全文获取类型
收费全文 | 5406篇 |
免费 | 362篇 |
出版年
2023年 | 18篇 |
2022年 | 62篇 |
2021年 | 100篇 |
2020年 | 45篇 |
2019年 | 81篇 |
2018年 | 120篇 |
2017年 | 95篇 |
2016年 | 157篇 |
2015年 | 223篇 |
2014年 | 279篇 |
2013年 | 413篇 |
2012年 | 456篇 |
2011年 | 450篇 |
2010年 | 281篇 |
2009年 | 205篇 |
2008年 | 343篇 |
2007年 | 343篇 |
2006年 | 326篇 |
2005年 | 325篇 |
2004年 | 286篇 |
2003年 | 231篇 |
2002年 | 249篇 |
2001年 | 55篇 |
2000年 | 51篇 |
1999年 | 55篇 |
1998年 | 52篇 |
1997年 | 37篇 |
1996年 | 44篇 |
1995年 | 39篇 |
1994年 | 32篇 |
1993年 | 42篇 |
1992年 | 29篇 |
1991年 | 16篇 |
1990年 | 18篇 |
1989年 | 18篇 |
1988年 | 16篇 |
1987年 | 20篇 |
1986年 | 16篇 |
1985年 | 15篇 |
1984年 | 21篇 |
1983年 | 14篇 |
1982年 | 6篇 |
1981年 | 15篇 |
1980年 | 9篇 |
1979年 | 7篇 |
1978年 | 6篇 |
1977年 | 7篇 |
1975年 | 6篇 |
1973年 | 5篇 |
1971年 | 10篇 |
排序方式: 共有5768条查询结果,搜索用时 15 毫秒
171.
172.
Maria Paola Giovannoni Igor A. Schepetkin Letizia Crocetti Giovanna Ciciani Agostino Cilibrizzi Gabriella Guerrini 《Journal of enzyme inhibition and medicinal chemistry》2016,31(4):628-639
Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value?=?56?nM) and chemical stability (t1/2?=?114?min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195. 相似文献
173.
Marie-Pierre Piccinni Letizia Lombardelli Federica Logiodice Ornela Kullolli Paola Parronchi Sergio Romagnani 《Clinical and molecular allergy : CMA》2016,14(1):11
Autoimmune disorders are characterized by tissue damage, caused by self-reactivity of different effectors mechanisms of the immune system, namely antibodies and T cells. Their occurrence may be associated with genetic and/or environmental predisposition and to some extent, have implications for fertility and obstetrics. The relationship between autoimmunity and reproduction is bidirectional. This review only addresses the impact of pregnancy on autoimmune diseases and not the influence of autoimmunity on pregnancy development. Th17/Th1-type cells are aggressive and pathogenic in many autoimmune disorders and inflammatory diseases. The immunology of pregnancy underlies the role of Th2-type cytokines to maintain the tolerance of the mother towards the fetal semi-allograft. Non-specific factors, including hormonal changes, favor a switch to Th2-type cytokine profile. In pregnancy Th2, Th17/Th2 and Treg cells accumulate in the decidua but may also be present in the mother’s circulation and can regulate autoimmune responses influencing the progression of autoimmune diseases. 相似文献
174.
Ketaki Ganti Paola Massimi Joaquin Manzo-Merino Vjekoslav Tomai? David Pim Martin P. Playford Marcela Lizano Sally Roberts Christian Kranjec John Doorbar Lawrence Banks 《PLoS pathogens》2016,12(9)
A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells. 相似文献
175.
Intense Chiral Optical Phenomena in Racemic Polymers by Cocrystallization With Chiral Guest Molecules: A Brief Overview 下载免费PDF全文
This review is devoted to the chiral optical behavior of films of racemic polymers whose chirality is induced by cocrystallization with nonracemic (also temporary) guest molecules. We provide examples of macromolecular amplification of chirality, produced by molecular and supramolecular mechanisms, on industrially relevant polymers like poly(2,6‐dimethyl‐1,4‐phenylene)oxide (PPO) and syndiotactic polystyrene (s‐PS). Chirality 28:29–38, 2016. © 2015 Wiley Periodicals, Inc. 相似文献
176.
Absolute Configuration Assignment of a Paraconic Acid Derivative via Vibrational Circular Dichroism Spectroscopy and Density Functional Theory Calculation 下载免费PDF全文
Sara Meninno Paola Rizzo Sergio Abbate Giovanna Longhi Giuseppe Mazzeo Guglielmo Monaco Alessandra Lattanzi Riccardo Zanasi 《Chirality》2016,28(2):110-115
Density functional theory calculation of the vibrational circular dichroism spectrum was used to assign the absolute configuration of an all‐carbon quaternary β‐stereocenter of a γ‐butyrolactone recently synthesized through an asymmetric organocatalytic tandem aldol/lactonization sequence. Comparison with the experimental spectrum is satisfactory, on account of the fact that spectroscopic features are weak due to the presence of multiple conformers. As a result, the (R) absolute configuration was assigned to the (+) optical isomer. Chirality 28:110–115, 2016. © 2015 Wiley Periodicals, Inc. 相似文献
177.
Water and carbon storage capacity in Isolatocereus dumortieri (Cactaceae) in an intertropical semiarid zone in Mexico 下载免费PDF全文
Numa P. Pavón Christian O. Ayala Ana Paola Martínez‐Falcón 《Plant Species Biology》2016,31(3):240-243
In the biosphere reserve Barranca de Metztitlán in Mexico, there is an extensive area with a semiarid scrub. The dominant species is the cactus Isolatocereus dumortieri. This is a key species in the ecosystem, because many species of birds, bats and insects are feeding from its nectar, pollen and fruits during the dry season thanks to their capacity to store water and carbon. However, there is no information about their potential to store water and carbon. The purpose of this study was to estimate the ability of I. dumortieri to store water and carbon. Water content per plant was estimated as 537.64 ± 71.59 L during the dry season and 692.24 ± 92.18 L during the wet season. In the same way the carbon stored per cactus was 16.75 kg ± 7.07 corresponding to 1.25 kg C m2. The results shows the importance of I. dumortieri in maintaining the ecosystem services of the scrub vegetation. 相似文献
178.
Paola A. Villanueva 《Marine and Freshwater Behaviour and Physiology》2016,49(4):291-300
We studied toxic effects of the dinoflagellate Alexandrium catenella on filtration activity and pre-ingestive selection efficiency in Tagelus dombeii (razor clam). Samples came from two populations with different histories of exposure to paralytic shellfish poisoning (PSP): Melinka, Aysén (with frequent exposure to PSP) and Corral, Valdivia (without previous exposure to PSP). Feeding activity of T. dombeii was affected by a diet containing A. catenella, showing a reduction in individuals from Corral, Valdivia and Melinka, Aysén. Furthermore, pre-ingestive selection efficiency was significantly higher in specimens from the population of Melinka, than those from Corral. Significantly higher values of clearance rate and pre-ingestive selection efficiency from the Melinka samples may reflect adaptation to specific environmental conditions where PSP events frequently occur. 相似文献
179.
Massimo Dal Monte Maurizio Cammalleri Valeria Pecci Monica Carmosino Giuseppe Procino Alessandro Pini Mario De Rosa Vincenzo Pavone Maria Svelto Paola Bagnoli 《Journal of cellular and molecular medicine》2019,23(2):1034-1049
The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches. 相似文献
180.
Maria Assunta Piano Lisa Gianesello Angela Grassi Paola Del Bianco Adriana Mattiolo Anna Maria Cattelan Lolita Sasset Paola Zanovello Maria Luisa Calabr 《Journal of cellular and molecular medicine》2019,23(2):1486-1494
The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as biomarkers in patients at risk for or affected by AIDS‐Kaposi's sarcoma (KS). Screening of 377 miRNAs was performed using low‐density arrays in pooled plasma samples of 10 HIV/human herpesvirus 8 (HHV8)‐infected asymptomatic and 10 AIDS‐KS patients before and after successful combined antiretroviral therapy (cART). MiR‐375 was identified as a potential marker of active KS, being the most down‐regulated in AIDS‐KS patients after cART and the most up‐regulated in naïve AIDS‐KS patients compared to naïve asymptomatic subjects. Validation on individual plasma samples confirmed that miR‐375 levels were higher in AIDS‐KS compared to asymptomatic patients, decreased after cART‐induced remission in most AIDS‐KS patients and increased in patients with active KS. In asymptomatic patients miR‐375 was up‐regulated after cART in both screening and validation. Statistical analyses revealed an association between miR‐375 changes and CD4 cell counts, which could explain the discordant cases and the opposite trend between asymptomatic and AIDS‐KS patients. These data suggest that circulating miR‐375 might be a good indicator of active AIDS‐KS. Moreover, changes in miR‐375 levels may have a prognostic value in HIV/HHV8‐infected patients undergoing treatment. Further large‐scale validation is needed. 相似文献