全文获取类型
收费全文 | 148篇 |
免费 | 8篇 |
出版年
2023年 | 1篇 |
2021年 | 2篇 |
2019年 | 1篇 |
2018年 | 5篇 |
2016年 | 8篇 |
2015年 | 12篇 |
2014年 | 11篇 |
2013年 | 15篇 |
2012年 | 11篇 |
2011年 | 18篇 |
2010年 | 8篇 |
2009年 | 4篇 |
2008年 | 12篇 |
2007年 | 5篇 |
2006年 | 7篇 |
2005年 | 5篇 |
2004年 | 2篇 |
2003年 | 3篇 |
2002年 | 4篇 |
2001年 | 2篇 |
1999年 | 1篇 |
1998年 | 4篇 |
1996年 | 2篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1988年 | 1篇 |
1982年 | 1篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1975年 | 2篇 |
1970年 | 1篇 |
排序方式: 共有156条查询结果,搜索用时 15 毫秒
101.
David A. Patten Shawn McGuirk Ujval Anilkumar Ghadi Antoun Karan Gandhi Gaganvir Parmar Mohamed Ariff Iqbal Jacob Wong Richard B. Richardson Julie St-Pierre Ruth S. Slack Mary-Ellen Harper 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2021,1868(1):118854
Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or are linked to numerous neurodegenerative, neuromuscular, and metabolic diseases. It is generally thought that cells with altered mitochondrial structure are prone to mitochondrial dysfunction, increased reactive oxygen species generation and widespread oxidative damage. The objective of the current study was to investigate the relationship between mitochondrial dynamics and the master cellular antioxidant, glutathione (GSH). We reveal that mouse embryonic fibroblasts (MEFs) lacking the mitochondrial fusion machinery display elevated levels of GSH, which limits oxidative damage. Moreover, targeted metabolomics and 13C isotopic labeling experiments demonstrate that cells lacking the inner membrane fusion GTPase OPA1 undergo widespread metabolic remodeling altering the balance of citric acid cycle intermediates and ultimately favoring GSH synthesis. Interestingly, the GSH precursor and antioxidant n-acetylcysteine did not increase GSH levels in OPA1 KO cells, suggesting that cysteine is not limiting for GSH production in this context. Post-mitotic neurons were unable to increase GSH production in the absence of OPA1. Finally, the ability to use glycolysis for ATP production was a requirement for GSH accumulation following OPA1 deletion. Thus, our results demonstrate a novel role for mitochondrial fusion in the regulation of GSH synthesis, and suggest that cysteine availability is not limiting for GSH synthesis in conditions of mitochondrial fragmentation. These findings provide a possible explanation for the heightened sensitivity of certain cell types to alterations in mitochondrial dynamics. 相似文献
102.
Association of Cry1Ac toxin resistance in Helicoverpa zea (Boddie) with increased alkaline phosphatase levels in the midgut lumen 总被引:2,自引:0,他引:2
Caccia S Moar WJ Chandrashekhar J Oppert C Anilkumar KJ Jurat-Fuentes JL Ferré J 《Applied and environmental microbiology》2012,78(16):5690-5698
Resistance to Bacillus thuringiensis Cry1Ac toxin was characterized in a population of Helicoverpa zea larvae previously shown not to have an alteration in toxin binding as the primary resistance mechanism to this toxin. Cry1Ac-selected larvae (AR1) were resistant to protoxins and toxins of Cry1Ab, Cry1Ac, and the corresponding modified proteins lacking helix α-1 (Cry1AbMod and Cry1AcMod). When comparing brush border membrane vesicles (BBMVs) prepared from susceptible (LC) and AR1 larval midguts, there were only negligible differences in overall Cry1Ac toxin binding, though AR1 had 18% reversible binding, in contrast to LC, in which all binding was irreversible. However, no differences were detected in Cry1Ac-induced pore formation activity in BBMVs from both strains. Enzymatic activities of two putative Cry1Ac receptors (aminopeptidase N [APN] and alkaline phosphatase [ALP]) were significantly reduced (2-fold and 3-fold, respectively) in BBMVs from AR1 compared to LC larvae. These reductions corresponded to reduced protein levels in midgut luminal contents only in the case of ALP, with an almost 10-fold increase in specific ALP activity in midgut fluids from AR1 compared to LC larvae. Partially purified H. zea ALP bound Cry1Ac toxin in ligand blots and competed with Cry1Ac toxin for BBMV binding. Based on these results, we suggest the existence of at least one mechanism of resistance to Cry1A toxins in H. zea involving binding of Cry1Ac toxin to an ALP receptor in the larval midgut lumen of resistant larvae. 相似文献
103.
Nagamani SC Campeau PM Shchelochkov OA Premkumar MH Guse K Brunetti-Pierri N Chen Y Sun Q Tang Y Palmer D Reddy AK Li L Slesnick TC Feig DI Caudle S Harrison D Salviati L Marini JC Bryan NS Erez A Lee B 《American journal of human genetics》2012,90(5):836-846
Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition. 相似文献
104.
A Pillai D Bruno AS Sarreal RT Hernando LA Saint-Louis J Nierenberg SD Ginsberg N Pomara PD Mehta H Zetterberg K Blennow PF Buckley 《PloS one》2012,7(7):e39358
Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted. 相似文献
105.
106.
Nucleic acid tests that detect HIV infection at an early phase are available and have been applied on individual dried blood
spot (DBS). The present study was undertaken with an aim to evaluate the feasibility of performing PCR for HIV-1 DNA on pools
of DBS as an alternative to individual testing. Standardization of PCR by a modified Amplicor HIV-1 DNA assay version 1.5
(Roche molecular diagnostics, USA), on pooled DBS was performed using five confirmed HIV reactive samples with known low viral
load of HIV-1 and HIV non-reactive samples in pools of 5, 10 and 20 DBS. After successful standardization of pooling procedure,
a total of 183 pools (of 10 DBS each) were prepared from 1,823 DBS samples, collected from a population-based study that tested
negative for HIV antibodies and p24 antigen. All these pools were screened for HIV-1 DNA by the Amplicor assay. Standardization
of pooling procedure indicated that pooling of 10 DBS gave an optimum result. Out of 183 pools tested, one pool of 10 samples
was positive and of these ten DBS that were tested individually to identify the positive DBS, one sample was detected to be
positive for HIV-1 DNA. Our study demonstrates that PCR for HIV-1 DNA can be successfully performed on pools of DBS. However,
this may be needed only on specialized studies of HIV and not for routine epidemiology studies as only a very small fraction
of cases would be missed if only antibody/antigen testing were done. 相似文献
107.
Accumulation of voltage-gated sodium (Na(v)) channels at nodes of Ranvier is paramount for action potential propagation along myelinated fibers, yet the mechanisms governing nodal development, organization, and stabilization remain unresolved. Here, we report that genetic ablation of the neuron-specific isoform of Neurofascin (Nfasc(NF1??)) in vivo results in nodal disorganization, including loss of Na(v) channel and ankyrin-G (AnkG) enrichment at nodes in the peripheral nervous system (PNS) and central nervous system (CNS). Interestingly, the presence of paranodal domains failed to rescue nodal organization in the PNS and the CNS. Most importantly, using ultrastructural analysis, we demonstrate that the paranodal domains invade the nodal space in Nfasc(NF1??) mutant axons and occlude node formation. Our results suggest that Nfasc(NF1??)-dependent assembly of the nodal complex acts as a molecular boundary to restrict the movement of flanking paranodal domains into the nodal area, thereby facilitating the stereotypic axonal domain organization and saltatory conduction along myelinated axons. 相似文献
108.
Kim SH Anilkumar GN Zawacki LG Zeng Q Yang DY Shao Y Dong G Xu X Yu W Jiang Y Jenh CH Hall JW Carroll CD Hobbs DW Baldwin JJ McGuinness BF Rosenblum SB Kozlowski JA Shankar BB Shih NY 《Bioorganic & medicinal chemistry letters》2011,21(23):6982-6986
The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study. 相似文献
109.
Panakkool-Thamban Aneesh Kappalli Sudha Ameri Kottarathil Helna Gopinathan Anilkumar Jean-Paul Trilles 《ZooKeys》2014,(457):339-353
Simultaneous multiple infestation of parasitic crustacean species involving a cymothoid isopod, Cymothoa
frontalis Milne Edward, 1840 and four species of copepods such as Lernanthropus
tylosuri Richiardi, 1880, Caligodes
lacinatus Kroyer, 1863, Bomolochus
bellones Burmeister, 1833 and Dermoergasilus
coleus Cressey & Collette, 1970 was frequently noticed on spot-tail needlefish, Strongylura
strongylura (Belonidae) captured from the Malabar coast (Kerala, India) during the period from April 2011 to March 2012. All the 43 fishes (Strongylura
strongylura) collected, were under the hyper-infection with parasitic crustaceans; a total of 388 parasitic crustaceans including 57 Cymothoa
frontalis, 252 Lernanthropus
tylosuri, 31 Caligodes
lacinatus, 24 Bomolochus
bellones and 32 Dermoergasilus
coleus were recovered from the host fish. 4 members (9.30%) of host fish were under quadruple parasitism, in two different combinations. Seventeen (39.53%) host fishes showed triple parasitism and 20 (46.51%) members exhibited double parasitism, with four and five parasitic combinations respectively. Remaining two (4.65%) fishes were parasitized only by the copepod, Lernanthropus
tylosuri. The infestations by all recovered parasitic crustaceans were highly site specific. The damage caused by the parasitic crustaceans was also discussed. 相似文献
110.