全文获取类型
收费全文 | 9094篇 |
免费 | 583篇 |
国内免费 | 3篇 |
专业分类
9680篇 |
出版年
2024年 | 3篇 |
2023年 | 64篇 |
2022年 | 119篇 |
2021年 | 245篇 |
2020年 | 148篇 |
2019年 | 162篇 |
2018年 | 307篇 |
2017年 | 238篇 |
2016年 | 340篇 |
2015年 | 503篇 |
2014年 | 570篇 |
2013年 | 726篇 |
2012年 | 827篇 |
2011年 | 813篇 |
2010年 | 497篇 |
2009年 | 424篇 |
2008年 | 568篇 |
2007年 | 493篇 |
2006年 | 507篇 |
2005年 | 421篇 |
2004年 | 354篇 |
2003年 | 346篇 |
2002年 | 353篇 |
2001年 | 63篇 |
2000年 | 54篇 |
1999年 | 54篇 |
1998年 | 100篇 |
1997年 | 72篇 |
1996年 | 48篇 |
1995年 | 36篇 |
1994年 | 40篇 |
1993年 | 28篇 |
1992年 | 29篇 |
1991年 | 18篇 |
1990年 | 16篇 |
1989年 | 15篇 |
1988年 | 13篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 8篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 9篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1977年 | 4篇 |
1976年 | 2篇 |
1971年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有9680条查询结果,搜索用时 0 毫秒
91.
92.
Francesca Vittoria Sbrana Benedetta Fiordi Jessica Bordini Daniela Belloni Federica Barbaglio Luca Russo Lydia Scarfò Paolo Ghia Cristina Scielzo 《Journal of cellular and molecular medicine》2023,27(4):576-586
Chronic Lymphocytic Leukaemia (CLL) is the most common adult B-cell leukaemia and despite improvement in patients' outcome, following the use of targeted therapies, it remains incurable. CLL supportive microenvironment plays a key role in both CLL progression and drug resistance through signals that can be sensed by the main components of the focal adhesion complex, such as FAK and PYK2 kinases. Dysregulations of both kinases have been observed in several metastatic cancers, but their role in haematological malignancies is still poorly defined. We characterized FAK and PYK2 expression and observed that PYK2 expression is higher in leukaemic B cells and its overexpression significantly correlates with their malignant transformation. When targeting both FAK and PYK2 with the specific inhibitor defactinib, we observed a dose–response effect on CLL cells viability and survival. In vivo treatment of a CLL mouse model showed a decrease of the leukaemic clone in all the lymphoid organs along with a significant reduction of macrophages and of the spleen weight and size. Our results first define a possible prognostic value for PYK2 in CLL, and show that both FAK and PYK2 might become putative targets for both CLL and its microenvironment (e.g. macrophages), thus paving the way to an innovative therapeutic strategy. 相似文献
93.
The protozoan parasite Trypanosoma cruzi has a complex biological cycle that involves vertebrate and invertebrate hosts. In mammals, the infective trypomastigote form of this parasite can invade several cell types by exploiting phagocytic-like or nonphagocytic mechanisms depending on the class of cell involved. Morphological studies showed that when trypomastigotes contact macrophages, they induce the formation of plasma membrane protrusions that differ from the canonical phagocytosis that occurs in the case of noninfective epimastigotes. In contrast, when trypomastigotes infect epithelial or muscle cells, the cell surface is minimally modified, suggesting the induction of a different class of process. Lysosomal-dependent or -independent T. cruzi invasion of host cells are two different models that describe the molecular and cellular events activated during parasite entry into nonphagocytic cells. In this context, we have previously shown that induction of autophagy in host cells before infection favors T. cruzi invasion. Furthermore, we demonstrate that autophagosomes and the autophagosomal protein LC3 are recruited to the T. cruzi entry sites and that the newly formed T. cruzi parasitophorous vacuole has characteristics of an autophagolysosome. This review summarizes the current knowledge of the molecular and cellular mechanisms of T. cruzi invasion in nonphagocytic cells. Based on our findings, we propose a new model in which T. cruzi takes advantage of the upregulation of autophagy during starvation to increase its successful colonization of host cells. 相似文献
94.
Fidalgo M Guerrero A Fraile M Iglesias C Pombo CM Zalvide J 《The Journal of biological chemistry》2012,287(14):11556-11565
While studying the functions of CCM3/PDCD10, a gene encoding an adaptor protein whose mutation results in vascular malformations, we have found that it is involved in a novel response to oxidative stress that results in phosphorylation and activation of the ezrin/radixin/moesin (ERM) family of proteins. This phosphorylation protects cells from accidental cell death induced by oxidative stress. We also present evidence that ERM phosphorylation is performed by the GCKIII kinase Mst4, which is activated and relocated to the cell periphery after oxidative stress. The cellular levels of Mst4 and its activation after oxidative stress depend on the presence of CCM3, as absence of the latter impairs the phosphorylation of ERM proteins and enhances death of cells exposed to reactive oxygen species. These findings shed new light on the response of cells to oxidative stress and identify an important pathophysiological situation in which ERM proteins and their phosphorylation play a significant role. 相似文献
95.
Giacometti S Marrano CA Bonza MC Luoni L Limonta M De Michelis MI 《Journal of experimental botany》2012,63(3):1215-1224
ACA8 is a plasma membrane-localized isoform of calmodulin (CaM)-regulated Ca(2+)-ATPase of Arabidopsis thaliana. Several phosphopeptides corresponding to portions of the regulatory N-terminus of ACA8 have been identified in phospho-proteomic studies. To mimic phosphorylation of the ACA8 N-terminus, each of the serines found to be phosphorylated in those studies (Ser19, Ser22, Ser27, Ser29, Ser57, and Ser99) has been mutated to aspartate. Mutants have been expressed in Saccharomyces cerevisiae and characterized: mutants S19D and S57D--and to a lesser extent also mutants S22D and S27D--are deregulated, as shown by their low activation by CaM and by tryptic cleavage of the N-terminus. The His-tagged N-termini of wild-type and mutant ACA8 (6His-(1)M-I(116)) were expressed in Escherichia coli, affinity-purified, and used to analyse the kinetics of CaM binding by surface plasmon resonance. All the analysed mutations affect the kinetics of interaction with CaM to some extent: in most cases, the altered kinetics result in marginal changes in affinity, with the exception of mutants S57D (K(D) ≈ 10-fold higher than wild-type ACA8) and S99D (K(D) about half that of wild-type ACA8). The ACA8 N-terminus is phosphorylated in vitro by two isoforms of A. thaliana calcium-dependent protein kinase (CPK1 and CPK16); phosphorylation of mutant 6His-(1)M-I(116) peptides shows that CPK16 is able to phosphorylate the ACA8 N-terminus at Ser19 and at Ser22. The possible physiological implications of the subtle modulation of ACA8 activity by phosphorylation of its N-terminus are discussed. 相似文献
96.
Laura Cristina Ceafalan Ana-Maria Enciu Tudor Emanuel Fertig Bogdan Ovidiu Popescu Mihaela Gherghiceanu Mihail Eugen Hinescu Eugen Radu 《European journal of cell biology》2018,97(6):442-461
Adult tissue homeostasis and repair relies on prompt and appropriate intervention by tissue-specific adult stem cells (SCs). SCs have the ability to self-renew; upon appropriate stimulation, they proliferate and give rise to specialized cells. An array of environmental signals is important for maintenance of the SC pool and SC survival, behavior, and fate. Within this special microenvironment, commonly known as the stem cell niche (SCN), SC behavior and fate are regulated by soluble molecules and direct molecular contacts via adhesion molecules providing connections to local supporting cells and the extracellular matrix. Besides the extensively discussed array of soluble molecules, the expression of adhesion molecules and molecular contacts is another fundamental mechanism regulating niche occupancy and SC mobilization upon activation. Some adhesion molecules are differentially expressed and have tissue-specific consequences, likely reflecting the structural differences in niche composition and design, especially the presence or absence of a stromal counterpart. However, the distribution and identity of intercellular molecular contacts for adhesion and adhesion-mediated signaling within stromal and non-stromal SCN have not been thoroughly studied. This review highlights common details or significant differences in cell-to-cell contacts within representative stromal and non-stromal niches that could unveil new standpoints for stem cell biology and therapy. 相似文献
97.
Rodrigo?A.?Mendes Shawan?K.?C.?Almeida Iuri?N.?Soares Cristina?A.?Barboza Renato?G.?Freitas Alex?Brown Gabriel?L.?C.?de?SouzaEmail authorView authors OrcID profile 《Journal of molecular modeling》2018,24(6):133
In this work, we present a computational study on the antioxidant potential of myricetin 3,4\(^{\prime }\)-di-O-α-L-rhamnopyranoside (Compound M). A density functional theory (DFT) approach with the B3LYP and LC-ωPBE functionals and with both the 6-311G(d,p) and 6-311+G(d,p) basis sets was used. The focus of the investigation was on the structural and energetic parameters including both bond dissociation enthalpies (BDEs) and ionization potentials (IPs), which provide information on the potential antioxidant activity. The properties computed were compared with BDEs and IPs available in the literature for myricetin, a compound well known for presenting antioxidant activity (and the parent molecule of the compound of interest in the present work). Myricetin 3,4\(^{\prime }\)-di-O-α-L-rhamnopyranoside presented the lowest BDE to be 79.13 kcal/mol (as determined using B3LYP/6-311G(d,p) in water) while myricetin has a quite similar value (within 3.4 kcal/mol). IPs computed in the gas phase [B3LYP/6-311G(d,p)] are 157.18 and 161.4 kcal/mol for myricetin 3,4\(^{\prime }\)-di-O-α-L-rhamnopyranoside and myricetin, respectively. As the values of BDEs are considerably lower than the ones probed for IPs (in the gas phase or in any given solvent environment), the hydrogen atom transfer mechanism is preferred over the single electron transfer mechanism. The BDEs obtained suggest that myricetin 3,4\(^{\prime }\)-di-O-α-L-rhamnopyranoside can present antioxidant potential as good as the parent molecule myricetin (a well-known antioxidant). Therefore, experimental tests on the antioxidant activity of Compound M are encouraged. 相似文献
98.
Ivan Muñoz Cristina Rodríguez Dominique Gillet Bruno M. Moerschbacher 《The International Journal of Life Cycle Assessment》2018,23(5):1151-1160
Purpose
The aim of this article is to present the first life cycle assessment of chitosan production based on data from two real producers located in India and Europe. The goal of the life cycle assessment (LCA) was to understand the main hot spots in the two supply chains, which are substantially different in terms of raw materials and production locations.Methods
The LCA is based on consequential modelling principles, whereby allocation is avoided by means of substitution, and market mixes include only flexible, i.e. non-constrained suppliers. The product system is cradle to gate and includes the production of raw materials, namely waste shells from snow crab and shrimp in Canada and India, respectively, the processing of these in China and India and the manufacture of chitosan in Europe and India. Primary data for chitin and chitosan production were obtained from the actual producers, whereas raw material acquisition as well as waste management activities were based on literature sources. The effects of indirect land use change (iLUC) were also included. Impact assessment was carried out at midpoint level by means of the recommended methods in the International Life Cycle Data (ILCD) handbook.Results and discussion
In the Indian supply chain, the production of chemicals (HCl and NaOH) appears as an important hot spot. The use of shrimp shells as raw material affects the market for animal feed, resulting in a credit in many impact indicators, especially in water use. The use of protein waste as fertilizer is also an important source of greenhouse-gas and ammonia emissions. In the European supply chain, energy use is the key driver for environmental impacts, namely heat production based on coal in China and electricity production in China and Europe. The use of crab shells as raw material avoids the composting process they would be otherwise subject to, leading to a saving in composting emissions, especially ammonia. In the Indian supply chain, the effect of iLUC is relevant, whereas in the European one, it is negligible.Conclusions
Even though we assessed two products from the same family, the results show that they have very different environmental profiles, reflecting their substantially different supply chains in terms of raw material (shrimp shells vs. crab shells), production locations (locally produced vs. a global supply chain involving three continents) and the different applications (general-purpose chitosan vs. chitosan for the medical sector).99.
“Bacillus thermoantarcticus” sp. nov., from Mount Melbourne,Antarctica: a novel thermophilic species
B. Nicolaus Licia Lama Enrico Esposito Maria Cristina Manca Guido di Prisco Agata Gambacorta 《Polar Biology》1996,16(2):101-104
A novel thermophilic Gram-positive bacillus, “Bacillus thermoantarcticus”, isolated from geothermal soil near the crater of Mount Melbourne, is described. The organism grows at an optimal temperature
of 63°C at pH 6.0, is oxidase-positive, catalase-negative and produces an exopolysaccharide, an exocellular xylanase, an intracellular
alcohol dehydrogenase and exo- and endocellular α-glucosidase(s). The sequence of 16S rDNA is very similar to that of “Bacillus thermoglucosidasius”; however, the guanine-plus-cytosine (G+C) content is 8 mol% higher. The type strain is “Bacillus thermoantarcticus” (DSM 9572).
Received : 3 February 1995/Accepted : 12 May 1995 相似文献
100.
Simona Cinta Pinzaru Alexandra Falamas Cristina Adriana Dehelean 《Journal of cellular and molecular medicine》2013,17(2):277-286
An interdisciplinary approach employing functionalized nanoparticles and ultrasensitive spectroscopic techniques is reported here to track the molecular changes in early stage of malignancy. Melanoma tissue tracking at molecular level using both labelled and unlabelled silver and gold nanoparticles has been achieved using surface enhanced Raman scattering (SERS) technique. We used skin tissue from ex vivo mice with induced melanoma. Raman and SERS molecular characterization of melanoma tissue is proposed here for the first time. Optical nanosensors based on Ag and Au nanoparticles with chemisorbed cresyl violet molecular species as labels revealed sensitive capability to tissues tagging and local molecular characterization. Sensitive information originating from surrounding native biological molecules is provided by the tissue SERS spectra obtained either with visible or NIR laser line. Labelled nanoparticles introduced systematic differences in tissue response compared with unlabelled ones, suggesting that the label functional groups tag specific tissue components revealed by proteins or nucleic acids bands. Vibrational data collected from tissue are presented in conjunction with the immunohistochemical analysis. The results obtained here open perspectives in applied plasmonic nanoparticles and SERS for the early cancer diagnostic based on the appropriate spectral databank. 相似文献