全文获取类型
收费全文 | 8241篇 |
免费 | 726篇 |
专业分类
8967篇 |
出版年
2024年 | 10篇 |
2023年 | 89篇 |
2022年 | 179篇 |
2021年 | 325篇 |
2020年 | 187篇 |
2019年 | 238篇 |
2018年 | 273篇 |
2017年 | 230篇 |
2016年 | 367篇 |
2015年 | 566篇 |
2014年 | 544篇 |
2013年 | 661篇 |
2012年 | 779篇 |
2011年 | 718篇 |
2010年 | 457篇 |
2009年 | 348篇 |
2008年 | 487篇 |
2007年 | 425篇 |
2006年 | 374篇 |
2005年 | 331篇 |
2004年 | 306篇 |
2003年 | 267篇 |
2002年 | 233篇 |
2001年 | 38篇 |
2000年 | 24篇 |
1999年 | 39篇 |
1998年 | 59篇 |
1997年 | 33篇 |
1996年 | 29篇 |
1995年 | 25篇 |
1994年 | 24篇 |
1993年 | 25篇 |
1992年 | 9篇 |
1991年 | 19篇 |
1990年 | 12篇 |
1989年 | 10篇 |
1988年 | 12篇 |
1987年 | 17篇 |
1986年 | 11篇 |
1985年 | 18篇 |
1984年 | 19篇 |
1983年 | 17篇 |
1982年 | 18篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 13篇 |
1978年 | 8篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1972年 | 8篇 |
排序方式: 共有8967条查询结果,搜索用时 15 毫秒
61.
Folkert Reck Alun Bermingham Johanne Blais Vladimir Capka Taryn Cariaga Anthony Casarez Richard Colvin Charles R. Dean Alex Fekete Wanben Gong Ellie Growcott Hongqiu Guo Adriana K. Jones Cindy Li Fengxia Li Xiaodong Lin Mika Lindvall Sara Lopez Qingming Zhu 《Bioorganic & medicinal chemistry letters》2018,28(4):748-755
Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE). 相似文献
62.
Fleming SD Pope MR Hoffman SM Moses T Bukovnik U Tomich JM Wagner LM Woods KM 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(10):6168-6178
Reperfusion of ischemic tissue induces significant tissue damage in multiple conditions, including myocardial infarctions, stroke, and transplantation. Although not as common, the mortality rate of mesenteric ischemia/reperfusion (IR) remains >70%. Although complement and naturally occurring Abs are known to mediate significant damage during IR, the target Ags are intracellular molecules. We investigated the role of the serum protein, β2-glycoprotein I as an initiating Ag for Ab recognition and β2-glycoprotein I (β2-GPI) peptides as a therapeutic for mesenteric IR. The time course of β2-GPI binding to the tissue indicated binding and complement activation within 15 min postreperfusion. Treatment of wild-type mice with peptides corresponding to the lipid binding domain V of β2-GPI blocked intestinal injury and inflammation, including cellular influx and cytokine and eicosanoid production. The optimal therapeutic peptide (peptide 296) contained the lysine-rich region of domain V. In addition, damage and most inflammation were also blocked by peptide 305, which overlaps with peptide 296 but does not contain the lysine-rich, phospholipid-binding region. Importantly, peptide 296 retained efficacy after replacement of cysteine residues with serine. In addition, infusion of wild-type serum containing reduced levels of anti-β2-GPI Abs into Rag-1(-/-) mice prevented IR-induced intestinal damage and inflammation. Taken together, these data suggest that the serum protein β2-GPI initiates the IR-induced intestinal damage and inflammatory response and as such is a critical therapeutic target for IR-induced damage and inflammation. 相似文献
63.
Jeemeng Lao Ai Oikawa Jennifer R. Bromley Peter McInerney Anongpat Suttangkakul Andreia M. Smith‐Moritz Hector Plahar Tsan‐Yu Chiu Susana M. González Fernández‐Niño Berit Ebert Fan Yang Katy M. Christiansen Sara F. Hansen Solomon Stonebloom Paul D. Adams Pamela C. Ronald Nathan J. Hillson Masood Z. Hadi Miguel E. Vega‐Sánchez Dominique Loqué Henrik V. Scheller Joshua L. Heazlewood 《The Plant journal : for cell and molecular biology》2014,79(3):517-529
The glycosyltransferases (GTs) are an important and functionally diverse family of enzymes involved in glycan and glycoside biosynthesis. Plants have evolved large families of GTs which undertake the array of glycosylation reactions that occur during plant development and growth. Based on the Carbohydrate‐Active enZymes (CAZy) database, the genome of the reference plant Arabidopsis thaliana codes for over 450 GTs, while the rice genome (Oryza sativa) contains over 600 members. Collectively, GTs from these reference plants can be classified into over 40 distinct GT families. Although these enzymes are involved in many important plant specific processes such as cell‐wall and secondary metabolite biosynthesis, few have been functionally characterized. We have sought to develop a plant GTs clone resource that will enable functional genomic approaches to be undertaken by the plant research community. In total, 403 (88%) of CAZy defined Arabidopsis GTs have been cloned, while 96 (15%) of the GTs coded by rice have been cloned. The collection resulted in the update of a number of Arabidopsis GT gene models. The clones represent full‐length coding sequences without termination codons and are Gateway® compatible. To demonstrate the utility of this JBEI GT Collection, a set of efficient particle bombardment plasmids (pBullet) was also constructed with markers for the endomembrane. The utility of the pBullet collection was demonstrated by localizing all members of the Arabidopsis GT14 family to the Golgi apparatus or the endoplasmic reticulum (ER). Updates to these resources are available at the JBEI GT Collection website http://www.addgene.org/ . 相似文献
64.
Resveratrol: one molecule, many targets 总被引:1,自引:0,他引:1
Resveratrol is one of the numerous polyphenolic compounds found in several vegetal sources. In recent years, the interest in this molecule has increased exponentially following the major findings that resveratrol (i) is shown to be chemopreventive in some cancer models, (ii) is cardioprotective, and (iii) has positive effects on several aspects of metabolism, leading to increased lifespan in all the metazoan models tested thus far, including small mammals. Such remarkable properties have elicited a vast interest towards the identification of target proteins of resveratrol and have led to the identification of enzymes inhibited by resveratrol and others whose activation is enhanced. In the vast majority of cases, resveratrol displays inhibitory/activatory effects in the micromolar range, which is potentially attainable pharmacologically, although targets with affinities in the nanomolar range have also been reported. Here, we provide an overview of the various classes of enzymes known to be inhibited (or activated) by resveratrol. It appears that resveratrol, as a pharmacological agent, has a wide spectrum of targets. The biological activities of resveratrol may thus be dependent on its simultaneous activity on multiple molecular targets. 相似文献
65.
Sara Bobone Gianfranco Bocchinfuso Yoonkyung Park Antonio Palleschi Kyung‐Soo Hahm Lorenzo Stella 《Journal of peptide science》2013,19(12):758-769
Antimicrobial peptides (AMPs) are promising compounds for developing new antibiotic drugs against drug‐resistant bacteria. Many of them kill bacteria by perturbing their membranes but exhibit no significant toxicity towards eukaryotic cells. The identification of the features responsible for this selectivity is essential for their pharmacological development. AMPs exhibit few conserved features, but a statistical analysis of an AMP sequence database indicated that many α‐helical AMPs surprisingly have a helix‐breaking Pro residue in the middle of their sequence. To discriminate among the different possible hypotheses for the functional role of this feature, we designed an analogue of the antimicrobial peptide P5, in which the central Pro was deleted (analogue P5Del). Pro removal resulted in a dramatic increase of toxicity. This was explained by the observation that P5Del binds both charged and neutral membranes, whereas P5 has no appreciable affinity towards neutral bilayers. CD and simulative data provided a rationalization of this behavior. In solution P5, due to the presence of Pro, attains compact conformations, in which its apolar residues are partially shielded from the solvent, whereas P5Del is more helical. These structural differences reduce the hydrophobic driving force for association of P5 to neutral membranes, whereas its binding to anionic bilayers can still take place because of electrostatic attraction. After membrane binding, the Pro residue does not preclude the attainment of a membrane‐active amphiphilic helical conformation. These findings shed light on the role of Pro residues in the selectivity of AMPs and provide hints for the design of new, highly selective compounds. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
66.
Carina Proença Marisa Freitas Daniela Ribeiro Eduardo F. T. Oliveira Joana L. C. Sousa Sara M. Tomé 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):1216-1228
α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG. 相似文献
67.
The genus Caldicellulosiruptor contains extremely thermophilic bacteria that grow on plant polysaccharides. The genomes of Caldicellulosiruptor species reveal certain surface layer homology (SLH) domain proteins that have distinguishing features, pointing to a role in lignocellulose deconstruction. Two of these proteins in Caldicellulosiruptor saccharolyticus (Csac_0678 and Csac_2722) were examined from this perspective. In addition to three contiguous SLH domains, the Csac_0678 gene encodes a glycoside hydrolase family 5 (GH5) catalytic domain and a family 28 carbohydrate-binding module (CBM); orthologs to Csac_0678 could be identified in all genome-sequenced Caldicellulosiruptor species. Recombinant Csac_0678 was optimally active at 75°C and pH 5.0, exhibiting both endoglucanase and xylanase activities. SLH domain removal did not impact Csac_0678 GH activity, but deletion of the CBM28 domain eliminated binding to crystalline cellulose and rendered the enzyme inactive on this substrate. Csac_2722 is the largest open reading frame (ORF) in the C. saccharolyticus genome (predicted molecular mass of 286,516 kDa) and contains two putative sugar-binding domains, two Big4 domains (bacterial domains with an immunoglobulin [Ig]-like fold), and a cadherin-like (Cd) domain. Recombinant Csac_2722, lacking the SLH and Cd domains, bound to cellulose and had detectable carboxymethylcellulose (CMC) hydrolytic activity. Antibodies directed against Csac_0678 and Csac_2722 confirmed that these proteins bound to the C. saccharolyticus S-layer. Their cellular localization and functional biochemical properties indicate roles for Csac_0678 and Csac_2722 in recruitment and hydrolysis of complex polysaccharides and the deconstruction of lignocellulosic biomass. Furthermore, these results suggest that related SLH domain proteins in other Caldicellulosiruptor genomes may also be important contributors to plant biomass utilization. 相似文献
68.
Uric Acid Amplifies Aβ Amyloid Effects Involved in the Cognitive Dysfunction/Dementia: Evidences From an Experimental Model In Vitro 下载免费PDF全文
69.
70.
DNA vaccines consisted of tumor-associated antigen (TAA) are well suited for immunotherapy against tumor. The construct can
contain TAA fused to an appropriate molecule (biologic adjuvant) to improve the efficacy of anti-tumor immune response. Heat
shock protein 70 (HSP70) has been shown to be an excellent candidate, capable of cross-priming TAA by antigen presenting cells
leading to a robust T-cell response. However, the relationship between strong T-cell responses and tumor rejection is not
always mutually exclusive, for which TAA loss or activation of suppressive mechanisms may occur. HSP70 fused to downstream
of Her2/neu as DNA vaccine has been shown to be efficient against Her2-expressing tumors. In this study, we examined if N-terminally
fusion of Her2/neu to HSP70 could also improve efficiency of Her2/neu DNA vaccine. Therefore, mice with an established Her2/neu
expressing tumor were immunized with DNA vaccine consisting of extracellular and trans-membrane domain (EC+TM) of rat Her2/neu
alone or N-terminally fused to HSP70 and immune response was evaluated. Administration of rat Her2/neu led to partial control
of tumor progression. Surprisingly, fusion of HSP70 to N-terminal of rat Her2/neu led to tumor progression. Our result proposes
that fusion direction of biologic adjuvant is an important consideration when Her2/neu is used. 相似文献