全文获取类型
收费全文 | 277篇 |
免费 | 38篇 |
专业分类
315篇 |
出版年
2022年 | 2篇 |
2021年 | 6篇 |
2020年 | 4篇 |
2018年 | 6篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 7篇 |
2014年 | 9篇 |
2013年 | 19篇 |
2012年 | 20篇 |
2011年 | 20篇 |
2010年 | 13篇 |
2009年 | 12篇 |
2008年 | 18篇 |
2007年 | 33篇 |
2006年 | 17篇 |
2005年 | 13篇 |
2004年 | 17篇 |
2003年 | 5篇 |
2002年 | 11篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 5篇 |
1997年 | 4篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1972年 | 4篇 |
1971年 | 2篇 |
1968年 | 5篇 |
1966年 | 1篇 |
1964年 | 2篇 |
1963年 | 1篇 |
1962年 | 1篇 |
1950年 | 1篇 |
1918年 | 1篇 |
排序方式: 共有315条查询结果,搜索用时 0 毫秒
151.
Dzierba CD Sielecki TM Arvanitis AG Galka A Johnson TL Takvorian AG Rafalski M Kasireddy-Polam P Vig S Dasgupta B Zhang G Molski TF Wong H Zaczek RC Lodge NJ Combs AP Gilligan PJ Trainor GL Bronson JJ Macor JE 《Bioorganic & medicinal chemistry letters》2012,22(15):4986-4989
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein. 相似文献
152.
Jeffrey A. Deskus Douglas D. Dischino Ronald J. Mattson Jonathan L. Ditta Michael F. Parker Derek J. Denhart Dmitry Zuev Hong Huang Richard A. Hartz Vijay T. Ahuja Henry Wong Gail K. Mattson Thaddeus F. Molski James E. Grace Larisa Zueva Julia M. Nielsen Heidi Dulac Yu-Wen Li Mary Guaraldi Michael Azure John E. Macor 《Bioorganic & medicinal chemistry letters》2012,22(21):6651-6655
Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [18F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments. 相似文献
153.
Yuneva MO Fan TW Allen TD Higashi RM Ferraris DV Tsukamoto T Matés JM Alonso FJ Wang C Seo Y Chen X Bishop JM 《Cell metabolism》2012,15(2):157-170
Highlights? MYC and MET affect glucose and glutamine metabolism differently in the liver ? Tissue context affects the outcome of metabolic reprogramming by MYC ? MYC overexpression sensitizes cells to inhibition of Gls1 glutaminase 相似文献
154.
Kelley EE Batthyany CI Hundley NJ Woodcock SR Bonacci G Del Rio JM Schopfer FJ Lancaster JR Freeman BA Tarpey MM 《The Journal of biological chemistry》2008,283(52):36176-36184
Xanthine oxidoreductase (XOR) generates proinflammatory oxidants and secondary nitrating species, with inhibition of XOR proving beneficial in a variety of disorders. Electrophilic nitrated fatty acid derivatives, such as nitro-oleic acid (OA-NO2), display anti-inflammatory effects with pleiotropic properties. Nitro-oleic acid inhibits XOR activity in a concentration-dependent manner with an IC50 of 0.6 microM, limiting both purine oxidation and formation of superoxide (O2.). Enzyme inhibition by OA-NO2 is not reversed by thiol reagents, including glutathione, beta-mercaptoethanol, and dithiothreitol. Structure-function studies indicate that the carboxylic acid moiety, nitration at the 9 or 10 olefinic carbon, and unsaturation is required for XOR inhibition. Enzyme turnover and competitive reactivation studies reveal inhibition of electron transfer reactions at the molybdenum cofactor accounts for OA-NO2-induced inhibition. Importantly, OA-NO2 more potently inhibits cell-associated XOR-dependent O2. production than does allopurinol. Combined, these data establish a novel role for OA-NO2 in the inhibition of XOR-derived oxidant formation. 相似文献
155.
Molinari F Foulquier F Tarpey PS Morelle W Boissel S Teague J Edkins S Futreal PA Stratton MR Turner G Matthijs G Gecz J Munnich A Colleaux L 《American journal of human genetics》2008,82(5):1150-1157
Mental retardation (MR) is the most frequent handicap among children and young adults. Although a large proportion of X-linked MR genes have been identified, only four genes responsible for autosomal-recessive nonsyndromic MR (AR-NSMR) have been described so far. Here, we report on two genes involved in autosomal-recessive and X-linked NSMR. First, autozygosity mapping in two sibs born to first-cousin French parents led to the identification of a region on 8p22-p23.1. This interval encompasses the gene N33/TUSC3 encoding one subunit of the oligosaccharyltransferase (OTase) complex, which catalyzes the transfer of an oligosaccharide chain on nascent proteins, the key step of N-glycosylation. Sequencing N33/TUSC3 identified a 1 bp insertion, c.787_788insC, resulting in a premature stop codon, p.N263fsX300, and leading to mRNA decay. Surprisingly, glycosylation analyses of patient fibroblasts showed normal N-glycan synthesis and transfer, suggesting that normal N-glycosylation observed in patient fibroblasts may be due to functional compensation. Subsequently, screening of the X-linked N33/TUSC3 paralog, the IAP gene, identified a missense mutation (c.932T-->G, p.V311G) in a family with X-linked NSMR. Recent studies of fucosylation and polysialic-acid modification of neuronal cell-adhesion glycoproteins have shown the critical role of glycosylation in synaptic plasticity. However, our data provide the first demonstration that a defect in N-glycosylation can result in NSMR. Together, our results demonstrate that fine regulation of OTase activity is essential for normal cognitive-function development, providing therefore further insights to understand the pathophysiological bases of MR. 相似文献
156.
Non-specific responses to treatment (commonly known as placebo response) are pervasive when treating mental illness. Subjects treated with an active drug may respond in part due to non-specific aspects of the treatment, i.e, those not related to the chemical effect of the drug. To determine the extent a subject responds due to the chemical effect of a drug, one must disentangle the specific drug effect from the non-specific placebo effect. This paper presents a unique statistical model that allows for the separate prediction of a specific effect and non-specific effects in drug treated subjects. Data from a clinical trial comparing fluoxetine to a placebo for treating depression is used to illustrate this methodology. 相似文献
157.
Marc C. Levesque M. Anthony Moody Kwan-Ki Hwang Dawn J. Marshall John F. Whitesides Joshua D. Amos Thaddeus C. Gurley Sallie Allgood Benjamin B. Haynes Nathan A. Vandergrift Steven Plonk Daniel C. Parker Myron S. Cohen Georgia D. Tomaras Paul A. Goepfert George M. Shaw J?rn E. Schmitz Joseph J. Eron Nicholas J. Shaheen Charles B. Hicks Hua-Xin Liao Martin Markowitz Garnett Kelsoe David M. Margolis Barton F. Haynes 《PLoS medicine》2009,6(7)
Background
The antibody response to HIV-1 does not appear in the plasma until approximately 2–5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1–specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4+ T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells.Methods and Findings
In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1–specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1–induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer''s patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis.Conclusions
Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1–induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors'' Summary 相似文献158.
Background
The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn''s disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn''s disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn''s disease.Methods and Findings
We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics.Conclusions
Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease. 相似文献159.
Composition of corn dry-grind ethanol by-products: DDGS, wet cake, and thin stillage 总被引:2,自引:1,他引:1
Kim Y Mosier NS Hendrickson R Ezeji T Blaschek H Dien B Cotta M Dale B Ladisch MR 《Bioresource technology》2008,99(12):5165-5176
DDGS and wet distillers' grains are the major co-products of the dry grind ethanol facilities. As they are mainly used as animal feed, a typical compositional analysis of the DDGS and wet distillers' grains mainly focuses on defining the feedstock's nutritional characteristics. With an increasing demand for fuel ethanol, the DDGS and wet distillers' grains are viewed as a potential bridge feedstock for ethanol production from other cellulosic biomass. The introduction of DDGS or wet distillers' grains as an additional feed to the existing dry grind plants for increased ethanol yield requires a different approach to the compositional analysis of the material. Rather than focusing on its nutritional value, this new approach aims at determining more detailed chemical composition, especially on polymeric sugars such as cellulose, starch and xylan, which release fermentable sugars upon enzymatic hydrolysis. In this paper we present a detailed and complete compositional analysis procedure suggested for DDGS and wet distillers' grains, as well as the resulting compositions completed by three different research groups. Polymeric sugars, crude protein, crude oil and ash contents of DDGS and wet distillers' grains were accurately and reproducibly determined by the compositional analysis procedure described in this paper. 相似文献
160.