全文获取类型
收费全文 | 851篇 |
免费 | 56篇 |
出版年
2022年 | 9篇 |
2021年 | 13篇 |
2020年 | 11篇 |
2019年 | 20篇 |
2018年 | 22篇 |
2017年 | 18篇 |
2016年 | 24篇 |
2015年 | 29篇 |
2014年 | 25篇 |
2013年 | 45篇 |
2012年 | 41篇 |
2011年 | 43篇 |
2010年 | 18篇 |
2009年 | 25篇 |
2008年 | 25篇 |
2007年 | 39篇 |
2006年 | 17篇 |
2005年 | 34篇 |
2004年 | 36篇 |
2003年 | 25篇 |
2002年 | 25篇 |
2001年 | 20篇 |
2000年 | 28篇 |
1999年 | 15篇 |
1998年 | 11篇 |
1997年 | 7篇 |
1996年 | 10篇 |
1995年 | 7篇 |
1994年 | 9篇 |
1993年 | 10篇 |
1992年 | 10篇 |
1991年 | 12篇 |
1990年 | 12篇 |
1989年 | 22篇 |
1988年 | 15篇 |
1987年 | 19篇 |
1986年 | 11篇 |
1985年 | 10篇 |
1983年 | 14篇 |
1982年 | 8篇 |
1979年 | 10篇 |
1978年 | 11篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1975年 | 13篇 |
1974年 | 9篇 |
1972年 | 6篇 |
1971年 | 5篇 |
1967年 | 9篇 |
1966年 | 7篇 |
排序方式: 共有907条查询结果,搜索用时 15 毫秒
41.
The decoupled sites representation (DSR) is a theoretical instrument which allows to regard complex pH titration curves of biomolecules with several interacting proton binding sites as composition of isolated, non-interacting sites, each with a standard Henderson–Hasselbalch titration curve. In this work, we present the mathematical framework in which the DSR is embedded and give mathematical proofs for several statements in the periphery of the DSR. These proofs also identify exceptions. To apply the DSR to any molecule, it is necessary to extend the set of binding energies from ${\mathbb{R}}$ to a stripe within ${\mathbb{C}}$ . An important observation in this context is that even positive interaction energies (repulsion) between the binding sites will not guarantee real binding energies in the decoupled system, at least if the molecule has more than four proton binding sites. Moreover, we show that for a given overall titration curve it is not only possible to find a corresponding system with an interaction energy of zero but with any arbitrary fix interaction energy. This result also effects practical work as it shows that for any given titration curve, there is an infinite number of corresponding hypothetical molecules. Furthermore, this implies that—using a common definition of cooperative binding on the level of interaction energies—a meaningful measure of cooperativity between the binding sites cannot be defined solely on the basis of the overall titration. Consequently, all measures of cooperativity based on the overall binding curve do not measure the type of cooperativity commonly defined on the basis of interaction energies. Understanding the DSR mathematically provides the basis of transferring the DSR to biomolecules with different types of interacting ligands, such as protons and electrons, which play an important role within electron transport chains like in photosynthesis. 相似文献
42.
Abstract Opportunistic sightings and strandings of Caperea marginata (n=196) from the vicinity of Australia and New Zealand (1884 to early 2007) were used to relate geographic and temporal patterns to oceanographic and broad-scale climatic variability. Records were not uniformly distributed along the coast and more (69%) were from Australia than New Zealand. Seven coastal whale ‘hotspots’ were identified which accounted for 61% of records with locality data. Half of the hotspot records were from southeast (37) and northwest (20) Tasmania—others each had 9–15 events. Upwelling and/or high zooplankton abundance has been documented near all whale hotspots. Records of C. marginata occurred in all months, with 75% in spring and summer. Inter-annual variability showed broad agreement between increased whale records (usually in spring/summer) and strongly positive ‘Niño 3.4’ during 1980–1995 but not thereafter. Coastal upwelling and productivity increase during climatic phenomena such as El Niño and are likely to be quickly beneficial to plankton-feeding whales such as C. marginata. 相似文献
43.
Giuseppe Firrao Marta Martini Paolo Ermacora Nazia Loi Emanuela Torelli Xavier Foissac Patricia Carle Bruce C. Kirkpatrick Lia Liefting Bernd Schneider Cristina Marzachì Sabrina Palmano 《Systematic and applied microbiology》2013
The phytoplasmas are currently named using the Candidatus category, as the inability to grow them in vitro prevented (i) the performance of tests, such as DNA-DNA hybridization, that are regarded as necessary to establish species boundaries, and (ii) the deposition of type strains in culture collections. The recent accession to complete or nearly complete genome sequence information disclosed the opportunity to apply to the uncultivable phytoplasmas the same taxonomic approaches used for other bacteria. In this work, the genomes of 14 strains, belonging to the 16SrI, 16SrIII, 16SrV and 16SrX groups, including the species “Ca. P. asteris”, “Ca. P. mali”, “Ca. P. pyri”, “Ca. P. pruni”, and “Ca. P. australiense” were analyzed along with Acholeplasma laidlawi, to determine their taxonomic relatedness. Average nucleotide index (ANIm), tetranucleotide signature frequency correlation index (Tetra), and multilocus sequence analysis of 107 shared genes using both phylogenetic inference of concatenated (DNA and amino acid) sequences and consensus networks, were carried out. The results were in large agreement with the previously established 16S rDNA based classification schemes. Moreover, the taxonomic relationships within the 16SrI, 16SrIII and 16SrX groups, that represent clusters of strains whose relatedness could not be determined by 16SrDNA analysis, could be comparatively evaluated with non-subjective criteria. “Ca. P. mali” and “Ca. P. pyri” were found to meet the genome characteristics for the retention into two different, yet strictly related species; representatives of subgroups 16SrI-A and 16SrI-B were also found to meet the standards used in other bacteria to distinguish separate species; the genomes of the strains belonging to 16SrIII were found more closely related, suggesting that their subdivision into Candidatus species should be approached with caution. 相似文献
44.
Qiaomei Fu Alissa Mittnik Philip L.F. Johnson Kirsten Bos Martina Lari Ruth Bollongino Chengkai Sun Liane Giemsch Ralf Schmitz Joachim Burger Anna Maria Ronchitelli Fabio Martini Renata G. Cremonesi Jiří Svoboda Peter Bauer David Caramelli Sergi Castellano David Reich Johannes Krause 《Current biology : CB》2013,23(7):553-559
45.
Eva Martini Evelyn Schneider Clemens Neufert Markus F. Neurath 《Cell cycle (Georgetown, Tex.)》2016,15(21):2875-2881
As an inhibitor of apoptosis (IAP) family member, Survivin is known for its role during regulation of apoptosis. More recently its function as a cell cycle regulator has become evident. Survivin was shown to play a pivotal role during embryonic development and is highly expressed in regenerative tissue as well as in many cancer types. We examined the function of Survivin during mouse intestinal organogenesis and in gut pathophysiology. We found high expression of Survivin in experimentally induced colon cancer in mice but also in colon tumors of humans. Moreover, Survivin was regulated by TGF-β and was found to be highly expressed during mucosal healing following intestinal inflammation. We identified that expression of Survivin is essential early on in life, as specific deletion of Survivin in Villin expressing cells led to embryonic death around day 12 post coitum. Together with our recent study on the role of Survivin in the gut of adult mice our data demonstrate that Survivin is an essential guardian of embryonic gut development and adult gut homeostasis protecting the epithelium from cell death promoting the proliferation of intestinal stem and progenitor cells. 相似文献
46.
C Agrati C Castilletti R Casetti A Sacchi L Falasca F Turchi N Tumino V Bordoni E Cimini D Viola E Lalle L Bordi S Lanini F Martini E Nicastri N Petrosillo V Puro M Piacentini A Di Caro G P Kobinger A Zumla G Ippolito M R Capobianchi 《Cell death & disease》2016,7(3):e2164
Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.Ebola virus (EBOV) is one of the most deadly human pathogens, causing a severe hemorrhagic fever syndrome in both humans and non-human primates with fatality rates ranging from 50 to 70%.1 The recent outbreak of Ebola Virus Diseases (EVD) in West Africa highlights the pathogenic nature of this virus, the high mortality rates and pandemic potential. To date, there have been over 27 700 cases and >11 280 deaths.1, 2 Although EVD is usually an acute illness, increasing evidences exist of persistent infections and post infection syndromes,3, 4, 5, 6 highlighting the need to identify immune correlates of a protective immune response.Defining human immune responses to EBOV infection, pathogenesis and correlates of protection are important for designing effective therapeutic and vaccination interventions. A decrease in lymphocytes has been observed in studies in mice,7 non-human primates8 and humans,9 and is attributed to apoptotic mechanisms.7, 10 Persistent B and T-cell activation has been described in four survivors as long as one month after discharge from the hospital, suggesting recurrent antigenic stimulation.11 While aberrant immune responses have been described after EBOV infection (reviewed in12, 13), and different patterns of inflammatory mediators have been associated with different clinical outcomes,9, 10, 11, 14, 15, 16, 17 data on human immune responses to Ebola virus remain scanty, due to difficulties in obtaining sequential samples through the course of illness and to limitations imposed by biosafety requirements for laboratory analyses.We conducted a longitudinal study aimed to characterize the kinetics of T-cell phenotypes, activation/differentiation profile, autophagic/apoptotic markers and functionality in two EVD patients from soon after symptom onset through their hospitalization until recovery. 相似文献
47.
48.
Sheng-Da Zhang Claire-Lise Santini Wei-Jia Zhang Valérie Barbe Sophie Mangenot Charlotte Guyomar Marc Garel Hai-Tao Chen Xue-Gong Li Qun-Jian Yin Yuan Zhao Jean Armengaud Jean-Charles Gaillard Séverine Martini Nathalie Pradel Claude Vidaud François Alberto Claudine Médigue Christian Tamburini Long-Fei Wu 《Extremophiles : life under extreme conditions》2016,20(3):301-310
Bacteria of the genus Photobacterium thrive worldwide in oceans and show substantial eco-physiological diversity including free-living, symbiotic and piezophilic life styles. Genomic characteristics underlying this variability across species are poorly understood. Here we carried out genomic and physiological analysis of Photobacterium phosphoreum strain ANT-2200, the first deep-sea luminous bacterium of which the genome has been sequenced. Using optical mapping we updated the genomic data and reassembled it into two chromosomes and a large plasmid. Genomic analysis revealed a versatile energy metabolic potential and physiological analysis confirmed its growth capacity by deriving energy from fermentation of glucose or maltose, by respiration with formate as electron donor and trimethlyamine N-oxide (TMAO), nitrate or fumarate as electron acceptors, or by chemo-organo-heterotrophic growth in rich media. Despite that it was isolated at a site with saturated dissolved oxygen, the ANT-2200 strain possesses four gene clusters coding for typical anaerobic enzymes, the TMAO reductases. Elevated hydrostatic pressure enhances the TMAO reductase activity, mainly due to the increase of isoenzyme TorA1. The high copy number of the TMAO reductase isoenzymes and pressure-enhanced activity might imply a strategy developed by bacteria to adapt to deep-sea habitats where the instant TMAO availability may increase with depth. 相似文献
49.
Gabriella Guerrini Giovanna Ciciani Samuele Ciattini Letizia Crocetti Simona Daniele Claudia Martini 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):195-204
To investigate the binding affinity of GABAA receptor subtype, new pyrazolo [1,5-a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5-unsubstituted new derivative, compound 15, has receptor recognition (Ki?=?834.7?nM). 相似文献