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991.
Tomoyuki Ohe Ryutaro Umezawa Yumina Kitagawara Daisuke Yasuda Kyoko Takahashi Shigeo Nakamura Akiko Abe Shuichi Sekine Kousei Ito Kentaro Okunushi Hanae Morio Tomomi Furihata Naohiko Anzai Tadahiko Mashino 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3708-3711
We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR. 相似文献
992.
Yaping Huang Geng Sun Pengfei Wang Rui Shi Yanchun Zhang Xiaoan Wen Hongbin Sun Caiping Chen 《Bioorganic & medicinal chemistry letters》2018,28(17):2957-2960
In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50?=?5.2?±?0.9?μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50?=?2.8?±?0.4?μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I. 相似文献
993.
Teppei Ikeya David Ban Donghan Lee Yutaka Ito Koichi Kato Christian Griesinger 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(2):287-306
Background
To understand the mechanisms related to the ‘dynamical ordering’ of macromolecules and biological systems, it is crucial to monitor, in detail, molecular interactions and their dynamics across multiple timescales. Solution nuclear magnetic resonance (NMR) spectroscopy is an ideal tool that can investigate biophysical events at the atomic level, in near-physiological buffer solutions, or even inside cells.Scope of review
In the past several decades, progress in solution NMR has significantly contributed to the elucidation of three-dimensional structures, the understanding of conformational motions, and the underlying thermodynamic and kinetic properties of biomacromolecules. This review discusses recent methodological development of NMR, their applications and some of the remaining challenges.Major conclusions
Although a major drawback of NMR is its difficulty in studying the dynamical ordering of larger biomolecular systems, current technologies have achieved considerable success in the structural analysis of substantially large proteins and biomolecular complexes over 1 MDa and have characterised a wide range of timescales across which biomolecular motion exists. While NMR is well suited to obtain local structure information in detail, it contributes valuable and unique information within hybrid approaches that combine complementary methodologies, including solution scattering and microscopic techniques.General significance
For living systems, the dynamic assembly and disassembly of macromolecular complexes is of utmost importance for cellular homeostasis and, if dysregulated, implied in human disease. It is thus instructive for the advancement of the study of the dynamical ordering to discuss the potential possibilities of solution NMR spectroscopy and its applications. This article is part of a Special Issue entitled “Biophysical Exploration of Dynamical Ordering of Biomolecular Systems” edited by Dr. Koichi Kato. 相似文献994.
Lin Wang Ziru Yu Shuyue Ren Junke Song Jinhua Wang Guanhua Du 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(10):2281-2292
Background
Metabolic reprogramming and hypoxia contribute to the resistance of conventional chemotherapeutic drugs in kinds of cancers. In this study, we investigated the effect of dihydrotanshinone I (DHTS) on reversing dysregulated metabolism of glucose and fatty acid in colon cancer and elucidated its mechanism of action.Methods
Cell viability was determined by MTT assay. Oxidative phosphorylation, glycolysis, and mitochondrial fuel oxidation were assessed by Mito stress test, glycolysis stress test, and mito fuel flex test, respectively. Anti-cancer activity of DHTS in vivo was evaluated in Colon cancer xenograft. Hexokinase activity and free fatty acid (FFA) content were assessed using respective Commercial kits. Gene expression patterns were determined by performing DNA microarray analysis and real-time PCR. Protein expression was assessed using immunoblotting and immunohistochemistry.Results
DHTS showed similar cytotoxicity against colon cancer cells under hypoxia and normoxia. DHTS decreased the efficiency of glucose and FA as mitochondrial fuels in HCT116 cells, which efficiently reversed by VO-OHpic trihydrate. DHTS reduced hexokinase activity and free fatty acid (FFA) content in tumor tissue of xenograft model of colon cancer. Gene expression patterns in metabolic pathways were dramatically differential between model and treatment group. Increases in PTEN and a substantial decrease in the expression of SIRT3, HIF1α, p-AKT, HKII, p-MTOR, RHEB, and p-ACC were detected.Conclusions
DHTS reversed metabolic reprogramming in colon cancer through PTEN/AKT/HIF1α-mediated signal pathway.General significance
The study is the first to report the reverse of metabolic reprogramming by DHTS in colon cancer. Meantime, SIRT3/PTEN/AKT/HIF1α mediated signal pathway plays a critical role during this process. 相似文献995.
996.
Hauke Ward Leonie Wenz Jan C. Steckel Jan C. Minx 《Journal of Industrial Ecology》2018,22(5):1080-1091
Process life cycle assessment (PLCA) is widely used to quantify environmental flows associated with the manufacturing of products and other processes. As PLCA always depends on defining a system boundary, its application involves truncation errors. Different methods of estimating truncation errors are proposed in the literature; most of these are based on artificially constructed system complete counterfactuals. In this article, we review the literature on truncation errors and their estimates and systematically explore factors that influence truncation error estimates. We classify estimation approaches, together with underlying factors influencing estimation results according to where in the estimation procedure they occur. By contrasting different PLCA truncation/error modeling frameworks using the same underlying input‐output (I‐O) data set and varying cut‐off criteria, we show that modeling choices can significantly influence estimates for PLCA truncation errors. In addition, we find that differences in I‐O and process inventory databases, such as missing service sector activities, can significantly affect estimates of PLCA truncation errors. Our results expose the challenges related to explicit statements on the magnitude of PLCA truncation errors. They also indicate that increasing the strictness of cut‐off criteria in PLCA has only limited influence on the resulting truncation errors. We conclude that applying an additional I‐O life cycle assessment or a path exchange hybrid life cycle assessment to identify where significant contributions are located in upstream layers could significantly reduce PLCA truncation errors. 相似文献
997.
Joanna Kamińska Olga M. Koper Edyta Siedlecka-Czykier Joanna Matowicka-Karna Jerzy Bychowski Halina Kemona 《Saudi Journal of Biological Sciences》2018,25(7):1263-1271
Introduction
Thrombotic and inflammatory mechanisms are involved in the pathophysiology of acute coronary syndrome (ACS). The aim of the study was the evaluation of inflammation (white blood cells count/WBC, C-reactive protein/CRP, interleukin-6/IL-6) and platelet (platelet count/PLT, mean platelet volume/MPV, large platelet/LPLT, beta-thromboglobulin/β-TG) biomarkers in the groups of ACS patients depending on the severity of signs and symptoms and compared to controls without coronary artery disease.Materials and methods
The study group included 93 patients categorized into 3 subgroups depending on the severity of signs and symptoms of ACS. PLT, MPV, LPLT, and WBC were determined on hematological analyzer, IL-6 and β-TG were measured using the ELISA method.Results
In the whole group of ACS patients WBC, CRP, IL-6, MPV, and β-TG were significantly higher as compared to controls. Analyzing the inflammation and platelet biomarkers depending on the severity of signs and symptoms in comparison to controls, statistically significant differences for above-mentioned parameters were also found. There were no significant differences between the advancement of coronary artery changes and inflammation as well as platelet parameters, except for CRP concentrations. The AUCs for all inflammation parameters tested were similar, however the highest AUCs showed WBC and CRP. Among platelet parameters the highest AUC revealed β-TG.Conclusion
Markers of inflammation and platelet activation may be associated to myocardial ischemia and myocardial injury. WBC, CRP and IL-6 as inflammation parameters and MPV and β-TG as platelet biomarkers may be useful indicators of the presence of coronary artery disease. 相似文献998.
Dengyuan Zhou Fan Jia Qiuyan Li Luping Zhang Zheng Chen Zikai Zhao Min Cui Yunfeng Song Huanchun Chen Shengbo Cao Jing Ye 《中国病毒学》2018,33(6):515-523
Japanese encephalitis virus(JEV) is a mosquito-borne virus and the major cause of viral encephalitis in Asia. NS1', a52-amino acid C-terminal extension of NS1, is generated with a-1 programmed ribosomal frameshift and is only present in members of the Japanese encephalitis serogroup of flaviviruses. Previous studies demonstrated that NS1' plays a vital role in virulence, but the mechanism is unclear. In this study, an NS1' defected(rG66A) virus was generated. We found that rG66A virus was less virulent than its parent virus(pSA14) in wild-type mice. However, similar mortality caused by the two viruses was observed in an IFNAR knockout mouse model. Moreover, we found that rG66A virus induced a greater type Ⅰ interferon(IFN) response than that by pSA14, and JEV NS1' significantly inhibited the production of IFN-b and IFN-stimulated genes. Taken together, our results reveal that NS1' plays a vital role in blocking type I IFN production to help JEV evade antiviral immunity and benefit viral replication. 相似文献
999.
J.I. Rodriguez-Barbosa M.C. Ferreras L. Buhler N.D. Jones P. Schneider J.A. Perez-Simon 《MABS-AUSTIN》2018,10(7):1030-1044
Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were implicated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting properties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic alloresponses refractory to current immunosuppression. 相似文献
1000.
Distinct hypoxic regulation of preadipocyte factor-1 (Pref-1) in preadipocytes and mature adipocytes
Yunwon Moon Seongyeol Lee Bongju Park Hyunsung Park 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2018,1865(2):334-342
Preadipocyte factor-1 (Pref-1) is a secretory soluble protein, which exerts pleiotropic effects on maintenance of cancer stem cell characteristics and commitment of mesenchymal stem cell lineages by inhibiting adipogenesis. Observations that obesity renders the microenvironment of adipose tissues hypoxic and that hypoxia inhibits adipogenesis lead us to investigate whether hypoxia increases the expression of anti-adipogenic Pref-1 in preadipocytes, mature adipocytes, and adipose tissues from obese mouse. In 3T3-L1 preadipocytes, hypoxia induces Pref-1 by a hypoxia-inducible factor 1 (HIF-1)-dependent mechanism accompanied by increase in the levels of the active histone mark, acetylated H3K9/14 (H3K9/14Ac). Adipogenesis increased the levels of the heterochromatin histone mark, trimethylated H3K27 (H3K27me3), whereas it decreased the levels of H3K4me3 and H3K9/14Ac euchromatin marks of the mouse Pref-1 promoter. However, differently from preadipocytes, in mature adipocytes hypoxia failed to reverse the repressive epigenetic changes of Pref-1 promoter and to increase its expression. Short term (8 weeks) high fat diet (HFD) increased HIF-1α protein in subcutaneous and epididymal adipose tissues, but did not increase Pref-1 expression. Unlike in 3T3-L1 preadipocytes, HIF-1α did not increase Pref-1 expression in adipose tissues in which mature adipocytes constitute the main population. Interestingly, long term (35 weeks) HFD increased Pref-1 in serum but not in obese adipose tissues. This study suggests that Pref-1 is an endocrine factor which is synergistically increased by obesity and age. 相似文献