasingly apparent that lipid hydroperoxide may play an important role in mediating cellular and molecular events in degenerative pathophysiological processes that lead to intestinal disorders, such as cancer. Yet, surprisingly, little is known of the intestinal disposition of peroxidized lipids and of the metabolic factors that determine mucosal peroxide elimination. The present paper summarizes the evidence for the pivotal role of reductant (GSH and NADPH) availability in intestinal peroxide detoxication. This information will provide important insights into the relationship between luminal lipid hydroperoxides and intestinal GSH redox homeostasis, and is pertinent to understanding how dietary oxidants like lipid peroxides, can impact intestinal integrity with implications for genesis of gut pathology. 相似文献
10.
Our recent finding that insulin increased the expression of the glutamate-cysteine ligase catalytic subunit (GCLc) with coincident increases in GCL activity and cellular glutathione (GSH) in human brain microvascular endothelial cells (IHECs) suggests a role for insulin in vascular GSH maintenance. Here, using IHECs stably transfected with promoter-luciferase reporter vectors, we found that insulin increased GCLc promoter activity, which required a prerequisite increase or decrease in medium glucose. An intact antioxidant response element-4 was essential for promoter activation, which was attenuated by inhibitors of PI3-kinase/Akt/mTOR signaling. Interestingly, only under low-glucose conditions did promoter activation correlate with increased GCLc expression and GSH synthesis. Low tert-butylhydroperoxide (tBH) concentrations similarly mediated promoter activation, but the maximal activation dose was decreased 10-fold by insulin. Insulin-tBH coadministration abrogated the low or high glucose requirement for promoter activation, suggesting possible ROS involvement. ROS production was elevated at low glucose without or with insulin; however, GSH increases were not inhibited by tempol, suggesting that ROS did not achieve the threshold for driving GCLc promoter activation and de novo GSH synthesis. The minor effect of pyruvate also ruled out a major role for hypoglycemia (± insulin)-induced metabolic stress on GSH induction under these conditions. 相似文献