全文获取类型
收费全文 | 1949篇 |
免费 | 137篇 |
专业分类
2086篇 |
出版年
2024年 | 2篇 |
2023年 | 21篇 |
2022年 | 47篇 |
2021年 | 99篇 |
2020年 | 49篇 |
2019年 | 65篇 |
2018年 | 75篇 |
2017年 | 55篇 |
2016年 | 81篇 |
2015年 | 136篇 |
2014年 | 145篇 |
2013年 | 167篇 |
2012年 | 200篇 |
2011年 | 171篇 |
2010年 | 103篇 |
2009年 | 87篇 |
2008年 | 109篇 |
2007年 | 88篇 |
2006年 | 73篇 |
2005年 | 61篇 |
2004年 | 63篇 |
2003年 | 44篇 |
2002年 | 30篇 |
2001年 | 11篇 |
2000年 | 8篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 5篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 9篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1985年 | 12篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1980年 | 3篇 |
1977年 | 2篇 |
1976年 | 5篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 2篇 |
1969年 | 1篇 |
1966年 | 1篇 |
1960年 | 1篇 |
排序方式: 共有2086条查询结果,搜索用时 15 毫秒
991.
Morigi M Galbusera M Gastoldi S Locatelli M Buelli S Pezzotta A Pagani C Noris M Gobbi M Stravalaci M Rottoli D Tedesco F Remuzzi G Zoja C 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(1):172-180
Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti-P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS. 相似文献
992.
Farzan SF Palermo LM Yokoyama CC Orefice G Fornabaio M Sarkar A Kellogg GE Greengard O Porotto M Moscona A 《The Journal of biological chemistry》2011,286(44):37945-37954
Paramyxoviruses, including the childhood pathogen human parainfluenza virus type 3, enter host cells by fusion of the viral and target cell membranes. This fusion results from the concerted action of its two envelope glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). The receptor-bound HN triggers F to undergo conformational changes that render it competent to mediate fusion of the viral and cellular membranes. We proposed that, if the fusion process could be activated prematurely before the virion reaches the target host cell, infection could be prevented. We identified a small molecule that inhibits paramyxovirus entry into target cells and prevents infection. We show here that this compound works by an interaction with HN that results in F-activation prior to receptor binding. The fusion process is thereby prematurely activated, preventing fusion of the viral membrane with target cells and precluding viral entry. This first evidence that activation of a paramyxovirus F can be specifically induced before the virus contacts its target cell suggests a new strategy with broad implications for the design of antiviral agents. 相似文献
993.
One of the central aims of cancer research is to identify and characterize cancer-causing alterations in cancer genomes. In recent years, unprecedented advances in genome-wide sequencing, functional genomics technologies for RNA interference screens and methods for evaluating three-dimensional chromatin organization in vivo have resulted in important discoveries regarding human cancer. The cancer-causing genes identified from these new genome-wide technologies have also provided opportunities for effective and personalized cancer therapy. In this review, we describe some of the most recent technologies for cancer gene discovery. We also provide specific examples in which these technologies have proven remarkably successful in uncovering important cancer-causing alterations. 相似文献
994.
Danilo Milardi Michele F. M. Sciacca Matteo Pappalardo Domenico M. Grasso Carmelo La Rosa 《European biophysics journal : EBJ》2011,40(1):1-12
Human islet amyloid polypeptide (hIAPP) is known to misfold and aggregate into amyloid deposits that may be found in pancreatic
tissues of patients affected by type 2 diabetes. Recent studies have shown that the highly amyloidogenic peptide LANFLVH,
corresponding the N-terminal 12–18 region of IAPP, does not induce membrane damage. Here we assess the role played by the
aromatic residue Phe in driving both amyloid formation and membrane interaction of LANFLVH. To this aim, a set of variant
heptapeptides in which the aromatic residue Phe has been substituted with a Leu and Ala is studied. Differential scanning
calorimetry (DSC) and membrane-leakage experiments demonstrated that Phe substitution noticeably affects the peptide-induced
changes in the thermotropic properties of the lipid bilayer but not its membrane damaging potential. Atomic force microscopy
(AFM), ThT fluorescence and Congo red birefringence assays evidenced that the Phe residue is not required for fibrillogenesis,
but it can influence the self-assembling kinetics. Molecular dynamics simulations have paralleled the outcome of the experimental
trials also providing informative details about the structure of the different peptide assemblies. These results support a
general theory suggesting that aromatic residues, although capable of affecting the self-assembly kinetics of small peptides
and peptide-membrane interactions, are not essential either for amyloid formation or membrane leakage, and indicate that other
factors such as β-sheet propensity, size and hydrophobicity of the side chain act synergistically to determine peptide properties. 相似文献
995.
996.
Moritz KM De Matteo R Dodic M Jefferies AJ Arena D Wintour EM Probyn ME Bertram JF Singh RR Zanini S Evans RG 《American journal of physiology. Regulatory, integrative and comparative physiology》2011,301(2):R500-R509
Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX; 0.48 mg/h) or cortisol (CORT; 5 mg/h) over days 26-28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (α-, β-, γ-subunits) and Na(+)-K(+)-ATPase (α-, β-, γ-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period. 相似文献
997.
Fogolari F Corazza A Varini N Rotter M Gumral D Codutti L Rennella E Viglino P Bellotti V Esposito G 《Proteins》2011,79(3):986-1001
β2‐Microglobulin has been a model system for the study of fibril formation for 20 years. The experimental study of β2‐microglobulin structure, dynamics, and thermodynamics in solution, at atomic detail, along the pathway leading to fibril formation is difficult because the onset of disorder and aggregation prevents signal resolution in Nuclear Magnetic Resonance experiments. Moreover, it is difficult to characterize conformers in exchange equilibrium. To gain insight (at atomic level) on processes for which experimental information is available at molecular or supramolecular level, molecular dynamics simulations have been widely used in the last decade. Here, we use molecular dynamics to address three key aspects of β2‐microglobulin, which are known to be relevant to amyloid formation: (1) 60 ns molecular dynamics simulations of β2‐microglobulin in trifluoroethanol and in conditions mimicking low pH are used to study the behavior of the protein in environmental conditions that are able to trigger amyloid formation; (2) adaptive biasing force molecular dynamics simulation is used to force cis‐trans isomerization at Proline 32 and to calculate the relative free energy in the folded and unfolded state. The native‐like trans‐conformer (known as intermediate 2 and determining the slow phase of refolding), is simulated for 10 ns, detailing the possible link between cis‐trans isomerization and conformational disorder; (3) molecular dynamics simulation of highly concentrated doxycycline (a molecule able to suppress fibril formation) in the presence of β2‐microglobulin provides details of the binding modes of the drug and a rationale for its effect. Proteins 2011. © 2010 Wiley‐Liss, Inc. 相似文献
998.
Sassera D Lo N Epis S D'Auria G Montagna M Comandatore F Horner D Peretó J Luciano AM Franciosi F Ferri E Crotti E Bazzocchi C Daffonchio D Sacchi L Moya A Latorre A Bandi C 《Molecular biology and evolution》2011,28(12):3285-3296
The initiation of the intracellular symbiosis that would give rise to mitochondria and eukaryotes was a major event in the history of life on earth. Hypotheses to explain eukaryogenesis fall into two broad and competing categories: those proposing that the host was a phagocytotic proto-eukaryote that preyed upon the free-living mitochondrial ancestor (hereafter FMA), and those proposing that the host was an archaebacterium that engaged in syntrophy with the FMA. Of key importance to these hypotheses are whether the FMA was motile or nonmotile, and the atmospheric conditions under which the FMA thrived. Reconstructions of the FMA based on genome content of Rickettsiales representatives-generally considered to be the closest living relatives of mitochondria-indicate that it was nonmotile and aerobic. We have sequenced the genome of Candidatus Midichloria mitochondrii, a novel and phylogenetically divergent member of the Rickettsiales. We found that it possesses unique gene sets found in no other Rickettsiales, including 26 genes associated with flagellar assembly, and a cbb(3)-type cytochrome oxidase. Phylogenomic analyses show that these genes were inherited in a vertical fashion from an ancestral α-proteobacterium, and indicate that the FMA possessed a flagellum, and could undergo oxidative phosphorylation under both aerobic and microoxic conditions. These results indicate that the FMA played a more active and potentially parasitic role in eukaryogenesis than currently appreciated and provide an explanation for how the symbiosis could have evolved under low levels of oxygen. 相似文献
999.
Al-Trawneh SA El-Abadelah MM Zahra JA Al-Taweel SA Zani F Incerti M Cavazzoni A Vicini P 《Bioorganic & medicinal chemistry》2011,19(8):2541-2548
A facile synthesis of model 4-oxopyrido[3',2':4,5]thieno[3,2-b]indole-3-carboxylic acids 9a-e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3-b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a-c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015-0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b-e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC(50) 1.6-2.8 μM and 2.6-6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics. 相似文献
1000.
Mameli M Bateson P 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1563):436-443
The concept of innateness is often used in explanations and classifications of biological and cognitive traits. But does this concept have a legitimate role to play in contemporary scientific discourse? Empirical studies and theoretical developments have revealed that simple and intuitively appealing ways of classifying traits (e.g. genetically specified versus owing to the environment) are inadequate. They have also revealed a variety of scientifically interesting ways of classifying traits each of which captures some aspect of the innate/non-innate distinction. These include things such as whether a trait is canalized, whether it has a history of natural selection, whether it developed without learning or without a specific set of environmental triggers, whether it is causally correlated with the action of certain specific genes, etc. We offer an analogy: the term ‘jade’ was once thought to refer to a single natural kind; it was then discovered that it refers to two different chemical compounds, jadeite and nephrite. In the same way, we argue, researchers should recognize that ‘innateness’ refers not to a single natural kind but to a set of (possibly related) natural kinds. When this happens, it will be easier to progress in the field of biological and cognitive sciences. 相似文献