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排序方式: 共有1961条查询结果,搜索用时 234 毫秒
91.
Debnath Bhuniya Rajendra K. Kharul Atul Hajare Nadim Shaikh Sandeep Bhosale Sandip Balwe Fouzia Begum Siddhartha De Sonalee Athavankar Dhananjay Joshi Vamsi Madgula Kaushal Joshi Amol A. Raje Ashwinkumar V. Meru Amol Magdum Kasim A. Mookhtiar Rashmi Barbhaiya 《Bioorganic & medicinal chemistry letters》2019,29(2):238-243
Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (?)-12a, (?)-12i, (?)-12l–m. The required (?)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (?)-12l and (?)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3–30?mg/kg po for 7?days. The effects at 30?mg/kg are comparable to that of PF-04457845 (10?mg/kg) and Tramadol (40?mg/kg). 相似文献
92.
Shakiru O. Alapafuja Michael S. Malamas Vidyanand Shukla Alexander Zvonok Sally Miller Laura Daily Girija Rajarshi Christina Yume Miyabe Honrao Chandrashekhar JodiAnne Wood Sergiy Tyukhtenko Alex Straiker Alexandros Makriyannis 《Bioorganic & medicinal chemistry》2019,27(1):55-64
Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6?h. This interconversion process “intrinsic reversibility” was exploited by modifications of the ligand’s size (length and bulkiness) to generate analogs with “tunable’ adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ~4.5?mmHg in a sustained manner for at least 12?h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma. 相似文献
93.
94.
Shukla Geeta Sharma Anuj Bhatia Ruchika Sharma Mridul 《Probiotics and antimicrobial proteins》2019,11(1):165-174
Probiotics and Antimicrobial Proteins - Giardiasis is a re-emerging infectious disease with outbreaks reported globally specially in children and malnourished individuals leading to malabsorption,... 相似文献
95.
The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy. 相似文献
96.
97.
Pranjal Kumar Seema Khadirnaikar Sudhanshu Kumar Shukla 《Journal of cellular physiology》2019,234(9):16021-16031
The prognostic signatures play an essential role in the era of personalised therapy for cancer patients including lung adenocarcinoma (LUAD). Long noncoding RNA (LncRNA), a relatively novel class of RNA, has shown to play a crucial role in all the areas of cancer biology. Here, we developed and validated a robust LncRNA-based prognostic signature for LUAD patients using three different cohorts. In the discovery cohort, four LncRNAs were identified with 10% false discovery rate and a hazard ratio of >10 using univariate Cox regression analysis. A risk score, generated from the four LncRNAs’ expression, was found to be a significant predictor of survival in the discovery and validation cohort (p = 9.97 × 10 −8 and 1.41 × 10 −3, respectively). Further optimisation of four LncRNAs signature in the validation cohort, generated a three LncRNAs prognostic score (LPS), which was found to be an independent predictor of survival in both the cohorts ( p = 1.00 × 10 −6 and 7.27 × 10 −4, respectively). The LPS also significantly divided survival in clinically important subsets, including Stage I ( p = 9.00 × 10 −4 and 4.40 × 10 −2, respectively), KRAS wild-type (WT), KRAS mutant ( p = 4.00 × 10 −3 and 4.30 × 10 −2, respectively) and EGFR WT ( p = 2.00 × 10 −4). In multivariate analysis LPS outperformed, eight previous prognosticators. Further, individual members of LPS showed a significant correlation with survival in microarray data sets. Mutation analysis showed that high-LPS patients have a higher mutation rate and inactivation of the TP53 pathway. In summary, we identified and validated a novel LncRNA signature LPS for LUAD. 相似文献
98.
Chandra Dinesh Srivastava Rashmi Gupta Vadakattu V. S. R. Franco Christopher M. M. Paasricha Nishat Saifi Shabnam K. Tuteja Narendra Sharma Anil Kumar 《Plant and Soil》2019,441(1-2):261-281
Plant and Soil - Plant growth promoting bacteria (PGPB) containing 1-aminocyclopropane-1-carboxylate (ACC) deaminase can play an important role in abiotic stress tolerance in plants, particularly... 相似文献
99.
Shukla Pawan Reddy Ramesha A. Ponnuvel Kangayam M. Rohela Gulab Khan Shabnam Aftab A. Ghosh M. K. Mishra Rakesh Kumar 《Molecular biology reports》2019,46(2):1809-1817
Molecular Biology Reports - Mulberry (Morus alba L.) is the sole food source for the mulberry silkworm, Bombyx mori and therefore important for sericulture industry. Different abiotic stress... 相似文献
100.
Mishra Aradhana Singh Satyendra Pratap Mahfooz Sahil Shukla Richa Mishra Nishtha Pandey Shipra Dwivedi Sanjay Pandey Vivek Shirke Pramod Arvind Nautiyal Chandra Shekhar 《Plant Molecular Biology Reporter》2019,37(5-6):499-499
Plant Molecular Biology Reporter - The original version of this article unfortunately contained missing information at author’s affiliations. The affiliation address of the author’s... 相似文献