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61.
62.
《Bioscience, biotechnology, and biochemistry》2013,77(3):772-782
The yeast MAPKKK Ste11 activates three MAP kinase pathways, including pheromone signaling, osmosensing, and pseudohyphal/invasive growth pathways. We identified two chemical compounds, BTB03006 and GK03225, that suppress growth defects induced by Ste11 activation in diploid yeast cells. BTB03006, but not GK03225, was found to suppress growth defects induced by both α-factor and Ste4 Gβ overexpression in the pheromone signaling pathway, suggesting that GK03225 is an osmosensing pathway-specific inhibitor. We also performed genome-wide suppressor analysis for Ste11 activation, using a yeast deletion strains collection, and identified PBS2 and HOG1, and several genes associated with chaperone functions, which represent potential target proteins of the drugs screened from Ste11 activation. GK03225 possesses an Iressa-like quinazoline ring structure, and its chemical analog, 11N-078, suppresses c-Abl human tyrosine kinase activity. These results suggest that drug screening in yeast can identify human tyrosine kinase inhibitors and other drugs for human diseases. 相似文献
63.
64.
《Molecular membrane biology》2013,30(2):217-227
AbstractThe increasing number of multidrug-resistant pathogenic microorganisms is a serious public health issue. Among the multitude of mechanisms that lead to multidrug resistance, the active extrusion of toxic compounds, mediated by MDR efflux pumps, plays an important role. In our study we analyzed the inhibitory capability of 26 synthesized zosuquidar derivatives on three ABC-type MDR efflux pumps, namely Saccharomyces cerevisiae Pdr5 as well as Lactococcus lactis LmrA and LmrCD. For Pdr5, five compounds could be identified that inhibited rhodamine 6G transport more efficiently than zosuquidar. One of these is a compound with a new catechol acetal structure that might represent a new lead compound. Furthermore, the determination of IC50 values for rhodamine 6G transport of Pdr5 with representative compounds reveals values between 0.3 and 0.9 μM. Thus the identified compounds are among the most potent inhibitors known for Pdr5. For the ABC-type efflux pumps LmrA and LmrCD from L. lactis, seven and three compounds, which inhibit the transport activity more than the lead compound zosuquidar, were found. Interestingly, transport inhibition for LmrCD was very specific, with a drastic reduction by one compound while its diastereomers showed hardly an effect. Thus, the present study reveals new potent inhibitors for the ABC-type MDR efflux pumps studied with the inhibitors of Pdr5 and LmrCD being of particular interest as these proteins are well known model systems for their homologs in pathogenic fungi and Gram-positive bacteria. 相似文献
65.
Yusuf Oloruntoyin AYIPO Sani Najib YAHAYA Halimah Funmilayo BABAMALE Iqrar AHMAD Harun PATEL Mohd Nizam MORDI 《Turkish Journal of Biology》2021,45(4):503
The nsp3 macrodomain is implicated in the viral replication, pathogenesis and host immune responses through the removal of ADP-ribosylation sites during infections of coronaviruses including the SARS-CoV-2. It has ever been modulated by macromolecules including the ADP-ribose until Ni and co-workers recently reported its inhibition and plasticity enhancement unprecedentedly by remdesivir metabolite, GS-441524, creating an opportunity for investigating other biodiverse small molecules such as β-Carboline (βC) alkaloids. In this study, 1497 βC analogues from the HiT2LEAD chemical database were screened, using computational approaches of Glide XP docking, molecular dynamics simulation and pk-CSM ADMET predictions. Selectively, βC ligands, 129, 584, 1303 and 1323 demonstrated higher binding affinities to the receptor, indicated by XP docking scores of –10.72, –10.01, –9.63 and –9.48 kcal/mol respectively than remdesivir and GS-441524 with –4.68 and –9.41 kcal/mol respectively. Consistently, their binding free energies were –36.07, –23.77, –24.07 and –17.76 kcal/mol respectively, while remdesivir and GS-441524 showed –21.22 and –24.20 kcal/mol respectively. Interestingly, the selected βC ligands displayed better stability and flexibility for enhancing the plasticity of the receptor than GS-441524, especially 129 and 1303. Their predicted ADMET parameters favour druggability and low expressions for toxicity. Thus, they are recommended as promising adjuvant/standalone anti-SARS-CoV-2 candidates for further study.Key words: SARS-CoV-2, nsp3 macrodomain, ADP-ribose, β-carboline, bioinformatics, drug design 相似文献
66.
Lingling Wang Lujing Wu Zhouting Zhu Qiong Zhang Wanyu Li Gwendolyn Michelle Gonzalez Yinsheng Wang Tariq M Rana 《The EMBO journal》2023,42(2)
Adenosine N6‐methylation (m6A) and N6,2′‐O‐dimethylation (m6Am) are regulatory modifications of eukaryotic mRNAs. m6Am formation is catalyzed by the methyl transferase phosphorylated CTD‐interacting factor 1 (PCIF1); however, the pathophysiological functions of this RNA modification and PCIF1 in cancers are unclear. Here, we show that PCIF1 expression is upregulated in colorectal cancer (CRC) and negatively correlates with patient survival. CRISPR/Cas9‐mediated depletion of PCIF1 in human CRC cells leads to loss of cell migration, invasion, and colony formation in vitro and loss of tumor growth in athymic mice. Pcif1 knockout in murine CRC cells inhibits tumor growth in immunocompetent mice and enhances the effects of anti‐PD‐1 antibody treatment by decreasing intratumoral TGF‐β levels and increasing intratumoral IFN‐γ, TNF‐α levels, and tumor‐infiltrating natural killer cells. We further show that PCIF1 modulates CRC growth and response to anti‐PD‐1 in a context‐dependent mechanism with PCIF1 directly targeting FOS, IFITM3, and STAT1 via m6Am modifications. PCIF1 stabilizes FOS mRNA, which in turn leads to FOS‐dependent TGF‐β regulation and tumor growth. While during immunotherapy, Pcif1‐Fos‐TGF‐β, as well as Pcif1‐Stat1/Ifitm3‐IFN‐γ axes, contributes to the resistance of anti‐PD‐1 therapy. Collectively, our findings reveal a role of PCIF1 in promoting CRC tumorigenesis and resistance to anti‐PD‐1 therapy, supporting that the combination of PCIF1 inhibition with anti‐PD‐1 treatment is a potential therapeutic strategy to enhance CRC response to immunotherapy. Finally, we developed a lipid nanoparticles (LNPs) and chemically modified small interfering RNAs (CMsiRNAs)‐based strategy to silence PCIF1 in vivo and found that this treatment significantly reduced tumor growth in mice. Our results therefore provide a proof‐of‐concept for tumor growth suppression using LNP‐CMsiRNA to silence target genes in cancer. 相似文献
67.
王佃亮 《中国生物工程杂志》2017,37(2):127-132
细胞药物具有自身特点和优势,对肿瘤、自身免疫性疾病等疑难病症具有较好疗效,起到了其他药物难以发挥的作用。但细胞药物在研发过程中,也存在伦理、安全等问题。针对这些问题,提出了一些解决策略,并介绍了细胞药物最新临床研发情况,对其广阔的发展前景进行了展望。 相似文献
68.
可持续的污水处理过程与展望 总被引:3,自引:0,他引:3
传统上,污水在处理过程中其所含有的能源和营养物质等也被消耗了。可持续的水处理不仅包括污水无害化处理,还包括能源和营养物的综合回收利用。综合论述了可持续的污水处理概念、理论、方法和污水处理过程中物质回收技术的发展。 相似文献
69.
观察神经梅毒的临床特点,以提高对神经梅毒的诊断与治疗水平。回顾性分析哈尔滨医科大学附属第一医院2005年1月至2010年12月收治的23例神经梅毒患者的临床资料。神经梅毒患者男17例(73.9%),女6例(26.1%),男女比约为2.8∶1;年龄27~71岁,平均年龄43.1岁。本组首发症状:麻痹性痴呆(7例)、精神异常(3例)、急性脑梗死(3例)、癫痫(2例)、脊髓病变(2例)、颅高压(2例)、周围神经损害(2例)、脑神经损害(1例)、无症状性神经梅毒(1例)。23例患者血清及脑脊液快速血浆反应素实验及梅毒螺旋体血凝试验均呈阳性反应。颅脑电子计算机断层扫描(CT)和/或磁共振成像(MRI)检查多表现为额叶、顶叶、颞叶、基底节等多发病变。本组患者经大剂量青霉素治疗后病情有显著改善20例,死亡1例,自动出院2例。神经梅毒的临床表现复杂多样,神经系统各部位均可受累,诊断依靠病史及临床表现、实验室血清及脑脊液梅毒抗体检测,误诊率高,应早期诊断,诊断后应进行规范治疗,早期治疗效果较好。 相似文献
70.
Treatment of Biogas Produced in Anaerobic Reactors for Domestic Wastewater: Odor Control and Energy/Resource Recovery 总被引:1,自引:0,他引:1
Adalberto Noyola Juan Manuel Morgan-Sagastume Jorge E. López-Hernández 《Reviews in Environmental Science and Biotechnology》2006,5(1):93-114
Anaerobic municipal wastewater treatment in developing countries has important potential applications considering their huge
lack of sanitation infrastructure and their advantageous climatic conditions. At present, among the obstacles that this technology
encounters, odor control and biogas utilization or disposal should be properly addressed. In fact, in most of small and medium
size anaerobic municipal treatment plants, biogas is just vented, transferring pollution from water to the atmosphere, contributing
to the greenhouse gas inventory. Anaerobic municipal sewage treatment should not be considered as an energy producer, unless
a significant wastewater flow is treated. In these cases, more than half of the methane produced is dissolved and lost in
the effluent so yield values will be between 0.08 and 0.18 N m3 CH4/kg COD removed. Diverse technologies for odor control and biogas cleaning are currently available. High pollutant concentrations
may be treated with physical-chemical methods, while biological processes are used mainly for odor control to prevent negative
impacts on the treatment facilities or nearby areas. In general terms, biogas treatment is accomplished by physico-chemical
methods, scrubbing being extensively used for H2S and CO2 removal. However, dilution (venting) has been an extensive disposal method in some small- and medium-size anaerobic plants
treating municipal wastewaters. Simple technologies, such as biofilters, should be developed in order to avoid this practice,
matching with the simplicity of anaerobic wastewater treatment processes. In any case, design and specification of biogas
handling system should consider safety standards. Resource recovery can be added to anaerobic sewage treatment if methane
is used as electron donor for denitrification and nitrogen control purposes. This would result in a reduction of operational
cost and in an additional advantage for the application of anaerobic sewage treatment. In developing countries, biogas conversion
to energy may apply for the clean development mechanism (CDM) of the Kyoto Protocol. This would increase the economic feasibility
of the project through the marketing of certified emission reductions (CERs). 相似文献