全文获取类型
收费全文 | 5241篇 |
免费 | 466篇 |
国内免费 | 3篇 |
专业分类
5710篇 |
出版年
2024年 | 3篇 |
2023年 | 24篇 |
2022年 | 52篇 |
2021年 | 100篇 |
2020年 | 65篇 |
2019年 | 51篇 |
2018年 | 77篇 |
2017年 | 67篇 |
2016年 | 125篇 |
2015年 | 234篇 |
2014年 | 272篇 |
2013年 | 346篇 |
2012年 | 426篇 |
2011年 | 430篇 |
2010年 | 281篇 |
2009年 | 265篇 |
2008年 | 331篇 |
2007年 | 353篇 |
2006年 | 353篇 |
2005年 | 346篇 |
2004年 | 308篇 |
2003年 | 339篇 |
2002年 | 298篇 |
2001年 | 46篇 |
2000年 | 31篇 |
1999年 | 54篇 |
1998年 | 71篇 |
1997年 | 46篇 |
1996年 | 44篇 |
1995年 | 32篇 |
1994年 | 35篇 |
1993年 | 29篇 |
1992年 | 29篇 |
1991年 | 21篇 |
1990年 | 19篇 |
1989年 | 14篇 |
1988年 | 6篇 |
1987年 | 14篇 |
1986年 | 13篇 |
1985年 | 9篇 |
1984年 | 9篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 2篇 |
1979年 | 5篇 |
1978年 | 7篇 |
1977年 | 4篇 |
1973年 | 4篇 |
1936年 | 1篇 |
排序方式: 共有5710条查询结果,搜索用时 15 毫秒
71.
Jean Velours Alain Dautant Bndicte Salin Isabelle Sagot Daniel Brthes 《The international journal of biochemistry & cell biology》2009,41(10):1783-1789
The mitochondrial F1F0-ATP synthase adopts supramolecular structures. The interaction domains between monomers involve components belonging to the F0 domains. In Saccharomyces cerevisiae, alteration of these components destabilizes the oligomeric structures, leading concomitantly to the appearance of monomeric species of ATP synthase and anomalous mitochondrial morphologies in the form of onion-like structures. The mitochondrial ultrastructure at the cristae level is thus modified. Electron microscopy on cross-sections of wild type mitochondria display many short cristae with narrowed intra-cristae space, whereas yeast mutants defected in supramolecular ATP synthases assembly present a low number of large lamellar cristae of constant thickness and traversing the whole organelle. The growth of these internal structures leads finally to mitochondria with sphere-like structures with a mean diameter of 1 μm that are easily identified by epifluorescence microscopy. As a result, ATP synthase is an actor of the mitochondrial ultrastructure in yeast. This paper reviews the ATP synthase components whose modifications lead to anomalous mitochondrial morphology and also provides a schema showing the formation of the so-called onion-like structures. 相似文献
72.
Del Angel VD Dupuis F Mornon JP Callebaut I 《Biochemical and biophysical research communications》2002,293(4):1153-1160
Viral envelope glycoproteins promote infection by mediating fusion between viral and cellular membranes. Fusion occurs after dramatic conformational changes within fusion proteins, leading to the exposure of a short stretch of mostly apolar residues, termed the fusion peptide, which is presumed to insert into the membrane and initiate the fusion process. The typical global composition of fusion peptides, rich in hydrophobic but also in small amino acids such as alanine and glycine, was used here as bait to detect other peptidic segments that can insert into membranes. We so evidenced a similar composition in several cytotoxic peptides, which promote pore formation such as peptides involved in amyloidoses and hydrophobic alpha-hairpins of pore-forming toxins. It is suggested that the structural plasticity observed for several membrane active peptides can be conferred by this particular global amino acid composition, which could be thus used to predict such functional behavior from genome data. 相似文献
73.
Gaston Tona Lutete Ghyslain Mombo-Ngoma Serge-Brice Assi Jude D. Bigoga Felix Koukouikila-Koussounda Nsengi Y. Ntamabyaliro Francine Ntoumi Selidji T. Agnandji Mirjam Groger Jangsik Shin Isabelle Borghini-Fuhrer Sarah Arbe-Barnes Stephen J. Allen Peter G. Kremsner Robert Miller Stephan Duparc Michael Ramharter the CANTAM study group 《PLoS medicine》2021,18(6)
BackgroundIn Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine–artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa.Methods and findingsThis single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine–artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine–artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine–artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated.ConclusionsPyronaridine–artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine–artesunate as an operationally useful addition to the management of acute uncomplicated malaria.Trial registrationClinicalTrials.gov .Gaston Tona Lutete and co-workers report on safety and effectiveness of the antimalarial drug pyronaridine-artesunate in African countries. NCT03201770相似文献
74.
Marta Marchetti Delphine Capela Renaud Poincloux Nacer Benmeradi Marie-Christine Auriac Aurélie Le Ru Isabelle Maridonneau-Parini Jacques Batut Catherine Masson-Boivin 《PloS one》2013,8(2)
Rhizobia are symbiotic soil bacteria able to intracellularly colonize legume nodule cells and form nitrogen-fixing symbiosomes therein. How the plant cell cytoskeleton reorganizes in response to rhizobium colonization has remained poorly understood especially because of the lack of an in vitro infection assay. Here, we report on the use of the heterologous HeLa cell model to experimentally tackle this question. We observed that the model rhizobium Sinorhizobium meliloti, and other rhizobia as well, were able to trigger a major reorganization of actin cytoskeleton of cultured HeLa cells in vitro. Cell deformation was associated with an inhibition of the three major small RhoGTPases Cdc42, RhoA and Rac1. Bacterial entry, cytoskeleton rearrangements and modulation of RhoGTPase activity required an intact S. meliloti biosynthetic pathway for queuosine, a hypermodifed nucleoside regulating protein translation through tRNA, and possibly mRNA, modification. We showed that an intact bacterial queuosine biosynthetic pathway was also required for effective nitrogen-fixing symbiosis of S. meliloti with its host plant Medicago truncatula, thus indicating that one or several key symbiotic functions of S. meliloti are under queuosine control. We discuss whether the symbiotic defect of que mutants may originate, at least in part, from an altered capacity to modify plant cell actin cytoskeleton. 相似文献
75.
Andrey M. Grishin Eunice Ajamian Linhua Zhang Isabelle Rouiller Mihnea Bostina Miroslaw Cygler 《The Journal of biological chemistry》2012,287(45):37986-37996
Microbial anaerobic and so-called hybrid pathways for degradation of aromatic compounds contain β-oxidation-like steps. These reactions convert the product of the opening of the aromatic ring to common metabolites. The hybrid phenylacetate degradation pathway is encoded in Escherichia coli by the paa operon containing genes for 10 enzymes. Previously, we have analyzed protein-protein interactions among the enzymes catalyzing the initial oxidation steps in the paa pathway (Grishin, A. M., Ajamian, E., Tao, L., Zhang, L., Menard, R., and Cygler, M. (2011) J. Biol. Chem. 286, 10735–10743). Here we report characterization of interactions between the remaining enzymes of this pathway and show another stable complex, PaaFG, an enoyl-CoA hydratase and enoyl-Coa isomerase, both belonging to the crotonase superfamily. These steps are biochemically similar to the well studied fatty acid β-oxidation, which can be catalyzed by individual monofunctional enzymes, multifunctional enzymes comprising several domains, or enzymatic complexes such as the bacterial fatty acid β-oxidation complex. We have determined the structure of the PaaFG complex and determined that although individually PaaF and PaaG are similar to enzymes from the fatty acid β-oxidation pathway, the structure of the complex is dissimilar from bacterial fatty acid β-oxidation complexes. The PaaFG complex has a four-layered structure composed of homotrimeric discs of PaaF and PaaG. The active sites of PaaF and PaaG are adapted to accept the intermediary components of the Paa pathway, different from those of the fatty acid β-oxidation. The association of PaaF and PaaG into a stable complex might serve to speed up the steps of the pathway following the conversion of phenylacetyl-CoA to a toxic and unstable epoxide-CoA by PaaABCE monooxygenase. 相似文献
76.
Uli Ohmayer Michael Gamalinda Martina Sauert Julius Ossowski Gisela P?ll Jan Linnemann Thomas Hierlmeier Jorge Perez-Fernandez Beril Kumcuoglu Isabelle Leger-Silvestre Marlène Faubladier Joachim Griesenbeck John Woolford Herbert Tschochner Philipp Milkereit 《PloS one》2013,8(7)
During the assembly process of ribosomal subunits, their structural components, the ribosomal RNAs (rRNAs) and the ribosomal proteins (r-proteins) have to join together in a highly dynamic and defined manner to enable the efficient formation of functional ribosomes. In this work, the assembly of large ribosomal subunit (LSU) r-proteins from the eukaryote S. cerevisiae was systematically investigated. Groups of LSU r-proteins with specific assembly characteristics were detected by comparing the protein composition of affinity purified early, middle, late or mature LSU (precursor) particles by semi-quantitative mass spectrometry. The impact of yeast LSU r-proteins rpL25, rpL2, rpL43, and rpL21 on the composition of intermediate to late nuclear LSU precursors was analyzed in more detail. Effects of these proteins on the assembly states of other r-proteins and on the transient LSU precursor association of several ribosome biogenesis factors, including Nog2, Rsa4 and Nop53, are discussed. 相似文献
77.
Missing data are unavoidable in environmental epidemiologic surveys. The aim of this study was to compare methods for handling large amounts of missing values: omission of missing values, single and multiple imputations (through linear regression or partial least squares regression), and a fully Bayesian approach. These methods were applied to the PARIS birth cohort, where indoor domestic pollutant measurements were performed in a random sample of babies'' dwellings. A simulation study was conducted to assess performances of different approaches with a high proportion of missing values (from 50% to 95%). Different simulation scenarios were carried out, controlling the true value of the association (odds ratio of 1.0, 1.2, and 1.4), and varying the health outcome prevalence. When a large amount of data is missing, omitting these missing data reduced statistical power and inflated standard errors, which affected the significance of the association. Single imputation underestimated the variability, and considerably increased risk of type I error. All approaches were conservative, except the Bayesian joint model. In the case of a common health outcome, the fully Bayesian approach is the most efficient approach (low root mean square error, reasonable type I error, and high statistical power). Nevertheless for a less prevalent event, the type I error is increased and the statistical power is reduced. The estimated posterior distribution of the OR is useful to refine the conclusion. Among the methods handling missing values, no approach is absolutely the best but when usual approaches (e.g. single imputation) are not sufficient, joint modelling approach of missing process and health association is more efficient when large amounts of data are missing. 相似文献
78.
ElFihry Raouia Elmessaoudi-Idrissi Mohcine Jadid Fatima-Zahra Zaidane Imane Chihab Hajar Tahiri Mohamed Kabine Mostafa Badre Wafaa Chemin Isabelle Marchio Agnes Pineau Pascal Ezzikouri Sayeh Benjelloun Soumaya 《中国病毒学》2020,35(5):566-574
Virologica Sinica - Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), induced by HCV have... 相似文献
79.
Beejan Asady Claudia F. Dick Karen Ehrenman Tejram Sahu Julia D. Romano Isabelle Coppens 《PLoS pathogens》2020,16(12)
Inorganic ions such as phosphate, are essential nutrients required for a broad spectrum of cellular functions and regulation. During infection, pathogens must obtain inorganic phosphate (Pi) from the host. Despite the essentiality of phosphate for all forms of life, how the intracellular parasite Toxoplasma gondii acquires Pi from the host cell is still unknown. In this study, we demonstrated that Toxoplasma actively internalizes exogenous Pi by exploiting a gradient of Na+ ions to drive Pi uptake across the plasma membrane. The Na+-dependent phosphate transport mechanism is electrogenic and functionally coupled to a cipargarmin sensitive Na+-H+-ATPase. Toxoplasma expresses one transmembrane Pi transporter harboring PHO4 binding domains that typify the PiT Family. This transporter named TgPiT, localizes to the plasma membrane, the inward buds of the endosomal organelles termed VAC, and many cytoplasmic vesicles. Upon Pi limitation in the medium, TgPiT is more abundant at the plasma membrane. We genetically ablated the PiT gene, and ΔTgPiT parasites are impaired in importing Pi and synthesizing polyphosphates. Interestingly, ΔTgPiT parasites accumulate 4-times more acidocalcisomes, storage organelles for phosphate molecules, as compared to parental parasites. In addition, these mutants have a reduced cell volume, enlarged VAC organelles, defects in calcium storage and a slightly alkaline pH. Overall, these mutants exhibit severe growth defects and have reduced acute virulence in mice. In survival mode, ΔTgPiT parasites upregulate several genes, including those encoding enzymes that cleave or transfer phosphate groups from phosphometabolites, transporters and ions exchangers localized to VAC or acidocalcisomes. Taken together, these findings point to a critical role of TgPiT for Pi supply for Toxoplasma and also for protection against osmotic stresses. 相似文献
80.
Jolivet Raphaël Clavreul Julie Brière Raphaël Besseau Romain Prieur Vernat Anne Sauze Marie Blanc Isabelle Douziech Mélanie Pérez-López Paula 《The International Journal of Life Cycle Assessment》2021,26(12):2457-2471
The International Journal of Life Cycle Assessment - In this paper, we present new tools to ease the analysis of the effect of variability and uncertainty on life cycle assessment (LCA) results.... 相似文献