全文获取类型
收费全文 | 548篇 |
免费 | 50篇 |
出版年
2022年 | 3篇 |
2021年 | 9篇 |
2018年 | 6篇 |
2017年 | 11篇 |
2016年 | 6篇 |
2015年 | 17篇 |
2014年 | 19篇 |
2013年 | 27篇 |
2012年 | 21篇 |
2011年 | 33篇 |
2010年 | 20篇 |
2009年 | 23篇 |
2008年 | 24篇 |
2007年 | 36篇 |
2006年 | 31篇 |
2005年 | 27篇 |
2004年 | 19篇 |
2003年 | 25篇 |
2002年 | 24篇 |
2001年 | 9篇 |
2000年 | 14篇 |
1999年 | 9篇 |
1998年 | 10篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 7篇 |
1992年 | 7篇 |
1990年 | 7篇 |
1989年 | 8篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 5篇 |
1984年 | 7篇 |
1983年 | 4篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1978年 | 6篇 |
1977年 | 8篇 |
1975年 | 3篇 |
1974年 | 5篇 |
1973年 | 5篇 |
1923年 | 3篇 |
1913年 | 2篇 |
1911年 | 2篇 |
1899年 | 3篇 |
排序方式: 共有598条查询结果,搜索用时 78 毫秒
221.
Torben Bjerregaard Larsen Peter Br?nnum Nielsen Flemming Skj?th Lars Hvilsted Rasmussen Gregory Y. H. Lip 《PloS one》2014,9(12)
Background
This study sought to investigate the relative efficacy and safety of non-vitamin K oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) in cancer patients.Methods
A systematic search of the PubMed, EMBASE, and ClinicalTrials.gov databases identified all multicentre, randomised phase III trials investigating the initial use of NOAC against a vitamin K antagonist (VKA) together with subcutaneous heparin or low molecular weight heparin (upstart) for treatment of VTE. Outcomes of interest were recurrent VTE (deep venous thrombosis or pulmonary embolism), and clinically relevant bleeding.Results
Four randomised controlled phase III trials were included, comprising a total of 19,060 patients randomised to either NOAC or VKA. For patients with active cancer (N = 759), the analysis on the efficacy outcomes demonstrated a trend in favour of NOAC (OR 0.56, 95% CI 0.28–1.13). Similar, analyses on the safety outcomes comparing NOAC to VKA and enoxaparin demonstrated a trend in favour of NOAC (OR 0.88, 95% CI 0.57–1.35).Conclusion
Point estimates of the effect size suggest an important estimated beneficial effect of NOAC in the treatment of VTE in cancer, in terms of efficacy and safety, but given the small numbers of patients with cancer in the randomised trials, statistical significance was not achieved. 相似文献222.
Christian Jansen Diana J. Leeming Mattias Mandorfer Inger Byrjalsen Robert Schierwagen Philipp Schwabl Morten A. Karsdal Evrim Anadol Christian P. Strassburg Jürgen Rockstroh Markus Peck-Radosavljevic S?ren M?ller Flemming Bendtsen Aleksander Krag Thomas Reiberger Jonel Trebicka 《PloS one》2014,9(9)
Background
Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection.Methods
Fifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen).Results
As expected, HVPG showed strong and significant correlations with FIB4-index (rs = 0.628; p = 7*10−7). Interestingly, PRO-C3 significantly correlated with HVPG (rs = 0.354; p = 0.02), alanine aminotransferase (rs = 0.30; p = 0.038), as well as with FIB4-index (rs = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg).Conclusion
PRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection. 相似文献223.
Olesen SH Christensen LL Sørensen FB Cabezón T Laurberg S Orntoft TF Birkenkamp-Demtröder K 《Molecular & cellular proteomics : MCP》2005,4(4):534-544
We initiated the present study to identify new genes associated with colorectal cancer. In a previously published microarray study an EST (W80763), later identified as the gene hFKBP10 (NM_021939), was found to be strongly expressed in tumors while absent in the normal mucosa. Here we describe this gene hFKBP10 together with its encoded protein hFKBP65 as a novel marker associated with colorectal cancer. Analysis of 31 colorectal adenocarcinomas and 14 normal colorectal mucosa by RealTime PCR for hFKBP10 showed a significant up-regulation in tumors, when compared with normal mucosa. Immunohistochemical analysis of 26 adenocarcinomas and matching normal mucosa, as well as benign hyperplastic polyps and adenomas, using a monoclonal anti-hFKBP65 antibody, showed that the protein was not present in normal colorectal epithelial cells, but strongly expressed in the tumor cells of colorectal cancer. The protein was also expressed in fibroblasts of both normal mucosa and tumor tissue. Western blot analysis of matched tumors and normal mucosa supported the finding of increased hFKBP65 expression in tumors compared with normal mucosa, in addition to identifying the molecular mass of hFKBP65 to approximately 72 kDa. Cellular localization and glycosylation studies revealed the hFKBP65 protein to be localized in the endoplasmic reticulum, and to be N-glycosylated. In conclusion, the protein hFKBP65 is associated with colorectal cancer, and we hypothesize the protein to be involved in fibroblast and transformed epithelial cell-specific protein synthesis in the endoplasmic reticulum. 相似文献
224.
Tagmose TM Zaragoza F Boonen HC Worsaae A Mogensen JP Nielsen FE Jensen AF Hansen JB 《Bioorganic & medicinal chemistry》2003,11(6):931-940
Pinacidil analogues, for example, N-cyano-N'-(3,5-dichlorophenyl)-N"-(3-methylbutyl)guanidine, 1, have previously been described as potassium channel openers on beta cells and smooth muscle cells. In the present study 3,3-diamino-sulfonylacrylonitrile, a new bioisostere of the cyanoguanidine group, was investigated. 3,3-Diamino-sulfonylacrylonitriles were prepared in a two step synthesis from the corresponding isothiocyanates and sulfonylacetonitriles. Single crystal X-ray crystallography and NMR spectroscopy were used to establish the structure of 2-(4-chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5-dichlorophenylamino)acrylonitrile 3i. The analysis confirmed that 3i assumes a staggered conformation considered as the energetically most favourable. The compounds synthesised have been identified as potent inhibitors of glucose stimulated insulin secretion from beta cell lines and rat pancreatic islets with minimal effects on vascular smooth muscle. 相似文献
225.
Palmisano G Jensen SS Le Bihan MC Lainé J McGuire JN Pociot F Larsen MR 《Molecular & cellular proteomics : MCP》2012,11(8):230-243
Microparticles and exosomes are two of the most well characterized membrane-derived microvesicles released either directly from the plasma membrane or released through the fusion of intracellular multivesicular bodies with the plasma membrane, respectively. They are thought to be involved in many significant biological processes such as cell to cell communication, rescue from apoptosis, and immunological responses. Here we report for the first time a quantitative study of proteins from β-cell-derived microvesicles generated after cytokine induced apoptosis using stable isotope labeled amino acids in cell culture combined with mass spectrometry. We identified and quantified a large number of β-cell-specific proteins and proteins previously described in microvesicles from other cell types in addition to new proteins located to these vesicles. In addition, we quantified specific sites of protein phosphorylation and N-linked sialylation in proteins associated with microvesicles from β-cells. Using pathway analysis software, we were able to map the most distinctive changes between microvesicles generated during growth and after cytokine stimulation to several cell death and cell signaling molecules including tumor necrosis factor receptor superfamily member 1A, tumor necrosis factor, α-induced protein 3, tumor necrosis factor-interacting kinase receptor-interacting serine-threonine kinase 1, and intercellular adhesion molecule 1. 相似文献
226.
PROTEOMICS in aquaculture: applications and trends 总被引:1,自引:0,他引:1
227.
Validation of a same-day real-time PCR method for screening of meat and carcass swabs for Salmonella
Charlotta L?fstr?m Michael Krause Mathilde H Josefsen Flemming Hansen Jeffrey Hoorfar 《BMC microbiology》2009,9(1):85
Background
One of the major sources of human Salmonella infections is meat. Therefore, efficient and rapid monitoring of Salmonella in the meat production chain is necessary. Validation of alternative methods is needed to prove that the performance is equal to established methods. Very few of the published PCR methods for Salmonella have been validated in collaborative studies. This study describes a validation including comparative and collaborative trials, based on the recommendations from the Nordic organization for validation of alternative microbiological methods (NordVal) of a same-day, non-commercial real-time PCR method for detection of Salmonella in meat and carcass swabs. 相似文献228.
Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion nuclear magnetic resonance (NMR) spectroscopy has emerged as a powerful method for quantifying chemical shifts of excited protein states. For many applications of the technique that involve the measurement of relaxation rates of carbon magnetization it is necessary to prepare samples with isolated (13)C spins so that experiments do not suffer from magnetization transfer between coupled carbon spins that would otherwise occur during the CPMG pulse train. In the case of (13)CO experiments however the large separation between (13)CO and (13)C(alpha) chemical shifts offers hope that robust (13)CO dispersion profiles can be recorded on uniformly (13)C labeled samples, leading to the extraction of accurate (13)CO chemical shifts of the invisible, excited state. Here we compare such chemical shifts recorded on samples that are selectively labeled, prepared using [1-(13)C]-pyruvate and NaH(13)CO(3,) or uniformly labeled, generated from (13)C-glucose. Very similar (13)CO chemical shifts are obtained from analysis of CPMG experiments recorded on both samples, and comparison with chemical shifts measured using a second approach establishes that the shifts measured from relaxation dispersion are very accurate. 相似文献
229.
Starch is the most important energy resource in human diet, and starch is used extensively as a food ingredient to manipulate
the quality of our food. In both applications, starch functionality is intimately related to its hydration level. This paper
aims at elucidating the starch granule hydration by investigating genotype-specific differences for native wheat, maize, and
potato starches by 1H high-resolution (HR) magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy. The preparations as analyzed
in D2O suspensions at room temperature provided NMR spectra with large differences in signal-to-noise (S/N) ratio ranging over
several orders of magnitude. It was possible to assign a wide range of components including anomeric α-1,4 and α-1,6-protons
from reducing and non-reducing ends, respectively. We utilized the effect that only mobile protons (e.g, dissolved or partially
hydrated) are observed using 1H HR-MAS spectroscopy, whereas immobile protons (e.g., in water-inaccessible regions) of the starch granule are not observed
due to strong homonuclear interactions to verify the hypothesis that the variations in signal intensities between the different
starches are caused by genotype-specific variations in assembly of the starch granules and that the signal intensity, thus,
indicates the extent of accessible granule hydration surfaces. Moreover, events taking place during thermal starch granule
hydration (gelatinization) were investigated for ten representative starches. NMR spectra of suspended samples were acquired
at 30, 45 and 70 °C and again after cooling at 30 °C. A substantial increase in NMR signal intensity occurs above the gelatinization
temperature due to extensive proton mobilization in the starch granule assembly. The relative integrated spectral intensities
at 30 °C before and after gelatinization at 70 °C showed differences in gain factors between 4 and 193. Also, 31P MAS NMR spectra displayed a similar significant intensity gain upon gelatinization. The results showed that the phosphate
groups in the starch granule are mobilized concomitantly with the protons and thus deeply “buried” in the immobile (water
inaccessible) domains. 相似文献
230.
Effects of ocean acidification increase embryonic sensitivity to thermal extremes in Atlantic cod,Gadus morhua
下载免费PDF全文
![点击此处可从《Global Change Biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Flemming T. Dahlke Elettra Leo Felix C. Mark Hans‐Otto Pörtner Ulf Bickmeyer Stephan Frickenhaus Daniela Storch 《Global Change Biology》2017,23(4):1499-1510
Thermal tolerance windows serve as a powerful tool for estimating the vulnerability of marine species and their life stages to increasing temperature means and extremes. However, it remains uncertain to which extent additional drivers, such as ocean acidification, modify organismal responses to temperature. This study investigated the effects of CO2‐driven ocean acidification on embryonic thermal sensitivity and performance in Atlantic cod, Gadus morhua, from the Kattegat. Fertilized eggs were exposed to factorial combinations of two PCO2 conditions (400 μatm vs. 1100 μatm) and five temperature treatments (0, 3, 6, 9 and 12 °C), which allow identifying both lower and upper thermal tolerance thresholds. We quantified hatching success, oxygen consumption (MO2) and mitochondrial functioning of embryos as well as larval morphometrics at hatch and the abundance of acid–base‐relevant ionocytes on the yolk sac epithelium of newly hatched larvae. Hatching success was high under ambient spawning conditions (3–6 °C), but decreased towards both cold and warm temperature extremes. Elevated PCO2 caused a significant decrease in hatching success, particularly at cold (3 and 0 °C) and warm (12 °C) temperatures. Warming imposed limitations to MO2 and mitochondrial capacities. Elevated PCO2 stimulated MO2 at cold and intermediate temperatures, but exacerbated warming‐induced constraints on MO2, indicating a synergistic interaction with temperature. Mitochondrial functioning was not affected by PCO2. Increased MO2 in response to elevated PCO2 was paralleled by reduced larval size at hatch. Finally, ionocyte abundance decreased with increasing temperature, but did not differ between PCO2 treatments. Our results demonstrate increased thermal sensitivity of cod embryos under future PCO2 conditions and suggest that acclimation to elevated PCO2 requires reallocation of limited resources at the expense of embryonic growth. We conclude that ocean acidification constrains the thermal performance window of embryos, which has important implication for the susceptibility of cod to projected climate change. 相似文献