全文获取类型
收费全文 | 185264篇 |
免费 | 8833篇 |
国内免费 | 923篇 |
专业分类
195020篇 |
出版年
2023年 | 357篇 |
2022年 | 805篇 |
2021年 | 1660篇 |
2020年 | 940篇 |
2019年 | 1242篇 |
2018年 | 13044篇 |
2017年 | 11744篇 |
2016年 | 9493篇 |
2015年 | 4448篇 |
2014年 | 4661篇 |
2013年 | 5528篇 |
2012年 | 11167篇 |
2011年 | 19280篇 |
2010年 | 15963篇 |
2009年 | 12093篇 |
2008年 | 15234篇 |
2007年 | 16773篇 |
2006年 | 5728篇 |
2005年 | 5796篇 |
2004年 | 6049篇 |
2003年 | 5910篇 |
2002年 | 5380篇 |
2001年 | 1203篇 |
2000年 | 872篇 |
1999年 | 1022篇 |
1998年 | 1310篇 |
1997年 | 905篇 |
1996年 | 823篇 |
1995年 | 769篇 |
1994年 | 661篇 |
1993年 | 764篇 |
1992年 | 680篇 |
1991年 | 597篇 |
1990年 | 570篇 |
1989年 | 550篇 |
1988年 | 523篇 |
1987年 | 481篇 |
1986年 | 435篇 |
1985年 | 609篇 |
1984年 | 687篇 |
1983年 | 634篇 |
1982年 | 721篇 |
1981年 | 658篇 |
1980年 | 660篇 |
1979年 | 387篇 |
1978年 | 465篇 |
1977年 | 396篇 |
1976年 | 398篇 |
1972年 | 456篇 |
1971年 | 457篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
David C. Pryde Martin Corless David R. Fenwick Helen J. Mason Blanda C. Stammen Peter T. Stephenson David Ellis David Bachelor David Gordon Christopher G. Barber Anthony Wood Donald S. Middleton David C. Blakemore Gemma C. Parsons Rachel Eastwood Michelle Y. Platts Keith Statham Kerry A. Paradowski Catherine Burt Wolfgang Klute 《Bioorganic & medicinal chemistry letters》2009,19(4):1084-1088
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential. 相似文献
992.
Xiaoyu Yang Wei Xu Svetlana Dukleska Sabrina Benchaar Selina Mengisen Valentyn Antochshuk Jason Cheung Leslie Mann Zulfia Babadjanova Jason Rowand Rico Gunawan Alexander McCampbell Maribel Beaumont David Meininger Daisy Richardson Alexandre Ambrogelly 《MABS-AUSTIN》2013,5(5):787-794
Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2−8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples. We present here three case studies reflecting three typical outcomes: (1) no major or unexpected degradation is found and the study results are used to inform early identification of degradation pathways and potential critical quality attributes within the Quality by Design framework defined by US Food and Drug Administration guidance documents; (2) identification of specific degradation pathway(s) that do not affect potency of the molecule, with subsequent definition of proper process control and formulation strategies; and (3) identification of degradation that affects potency, resulting in program termination and reallocation of resources. 相似文献
993.
A taxonomic review of the genus Banjos (Perciformes: Banjosidae), previously restricted to a single species, Banjos banjos (Richardson 1846), recorded from the northwestern Pacific Ocean from the South China Sea north to Japan, as well as Lombok (Indonesia), New Caledonia and Australia, resulted in the recognition of three species, including B. banjos (northwestern Pacific Ocean, Indonesia and western Australia), Banjos aculeatus sp. nov. (eastern Australia) and Banjos peregrinus sp. nov. [northern Australia (Timor Sea)]. Records of B. banjos from New Caledonia probably also represent B. aculeatus, which is clearly distinct from other congeners in having a relatively long, strongly serrated spine at the posteroventral angle of the preopercle and an entirely dusky membrane on the spinous dorsal fin in juveniles < ca. 70 mm SL, in addition to slightly longer first and second dorsal-fin spines. Banjos peregrinus is characterized by a relatively greater head length, orbit diameter, postorbital length and pre-pelvic-fin length, as well as poorly developed serration of the exposed margin of the cleithrum. Within B. banjos, a population from the southeastern Indian Ocean, including Indonesia and western Australia, is regarded as a distinct subspecies (Banjos banjos brevispinis ssp. nov.), distinguishable from B. b. banjos from the northwestern Pacific Ocean by a relatively narrow least interorbital width, and shorter second and eighth dorsal-fin spines. Ontogenetic morphological changes within the genus and the status of the holotype of Anoplus banjos Richardson 1846 are discussed in detail. 相似文献
994.
995.
Hiroki Tawaratsumida Takao Setoguchi Yoshiya Arishima Hideo Ohtsubo Masaki Akimoto Yasuhiro Ishidou Satoshi Nagano Eiji Taketomi Nobuhiko Sunahara Setsuro Komiya 《BMC research notes》2017,10(1):765
Objective
Osteoporosis is a complication of rheumatoid arthritis. We examined the risk factors for bone loss in rheumatoid arthritis patients receiving biological disease-modifying anti-rheumatic drugs. Lumbar spine and femoral neck bone mineral density was measured at two time points in 153 patients with rheumatoid arthritis managed with biological disease-modifying anti-rheumatic drugs. We examined patients’ variables to identify risk factors for least significant reduction of bone mineral density.Results
Least significant reduction of lumbar spine bone mineral density (≤ ? 2.4%) was seen in 13.1% of patients. Least significant reduction of femoral neck bone mineral density (≤ ? 1.9%) was seen in 34.0% of patients. Multiple logistic regression analysis showed that a risk factor for least significant reduction of the lumbar spine was high-dose methylprednisolone use. Multiple regression analysis showed that a risk factor for least significant reduction of the femoral neck was short disease duration. Our findings showed that a risk factor for femoral neck bone mineral density reduction was a short disease duration. These findings suggest that rheumatoid arthritis patients receiving treatment with biological disease-modifying anti-rheumatic drugs may benefit from earlier osteoporosis treatments to prevent femoral neck bone loss.996.
Gompels LL Malik NM Madden L Jin P Feldmann M Shepard HM Paleolog EM 《Arthritis research & therapy》2011,13(5):R161
Introduction
Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA. 相似文献997.
Autophagy is an evolutionarily conserved mechanism for protein degradation that is critical for the maintenance of homeostasis in man. Autophagy has unexpected pleiotropic functions that favor survival of the cell, including nutrient supply under starvation, cleaning of the cellular interior, defense against infection and antigen presentation. Moreover, defective autophagy is associated with a diverse range of disease states, including neurodegeneration, cancer and Crohn's disease. Here we discuss the roles of mammalian autophagy in health and disease and highlight recent advances in pharmacological manipulation of autophagic pathways as a therapeutic strategy for a variety of pathological conditions. 相似文献
998.
Tissue-specific manipulation of known copper transport genes in Drosophila tissues results in phenotypes that are presumably due to an alteration in copper levels in the targeted cells. However direct confirmation of this has to date been technically challenging. Measures of cellular copper content such as expression levels of copper-responsive genes or cuproenzyme activity levels, while useful, are indirect. First-generation copper-sensitive fluorophores show promise but currently lack the sensitivity required to detect subtle changes in copper levels. Moreover such techniques do not provide information regarding other relevant biometals such as zinc or iron. Traditional techniques for measuring elemental composition such as inductively coupled plasma mass spectroscopy are not sensitive enough for use with the small tissue amounts available in Drosophila research. Here we present synchrotron x-ray fluorescence microscopy analysis of two different Drosophila tissues, the larval wing imaginal disc, and sectioned adult fly heads and show that this technique can be used to detect changes in tissue copper levels caused by targeted manipulation of known copper homeostasis genes. 相似文献
999.
1000.
Bhabhra R Richie DL Kim HS Nierman WC Fortwendel J Aris JP Rhodes JC Askew DS 《Eukaryotic cell》2008,7(4):575-583
Aspergillus fumigatus is an important opportunistic fungal pathogen that is responsible for high mortality rates in the immunosuppressed population. CgrA, the A. fumigatus ortholog of a Saccharomyces cerevisiae nucleolar protein involved in ribosome biogenesis, contributes to the virulence of this fungus by supporting rapid growth at 37 degrees C. To determine how CgrA affects ribosome biogenesis in A. fumigatus, polysome profile and ribosomal subunit analyses were performed on both wild-type A. fumigatus and a DeltacgrA mutant. The loss of CgrA was associated with a reduction in the level of 80S monosomes as well as an imbalance in the 60S:40S subunit ratio and the appearance of half-mer ribosomes. The gene expression profile in the DeltacgrA mutant revealed increased abundance of a subset of translational machinery mRNAs relative to the wild type, suggesting a potential compensatory response to CgrA deficiency. Although DeltacgrA conidia germinated normally at 22 degrees C, they swelled excessively when incubated at 37 degrees C and accumulated abnormally high numbers of nuclei. This hypernucleated phenotype could be replicated pharmacologically by germinating wild-type conidia under conditions of reductive stress. These findings indicate that the germination process is particularly vulnerable to global disruption of protein synthesis and suggest that CgrA is involved in both ribosome biogenesis and polarized cell growth in A. fumigatus. 相似文献