全文获取类型
收费全文 | 1304篇 |
免费 | 47篇 |
国内免费 | 7篇 |
出版年
2023年 | 14篇 |
2022年 | 23篇 |
2021年 | 93篇 |
2020年 | 27篇 |
2019年 | 46篇 |
2018年 | 40篇 |
2017年 | 33篇 |
2016年 | 55篇 |
2015年 | 59篇 |
2014年 | 79篇 |
2013年 | 108篇 |
2012年 | 118篇 |
2011年 | 99篇 |
2010年 | 43篇 |
2009年 | 57篇 |
2008年 | 61篇 |
2007年 | 65篇 |
2006年 | 55篇 |
2005年 | 64篇 |
2004年 | 37篇 |
2003年 | 38篇 |
2002年 | 22篇 |
2001年 | 9篇 |
2000年 | 10篇 |
1999年 | 10篇 |
1998年 | 5篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 12篇 |
1994年 | 7篇 |
1993年 | 8篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 4篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1973年 | 1篇 |
1970年 | 2篇 |
排序方式: 共有1358条查询结果,搜索用时 265 毫秒
41.
Xuexin Zhang José C. González-Cobos Rainer Schindl Martin Muik Brian Ruhle Rajender K. Motiani Jonathan M. Bisaillon Wei Zhang Marc Fahrner Margarida Barroso Khalid Matrougui Christoph Romanin Mohamed Trebak 《Molecular and cellular biology》2013,33(18):3715-3723
We recently showed, in primary vascular smooth muscle cells (VSMCs), that the platelet-derived growth factor activates canonical store-operated Ca2+ entry and Ca2+ release-activated Ca2+ currents encoded by Orai1 and STIM1 genes. However, thrombin activates store-independent Ca2+ selective channels contributed by both Orai3 and Orai1. These store-independent Orai3/Orai1 channels are gated by cytosolic leukotriene C4 (LTC4) and require STIM1 downstream LTC4 action. However, the source of LTC4 and the signaling mechanisms of STIM1 in the activation of this LTC4-regulated Ca2+ (LRC) channel are unknown. Here, we show that upon thrombin stimulation, LTC4 is produced through the sequential activities of phospholipase C, diacylglycerol lipase, 5-lipo-oxygenease, and leukotriene C4 synthase. We show that the endoplasmic reticulum-resident STIM1 is necessary and sufficient for LRC channel activation by thrombin. STIM1 does not form sustained puncta and does not colocalize with Orai1 either under basal conditions or in response to thrombin. However, STIM1 is precoupled to Orai3 and Orai3/Orai1 channels under basal conditions as shown using Forster resonance energy transfer (FRET) imaging. The second coiled-coil domain of STIM1 is required for coupling to either Orai3 or Orai3/Orai1 channels and for LRC channel activation. We conclude that STIM1 employs distinct mechanisms in the activation of store-dependent and store-independent Ca2+ entry pathways. 相似文献
42.
Rais Ahmad Khan Hamad A. Al-Lohedan Mohammad Abul Farah Mohd Sajid Ali Ali Alsalme Khalid Mashay Al-Anazi 《Journal of biomolecular structure & dynamics》2013,31(15):3905-3913
abstractThe designing of metal-based anticancer therapeutic agents can be optimized in a better and rapid way if the ligands utilized have standalone properties. Therefore, even when the organometallic/coordination complex (i.e., metallodrug) gets dissociated in extreme conditions, the ligand can endorse its biological properties. Herein, we have synthesized and characterized ?6-p-cymene ruthenium diclofenac complex. Furthermore, the ruthenium complex interactions with human serum albumin (HSA) and ct-DNA have been studied using various spectroscopic studies viz., UV, fluorescence, and circular dichroism and exhibited a significant binding propensity. Furthermore, in vitro cytotoxicity assays were carried out against human breast cancer “MCF-7” cell line. The ?6-p-cymene ruthenium diclofenac complex registered significant cytotoxicity with an IC50 value of ~25.0?µM which is comparable to the standard drugs. The ?6-p-cymene ruthenium diclofenac complex was able to decrease the MCF-7 cell proliferation and induced significant levels of apoptosis with relatively low toxicity. 相似文献
43.
Gustavo Basurto-Islas Inge Grundke-Iqbal Yunn Chyn Tung Fei Liu Khalid Iqbal 《The Journal of biological chemistry》2013,288(24):17495-17507
Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2PP2A. In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2PP2A is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2PP2A translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2PP2A, except when I2PP2A was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2PP2A, inhibition of protein phosphatase 2A, and hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2PP2A-protein phosphatase 2A-Tau hyperphosphorylation pathway as a therapeutic target. 相似文献
44.
Olympe Chazara Chi-Sheng Chang Nicolas Bruneau Khalid Benabdeljelil Jean-Claude Fotsa Boniface B. Kayang N’Goran E. Loukou Richard Osei-Amponsah Valentine Yapi-Gnaore Issaka A. K. Youssao Chih-Feng Chen Marie-Hélène Pinard-van der Laan Michèle Tixier-Boichard Bertrand Bed’Hom 《Immunogenetics》2013,65(6):447-459
The chicken major histocompatibility complex (MHC) is located on the microchromosome 16 and is described as the most variable region in the genome. The genes of the MHC play a central role in the immune system. Particularly, genes encoding proteins involved in the antigen presentation to T cells. Therefore, describing the genetic polymorphism of this region is crucial in understanding host–pathogen interactions. The tandem repeat LEI0258 is located within the core area of the B region of the chicken MHC (MHC-B region) and its genotypes correlate with serology. This marker was used to provide a picture of the worldwide diversity of the chicken MHC-B region and to categorize chicken MHC haplotypes. More than 1,600 animals from 80 different populations or lines of chickens from Africa, Asia, and Europe, including wild fowl species, were genotyped at the LEI0258 locus. Fifty novel alleles were described after sequencing. The resulting 79 alleles were classified into 12 clusters, based on the SNPs and indels found within the sequences flanking the repeats. Furthermore, hypotheses were formulated on the evolutionary dynamics of the region. This study constitutes the largest variability report for the chicken MHC and establishes a framework for future diversity or association studies. 相似文献
45.
46.
Atika?MansoorEmail author Lubna?Ali Noor-ul?Sabah Asraf?Hussain?Hashmi Mohammad?Haroon?Khan Syed?Ali?Raza?Kazmi Nafees?Ahmad Saima?Siddiqi Khalid?Mehmood?Khan 《Virology journal》2013,10(1):352
Background
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma and infects about 3% world population. Response to interferon therapy depends upon the genotype of the virus and factors associated with the host. Despite a good response to interferon therapy, a considerable number of genotype 3a infected patients remains unalleviated.Results
In total forty-nine patients including twenty-five non-responders (non-SVR) and twenty-four responders (SVR) were recruited. Patients were tested for viral status at different intervals and the isolated RNA was sequenced for the NS5A region in both groups. The comparison of PKRBD of HCV between the SVR and non-SVR patients did not confirm any significant difference in the number of mutations. However, when the sequence downstream to the PKRBD of NS5A was compared, two important statistically significant mutations were observed; at positions 2309 (Ala to Ser) and 2326 (Gly to Ala). These mutations were then analysed for tertiary protein structure and important structural changes were observed. Statistically significant difference was also observed when age groups of patients were compared; younger patients showed better response than the older ones.Conclusions
The region between PKRBD and IRRDR may be important for prediction of response to IFN therapy for genotype 3a. ISDR and PKRBD have not shown any involvement in treatment response. Further functional analyses of these findings can help in understanding the involvement of the NS5A region in interferon treatment of HCV-3a infected patients.47.
Hiranmoy Das Zhihui Wang M. Khalid Khan Niazi Reeva Aggarwal Jingwei Lu Suman Kanji Manjusri Das Matthew Joseph Metin Gurcan Vittorio Cristini 《PloS one》2013,8(4)
Molecular-focused cancer therapies, e.g., molecularly targeted therapy and immunotherapy, so far demonstrate only limited efficacy in cancer patients. We hypothesize that underestimating the role of biophysical factors that impact the delivery of drugs or cytotoxic cells to the target sites (for associated preferential cytotoxicity or cell signaling modulation) may be responsible for the poor clinical outcome. Therefore, instead of focusing exclusively on the investigation of molecular mechanisms in cancer cells, convection-diffusion of cytotoxic molecules and migration of cancer-killing cells within tumor tissue should be taken into account to improve therapeutic effectiveness. To test this hypothesis, we have developed a mathematical model of the interstitial diffusion and uptake of small cytotoxic molecules secreted by T-cells, which is capable of predicting breast cancer growth inhibition as measured both in vitro and in vivo. Our analysis shows that diffusion barriers of cytotoxic molecules conspire with γδ T-cell scarcity in tissue to limit the inhibitory effects of γδ T-cells on cancer cells. This may increase the necessary ratios of γδ T-cells to cancer cells within tissue to unrealistic values for having an intended therapeutic effect, and decrease the effectiveness of the immunotherapeutic treatment. 相似文献
48.
Harshita Chodavarapu Nadja Grobe Hari K. Somineni Esam S. B. Salem Malav Madhu Khalid M. Elased 《PloS one》2013,8(4)
Alterations within the renal renin angiotensin system play a pivotal role in the development and progression of cardiovascular and renal disease. Angiotensin converting enzyme 2 (ACE2) is highly expressed in renal tubules and has been shown to be renoprotective in diabetes. The protease, a disintegrin and metalloprotease (ADAM) 17, is involved in the ectodomain shedding of several transmembrane proteins including ACE2. Renal ACE2 and ADAM17 were significantly increased in db/db mice compared to controls. We investigated the effect of the insulin sensitizer, rosiglitazone, on albuminuria, renal ADAM17 protein expression and ACE2 shedding in db/db diabetic mice. Rosiglitazone treatment of db/db mice normalized hyperglycemia, attenuated renal injury and decreased urinary ACE2 and renal ADAM17 protein expression. Urinary excreted ACE2 is enzymatically active. Western blot analysis of urinary ACE2 demonstrated two prominent immunoreactive bands at approximately 70 & 90 kDa. The predominant immunoreactive band is approximately 20 kDa shorter than the one demonstrated for kidney lysate, indicating possible ectodomain shedding of active renal ACE2 in the urine. Therefore, it is tempting to speculate that renoprotection of rosiglitazone could be partially mediated via downregulation of renal ADAM17 and ACE2 shedding. In addition, there was a positive correlation between blood glucose, urinary albumin, plasma glucagon, and triglyceride levels with urinary ACE2 excretion. In conclusion, urinary ACE2 could be used as a sensitive biomarker of diabetic nephropathy and for monitoring the effectiveness of renoprotective medication. 相似文献
49.
Fatema Alzahrani Hiroyuki Kuwahara Yongkang Long Mohammed Al-Owain Mohamed Tohary Moeenaldeen AlSayed Mohammed Mahnashi Lana Fathi Maha Alnemer Mohamed H. Al-Hamed Gabrielle Lemire Kym M. Boycott Mais Hashem Wenkai Han Almundher Al-Maawali Feisal Al Mahrizi Khalid Al-Thihli Xin Gao Fowzan S. Alkuraya 《American journal of human genetics》2020,107(6):1178
50.
Xiang Liu Shangqi Li Wenzhu Peng Shuaisheng Feng Jianxin Feng Shahid Mahboob Khalid A. Al-Ghanim Peng Xu 《PloS one》2016,11(4)
The ATP-binding cassette (ABC) gene family is considered to be one of the largest gene families in all forms of prokaryotic and eukaryotic life. Although the ABC transporter genes have been annotated in some species, detailed information about the ABC superfamily and the evolutionary characterization of ABC genes in common carp (Cyprinus carpio) are still unclear. In this research, we identified 61 ABC transporter genes in the common carp genome. Phylogenetic analysis revealed that they could be classified into seven subfamilies, namely 11 ABCAs, six ABCBs, 19 ABCCs, eight ABCDs, two ABCEs, four ABCFs, and 11 ABCGs. Comparative analysis of the ABC genes in seven vertebrate species including common carp, showed that at least 10 common carp genes were retained from the third round of whole genome duplication, while 12 duplicated ABC genes may have come from the fourth round of whole genome duplication. Gene losses were also observed for 14 ABC genes. Expression profiles of the 61 ABC genes in six common carp tissues (brain, heart, spleen, kidney, intestine, and gill) revealed extensive functional divergence among the ABC genes. Different copies of some genes had tissue-specific expression patterns, which may indicate some gene function specialization. This study provides essential genomic resources for future studies in common carp. 相似文献