全文获取类型
收费全文 | 770篇 |
免费 | 37篇 |
出版年
2022年 | 11篇 |
2021年 | 26篇 |
2020年 | 16篇 |
2019年 | 22篇 |
2018年 | 14篇 |
2017年 | 14篇 |
2016年 | 25篇 |
2015年 | 38篇 |
2014年 | 41篇 |
2013年 | 48篇 |
2012年 | 56篇 |
2011年 | 60篇 |
2010年 | 45篇 |
2009年 | 38篇 |
2008年 | 35篇 |
2007年 | 40篇 |
2006年 | 40篇 |
2005年 | 21篇 |
2004年 | 20篇 |
2003年 | 17篇 |
2002年 | 15篇 |
2001年 | 11篇 |
2000年 | 9篇 |
1999年 | 11篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1996年 | 5篇 |
1995年 | 4篇 |
1994年 | 3篇 |
1993年 | 5篇 |
1992年 | 11篇 |
1990年 | 10篇 |
1988年 | 5篇 |
1987年 | 10篇 |
1986年 | 5篇 |
1985年 | 6篇 |
1983年 | 7篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1978年 | 2篇 |
1975年 | 3篇 |
1974年 | 5篇 |
1973年 | 2篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1967年 | 3篇 |
1966年 | 3篇 |
1962年 | 2篇 |
1959年 | 2篇 |
排序方式: 共有807条查询结果,搜索用时 31 毫秒
721.
Vidya Nand Ravi Das Ravindra Nath Pandey Krishna Pandey Varsha Singh Vijay Kumar Greg Matlashewski Pradeep Das 《PLoS neglected tropical diseases》2014,8(5)
Background
One of the major challenges for management of visceral leishmaniasis (VL) is early diagnosis of cases to improve treatment outcome and reduce transmission. We have therefore investigated active case detection of VL with the help of accredited social health activists (ASHA). ASHAs are women who live in the community and receive performance-based incentives for overseeing maternal and other health-related issues in their village.Methods and Principal Finding
Through conducting interviews with 400 randomly selected ASHAs from four primary health care centers (PHCs), it was observed that their level of knowledge about visceral leishmaniasis (VL) regarding transmission, diagnosis, and treatment was limited. The baseline data indicated that less than 10% of VL cases seeking treatment at the PHCs were referred by ASHAs. To increase the knowledge and the referral rate of VL cases by ASHAs, training sessions were carried out during the monthly ASHA meetings at their respective PHCs. Following a single training session, the referral rate increased from less than 10% to over 27% and the overall knowledge about VL substantially improved. It was not possible, however, to demonstrate that ASHA training reduced the time that individuals had fever before treatment at the PHC.Conclusions
Training ASHAs to identify VL cases in villages for early diagnosis and treatment at the local PHC is feasible and should be undertaken routinely to improve knowledge about VL. 相似文献722.
Manoraj Navaratnarajah Urszula Siedlecka Michael Ibrahim Carin van Doorn Gopal Soppa Ajay Gandhi Adarsh Shah Punam Kukadia Magdi H. Yacoub Cesare M. Terracciano 《PloS one》2014,9(9)
Background
Clenbuterol (Cl), a β2 agonist, is associated with enhanced myocardial recovery during left ventricular assist device (LVAD) support, and exerts beneficial remodelling effects during mechanical unloading (MU) in rodent heart failure (HF). However, the specific effects of combined Cl+β1 blockade during MU are unknown.Methods and Results
We studied the chronic effects (4 weeks) of β2-adrenoceptor (AR) stimulation via Cl (2 mg/kg/day) alone, and in combination with β1-AR blockade using metoprolol ((Met), 250 mg/kg/day), on whole heart/cell structure, function and excitation-contraction (EC) coupling in failing (induced by left coronary artery (LCA) ligation), and unloaded (induced by heterotopic abdominal heart transplantation (HATx)) failing rat hearts. Combined Cl+Met therapy displayed favourable effects in HF: Met enhanced Cl''s improvement in ejection fraction (EF) whilst preventing Cl-induced hypertrophy and tachycardia. During MU combined therapy was less beneficial than either mono-therapy. Met, not Cl, prevented MU-induced myocardial atrophy, with increased atrophy occurring during combined therapy. MU-induced recovery of Ca2+ transient amplitude, speed of Ca2+ release and sarcoplasmic reticulum Ca2+ content was enhanced equally by Cl or Met mono-therapy, but these benefits, together with Cl''s enhancement of sarcomeric contraction speed, and MU-induced recovery of Ca2+ spark frequency, disappeared during combined therapy.Conclusions
Combined Cl+Met therapy shows superior functional effects to mono-therapy in rodent HF, but appears inferior to either mono-therapy in enhancing MU-induced recovery of EC coupling. These results suggest that combined β2-AR simulation +β1-AR blockade therapy is likely to be a safe and beneficial therapeutic HF strategy, but is not as effective as mono-therapy in enhancing myocardial recovery during LVAD support. 相似文献723.
724.
Samip Gandhi 《Computer methods in biomechanics and biomedical engineering》2016,19(10):1099-1106
Introduction: The mechanical bidomain model predicts forces on integrin proteins in the membrane. It has been solved analytically for idealized examples, but a numerical algorithm is needed to address realistic problems. Methods: The bidomain equations are approximated using finite differences. An ischemic region is modeled as a circular area having no active tension, surrounded by normal tissue. Results: The membrane force is large in the ischemic border zone, but is small elsewhere. Strain is distributed widely throughout the ischemic region and surrounding tissue. Conclusion: This calculation provides a testable prediction for the mechanism of mechanotransduction and remodeling in cardiac tissue. 相似文献
725.
Jianbo Yang Varsha Singh Tian-E Chen Rafiquel Sarker Lishou Xiong Boyoung Cha Shi Jin Xuhang Li C. Ming Tse Nicholas C. Zachos Mark Donowitz 《The Journal of biological chemistry》2014,289(29):20039-20053
NHERF1, NHERF2, and NHERF3 belong to the NHERF (Na+/H+ exchanger regulatory factor) family of PSD-95/Discs-large/ZO-1 (PDZ) scaffolding proteins. Individually, each NHERF protein has been shown to be involved in the regulation of multiple receptors or transporters including Na+/H+ exchanger 3 (NHE3). Although NHERF dimerizations have been reported, results have been inconsistent, and the physiological function of NHERF dimerizations is still unknown. The current study semiquantitatively compared the interaction strength among all possible homodimerizations and heterodimerizations of these three NHERF proteins by pulldown and co-immunoprecipitation assays. Both methods showed that NHERF2 and NHERF3 heterodimerize as the strongest interaction among all NHERF dimerizations. In vivo NHERF2/NHERF3 heterodimerization was confirmed by FRET and FRAP (fluorescence recovery after photobleach). NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. The NHERF3-4A mutant is defective in heterodimerization with NHERF2 and does not support the inhibition of NHE3 by carbachol. This suggests a role for NHERF2/NHERF3 heterodimerization in the regulation of NHE3 activity. In addition, both PDZ domains of NHERF2 could be simultaneously occupied by NHERF3 and another ligand such as NHE3, α-actinin-4, and PKCα, promoting formation of NHE3 macrocomplexes. This study suggests that NHERF2/NHERF3 heterodimerization mediates the formation of NHE3 macrocomplexes, which are required for the inhibition of NHE3 activity by carbachol. 相似文献
726.
727.
Weichao Zhang Xi Yang Liang Chen Yun-Yu Liu Varsha Venkatarangan Lucas Reist Phyllis Hanson Haoxing Xu Yanzhuang Wang Ming Li 《PLoS biology》2021,19(7)
The lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate its membrane proteins is poorly understood. In this study, we performed a cycloheximide (CHX) chase assay to measure the half-lives of approximately 30 human lysosomal membrane proteins (LMPs) and identified RNF152 and LAPTM4A as short-lived membrane proteins. The degradation of both proteins is ubiquitin dependent. RNF152 is a transmembrane E3 ligase that ubiquitinates itself, whereas LAPTM4A uses its carboxyl-terminal PY motifs to recruit NEDD4-1 for ubiquitination. After ubiquitination, they are internalized into the lysosome lumen by the endosomal sorting complexes required for transport (ESCRT) machinery for degradation. Strikingly, when ectopically expressed in budding yeast, human RNF152 is still degraded by the vacuole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a conserved mechanism to down-regulate lysosome membrane proteins.A study of how lysosomal membrane proteins are down-regulated reveals a conserved pathway involving ubiquitination of the membrane protein and subsequent internalization into the lysosome lumen by the ESCRT machinery for degradation. 相似文献
728.
Weiling Niu Zhiwei Chen Leslie A. Bush-Pelc Alaji Bah Prafull S. Gandhi Enrico Di Cera 《The Journal of biological chemistry》2009,284(52):36175-36185
The molecular mechanism of thrombin activation by Na+ remains elusive. Its kinetic formulation requires extension of the classical Botts-Morales theory for the action of a modifier on an enzyme to correctly account for the contribution of the E*, E, and E:Na+ forms. The extended scheme establishes that analysis of kcat unequivocally identifies allosteric transduction of Na+ binding into enhanced catalytic activity. The thrombin mutant N143P features no Na+-dependent enhancement of kcat yet binds Na+ with an affinity comparable to that of wild type. Crystal structures of the mutant in the presence and absence of Na+ confirm that Pro143 abrogates the important H-bond between the backbone N atom of residue 143 and the carbonyl O atom of Glu192, which in turn controls the orientation of the Glu192-Gly193 peptide bond and the correct architecture of the oxyanion hole. We conclude that Na+ activates thrombin by securing the correct orientation of the Glu192-Gly193 peptide bond, which is likely flipped in the absence of cation. Absolute conservation of the 143–192 H-bond in trypsin-like proteases and the importance of the oxyanion hole in protease function suggest that this mechanism of Na+ activation is present in all Na+-activated trypsin-like proteases. 相似文献
729.
Jameel NM Thirunavukkarasu C Wu T Watkins SC Friedman SL Gandhi CR 《Journal of cellular physiology》2009,218(1):157-166
Reactive oxygen species (ROS) activate retinoid-containing quiescent hepatic stellate cells (qHSCs) to retinoid-deficient fibrogenic myofibroblast-like cells (aHSCs). However, ROS also cause apoptosis of aHSCs, and apoptotic aHSCs are observed in inflammatory fibrotic liver. Here, we investigated mechanisms of the effects of oxidative stress on the survival of qHSCs and aHSCs. HSCs from normal rat liver were used after overnight culture (qHSCs), or in 3-5 passages (aHSCs). For in vivo induction of oxidative stress, tert-butylhydroperoxide was injected into control and CCl4-induced cirrhotic rats. Spontaneous caspase-3 activation and apoptosis, observed in cultured qHSCs, decreased with time and were unaffected by superoxide. In contrast, superoxide caused caspase-3 and p38-MAPK activation, reduction in Bcl-xL expression, and apoptosis in aHSCs. Inhibition of caspase-3 and p38-MAPK did not affect the viability of qHSCs in the absence or presence of superoxide, but inhibited superoxide-induced death of aHSCs. Glutathione (GSH) level and activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were lower in aHSCs than qHSCs. Superoxide increased GSH content, and activities of SOD, catalase and GPx in qHSCs but not in aHSCs. Incubation of 13-cis-retinoic acid (RA)-treated aHSCs with superoxide increased their GSH content significantly, and prevented superoxide-induced p38-MAPK and caspase-3 activation while dramatically reducing the extent of apoptosis. Finally, oxidative stress induced in vivo caused apoptosis of aHSCs in cirrhotic but not of qHSCs in control rats. These results suggest that the absence of retinoids render aHSCs susceptible to superoxide-induced apoptosis via caspase-3 and p38-MAPK activation. 相似文献
730.