全文获取类型
收费全文 | 15792篇 |
免费 | 1258篇 |
国内免费 | 7篇 |
专业分类
17057篇 |
出版年
2024年 | 24篇 |
2023年 | 96篇 |
2022年 | 247篇 |
2021年 | 458篇 |
2020年 | 242篇 |
2019年 | 312篇 |
2018年 | 420篇 |
2017年 | 367篇 |
2016年 | 599篇 |
2015年 | 868篇 |
2014年 | 952篇 |
2013年 | 1119篇 |
2012年 | 1438篇 |
2011年 | 1427篇 |
2010年 | 886篇 |
2009年 | 683篇 |
2008年 | 1052篇 |
2007年 | 927篇 |
2006年 | 898篇 |
2005年 | 862篇 |
2004年 | 744篇 |
2003年 | 629篇 |
2002年 | 621篇 |
2001年 | 113篇 |
2000年 | 84篇 |
1999年 | 116篇 |
1998年 | 132篇 |
1997年 | 96篇 |
1996年 | 74篇 |
1995年 | 57篇 |
1994年 | 53篇 |
1993年 | 59篇 |
1992年 | 51篇 |
1991年 | 33篇 |
1990年 | 44篇 |
1989年 | 47篇 |
1988年 | 17篇 |
1987年 | 29篇 |
1986年 | 16篇 |
1985年 | 20篇 |
1984年 | 17篇 |
1983年 | 13篇 |
1982年 | 11篇 |
1981年 | 16篇 |
1980年 | 13篇 |
1979年 | 9篇 |
1978年 | 7篇 |
1977年 | 14篇 |
1976年 | 9篇 |
1975年 | 12篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
41.
Kiran Siwach Amit Kumar Harish Panchal Rajiv Kumar Jitender Kumar Bhardwaj Andrea Angeli Claudiu T. Supuran Pawan K. Sharma 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1454
In search of selective carbonic anhydrase (CA) IX inhibitors endowed with apoptotic inducing properties, we designed and synthesised two subsets of 4- and 3-(5-aryl-(4-phenylsulphonyl)-1H-1,2,3-triazol-1-yl)benzenesulphonamides. All compounds were assayed for human carbonic anhydrase (hCA) isoforms I, II, IV, and IX inhibition. Isoforms hCA I and hCA IV were weakly inhibited by most of the synthesised compounds. Many four-substituted benzenesulphonamides displayed low nanomolar inhibition against isoform hCA II, unlike the three-substituted analogues. All target compounds exhibited good inhibition profile with KI values ranging from 16.4 to 66.0 nM against tumour-associated isoform hCA IX. Some selective and potent inhibitors of hCA IX were assayed for in vitro apoptotic induction in goat testicular cells. Compounds 10d and 10h showed interesting apoptotic induction potential. The present study may provide insights into a strategy for the design of novel anticancer agents based on hCA inhibitors endowed with apoptotic interference. 相似文献
42.
Andrea Ameruoso Maria Claudia Villegas
Kcam Katherine
Piper Cohen James Chappell 《Nucleic acids research》2022,50(13):7751
The rise of antibiotic-resistant bacteria represents a major threat to global health, creating an urgent need to discover new antibiotics. Natural products derived from the genus Streptomyces represent a rich and diverse repertoire of chemical molecules from which new antibiotics are likely to be found. However, a major challenge is that the biosynthetic gene clusters (BGCs) responsible for natural product synthesis are often poorly expressed under laboratory culturing conditions, thus preventing the isolation and screening of novel chemicals. To address this, we describe a novel approach to activate silent BGCs through rewiring endogenous regulation using synthetic gene regulators based upon CRISPR-Cas. First, we refine CRISPR interference (CRISPRi) and create CRISPR activation (CRISPRa) systems that allow for highly programmable and effective gene repression and activation in Streptomyces. We then harness these tools to activate a silent BGC by perturbing its endogenous regulatory network. Together, this work advances the synthetic regulatory toolbox for Streptomyces and facilitates the programmable activation of silent BGCs for novel chemical discovery. 相似文献
43.
Giulio Poli Ivana Barravecchia Gian Carlo Demontis Andrea Sodi Alessandro Saba Stanislao Rizzo Marco Macchia Tiziano Tuccinardi 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1765
The human retinal pigment epithelium-specific 65-kDa protein (hRPE65) plays a crucial role within the retinoid visual cycle and several mutations affecting either its expression level or its enzymatic function are associated with inherited retinal diseases such as Retinitis Pigmentosa. The gene therapy product voretigene neparvovec (Luxturna) has been recently approved for treating hereditary retinal dystrophies; however, the treatment is currently accessible only to patients presenting confirmed biallelic mutations that severely impair hRPE65 function, and many reported hRPE65 missense mutations lack sufficient evidences for proving their pathogenicity. In this context, we developed a computational approach aimed at evaluating the potential pathogenic effect of hRPE65 missense variants located on the dimerisation domain of the protein. The protocol evaluates how mutations may affect folding and conformation stability of this protein region, potentially helping clinicians to evaluate the eligibility for gene therapy of patients diagnosed with this type of hRPE65 variant of uncertain significance. 相似文献
44.
Juan Morales-Magaa Ivonne Maciel Arciniega-Martínez Maria Elisa Drago-Serrano Aldo Arturo Resndiz-Albor Rosa Adriana Jarillo-Luna Andrea Cruz-Baquero Modesto Gmez-Lpez Fabiola Guzmn-Mejía Judith Pacheco-Ypez 《Current issues in molecular biology》2022,44(6):2542
Cholecystokinin 8 (CCK8) is an entero-octapeptide that participates in crosstalk with components of intestinal immunity via the CCK receptor (CCKR), but its role in modulation of the IgA response is not fully known under physiological conditions. Male eight-week-old BALB/c mice each were intraperitoneally injected once during 7 days with CCK8, devazapide (CCKR1 antagonist), L365,260 (CCKR2 antagonist) or vehicle (sham group). In intestinal lavages, total and secretory IgA (SIgA) were determined by ELISA; in lamina propria, IgA+ B lymphocytes and IgA+ plasma cells were analyzed by flow cytometry; mRNA levels of polymeric immunoglobulin receptor (pIgR) in epithelial cells and α chain, interleukins (ILs) in lamina propria cells were assessed by qRTPCR. Regarding the sham conditions, IgA+ plasma-cell percentage and IL-2, IL-5, IL-10 and transforming growth factor-β (TGF-β) mRNA levels were either increased by CCK8 or decreased by both CCKR antagonists. For IgA/SIgA responses, IL-4/IL-6 mRNA levels were decreased by all drugs and pIgR mRNA was increased by CCK8 and reduced by L365,260. IgA+ B cell percentage and α chain mRNA levels were elicited by CCK8 and L365,260. Data suggested a presumable differential role of CCK/CCKR on the IgA-response; outcome of L365,260 on the elicitation of IgA+ B cells and α chain mRNA needs further examination. 相似文献
45.
46.
Hanne Steel Freija Verdoodt Andrea Čerevková Marjolein Couvreur Pamela Fonderie Tom Moens Wim Bert 《Invertebrate Biology》2013,132(2):108-119
Nematodes are omnipresent in composts and are active in virtually all stages of the composting process. Major shifts in species composition, life strategies, and feeding behavior occur during the composting process. Due to the heat peak, nematodes can be virtually absent, but several taxa appear immediately when the temperatures drop. These comprise both taxa present before the heat peak and new taxa. However, it is not known how nematodes populate the compost. In this study, we aimed to assess the survival and colonization capacity of nematodes in compost. Our results showed that composting processes inaccessible to insects or not in contact with soil did not significantly influence nematode succession during composting. However, differences between treatments were found for some specific taxa (i.e., for Acrostichus sp., Neodiplogasteridae sp., Nygolaimoides sp., and Rhabditidae sp. 1), illustrating the importance of insects for the dispersal of nematodes to compost. Experiments in the lab with the blue bottle fly as a possible carrier demonstrated actual transport of nematodes isolated from compost by the fly (i.e., Halicephalobus cfr. gingivalis, Diploscapter coronatus, Diplogasteritus sp., Acrostichus sp., and Mesorhabditis sp.). Juveniles and dauer stages of Aphelenchoides sp., Panagrolaimus sp., and rhabditids survived an experimentally induced temperature peak, while members of Tylenchidae did not. In conclusion, our results indicate that the rapidly changing nematode community in compost is the result of both differential survival and colonization capacities. 相似文献
47.
Andrea P. Castillo‐Monroy Matthew A. Bowker Fernando T. Maestre Susana Rodríguez‐Echeverría Isabel Martinez Claudia E. Barraza‐Zepeda Cristina Escolar 《植被学杂志》2011,22(1):165-174
Questions: To what degree do biological soil crusts (BSCs), which are regulators of the soil surface boundary, influence associated microbial communities? Are these associations important to ecosystem functioning in a Mediterranean semi‐arid environment? Location: Gypsum outcrops near Belmonte del Tajo, Central Spain. Methods: We sampled a total of 45 (50 cm × 50 cm) plots, where we estimated the cover of every lichen and BSC‐forming lichen species. We also collected soil samples to estimate bacterial species richness and abundance, and to assess different surrogates of ecosystem functioning. We used path analysis to evaluate the relationships between the richness/abundance of above‐ and below‐ground species and ecosystem functioning. Results: We found that the greatest direct effect upon the ecosystem function matrix was that of the biological soil crust (BSC) richness matrix. A few bacterial species were sensitive to the lichen community, with a disproportionate effect of Collema crispum and Toninia sedifolia compared to their low abundance and frequency. The lichens Fulgensia subbracteata and Toninia spp. also had negative effects on bacteria, while Diploschistes diacapsis consistently affected sensitive bacteria, sometimes positively. Despite these results, very few of the BSC effects on ecosystem function could be ascribed to changes within the bacterial community. Conclusion: Our results suggest the primary importance of the richness of BSC‐forming lichens as drivers of small‐scale changes in ecosystem functioning. This study provides valuable insights on semi‐arid ecosystems where plant cover is spatially discontinuous and ecosystem function in plant interspaces is regulated largely by BSCs. 相似文献
48.
Andrea M. Price Vera Pospelova Michael R. S. Coffin James S. Latimer Gail L. Chmura 《Ecology and evolution》2016,6(16):5648-5662
Few biogeographic studies of dinoflagellate cysts include the near‐shore estuarine environment. We determine the effect of estuary type, biogeography, and water quality on the spatial distribution of organic‐walled dinoflagellate cysts from the Northeast USA (Maine to Delaware) and Canada (Prince Edward Island). A total of 69 surface sediment samples were collected from 27 estuaries, from sites with surface salinities >20. Dinoflagellate cysts were examined microscopically and compared to environmental parameters using multivariate ordination techniques. The spatial distribution of cyst taxa reflects biogeographic provinces established by other marine organisms, with Cape Cod separating the northern Acadian Province from the southern Virginian Province. Species such as Lingulodinium machaerophorum and Polysphaeridinium zoharyi were found almost exclusively in the Virginian Province, while others such as Dubridinium spp. and Islandinium? cezare were more abundant in the Acadian Province. Tidal range, sea surface temperature (SST), and sea surface salinity (SSS) are statistically significant parameters influencing cyst assemblages. Samples from the same type of estuary cluster together in canonical correspondence analysis when the estuaries are within the same biogeographic province. The large geographic extent of this study, encompassing four main estuary types (riverine, lagoon, coastal embayment, and fjord), allowed us to determine that the type of estuary has an important influence on cyst assemblages. Due to greater seasonal variations in SSTs and SSSs in estuaries compared to the open ocean, cyst assemblages show distinct latitudinal trends. The estuarine context is important for understanding present‐day species distribution, the factors controlling them, and to better predict how they may change in the future. 相似文献
49.
Maura Marinozzi Andrea Carotti Roccaldo Sardella Federica Buonerba Federica Ianni Benedetto Natalini Daniela Passeri Giovanni Rizzo Roberto Pellicciari 《Bioorganic & medicinal chemistry》2013,21(13):3780-3789
An asymmetric synthetic strategy was designed for the preparation of the four possible diastereoisomers of 3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one, a non-steroidal FXR agonist, we recently discovered following a virtual screening approach. The results obtained from an AlphaScreen assay clearly demonstrated that only the isomer endowed with 4R,6S absolute configuration is responsible for the biological activity. A deep investigation of the different putative binding modes adopted by these enantiomerically pure ligands using computational modeling studies confirmed the enantioselectivity of FXR towards this class of molecules. 相似文献
50.
Roberto Pilu Andrea Bucci Laura Casella Chiara Lago Francesco Cerino Badone Elena Cassani Michela Landoni 《Molecular breeding : new strategies in plant improvement》2012,30(2):799-807
We produced and studied for 3?years two synthetic populations of maize differing in their constitution only for the selected alleles present at the red color 1 (r1) locus (R-sc vs. r?Cr). r1 is a regulatory gene conferring anthocyanin pigmentation in different tissues: the R-sc allele confers pigmentation only in the aleurone seed layer, while the r?Cr allele confers pigmentation in several tissues such as root, silk and anther but the seed is colourless. The colourless population (r?Cr/r?Cr) was characterized by improved agronomic features, such as ear weight and plant height, compared with the R-sc/R-sc coloured population. This finding was confirmed by studying single F4 R/r families where the presence of the r?Cr allele conferred positive features, acting as a dominant trait. Quantitative trait locus (QTL) analysis performed using molecular markers on the long arm of chromosome 10 (bin 10.06), where the r1 gene maps, identified a QTL map position for plant height tightly associated to the r1 gene. Thus the r1 gene may represent a major QTL or it could be closely linked to another gene involved in the agronomic performance of the two populations studied. 相似文献