全文获取类型
收费全文 | 1527篇 |
免费 | 109篇 |
国内免费 | 1篇 |
出版年
2022年 | 8篇 |
2021年 | 20篇 |
2020年 | 14篇 |
2019年 | 10篇 |
2018年 | 20篇 |
2017年 | 14篇 |
2016年 | 26篇 |
2015年 | 51篇 |
2014年 | 76篇 |
2013年 | 67篇 |
2012年 | 101篇 |
2011年 | 98篇 |
2010年 | 64篇 |
2009年 | 51篇 |
2008年 | 81篇 |
2007年 | 68篇 |
2006年 | 67篇 |
2005年 | 67篇 |
2004年 | 64篇 |
2003年 | 53篇 |
2002年 | 55篇 |
2001年 | 23篇 |
2000年 | 26篇 |
1999年 | 26篇 |
1998年 | 13篇 |
1997年 | 18篇 |
1996年 | 18篇 |
1995年 | 9篇 |
1994年 | 12篇 |
1993年 | 6篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 20篇 |
1989年 | 14篇 |
1988年 | 11篇 |
1987年 | 9篇 |
1986年 | 11篇 |
1985年 | 18篇 |
1984年 | 30篇 |
1983年 | 16篇 |
1982年 | 43篇 |
1981年 | 35篇 |
1980年 | 29篇 |
1979年 | 44篇 |
1978年 | 25篇 |
1977年 | 31篇 |
1976年 | 9篇 |
1975年 | 7篇 |
1971年 | 4篇 |
1969年 | 4篇 |
排序方式: 共有1637条查询结果,搜索用时 15 毫秒
191.
Claudio Gemperle Mattia Schmid Magdalena Herova Jacqueline Marti-Jaun Sophia J. A. Wuest Christa Loretz Martin Hersberger 《PloS one》2012,7(11)
The formyl peptide receptor 1 (FPR1) is mainly expressed by mammalian phagocytic leukocytes and plays a role in chemotaxis, killing of microorganisms through phagocytosis, and the generation of reactive oxygen species. A large number of ligands have been identified triggering FPR1 including formylated and non-formylated peptides of microbial and endogenous origin. While the expression of FPR1 in neutrophils has been investigated intensively, knowledge on the regulation of FPR1 expression in polarized macrophages is lacking. In this study we show that primary human neutrophils, monocytes and resting macrophages do express the receptor on their cell surface. Polarization of macrophages with IFNγ, LPS and with the TLR8 ligand 3M-002 further increases FPR1 mRNA levels but does not consistently increase protein expression or chemotaxis towards the FPR1 ligand fMLF. In contrast, polarization of primary human macrophages with IL-4 and IL-13 leading to the alternative activated macrophages, reduces FPR1 cell surface expression and abolishes chemotaxis towards fMLF. These results show that M2 macrophages will not react to triggering of FPR1, limiting the role for FPR1 to chemotaxis and superoxide production of resting and pro-inflammatory M1 macrophages. 相似文献
192.
Patrick A. Randall Marta Pardo Eric J. Nunes Laura López Cruz V. Kiran Vemuri Alex Makriyannis Younis Baqi Christa E. Müller Mercè Correa John D. Salamone 《PloS one》2012,7(10)
Mesolimbic dopamine (DA) is involved in behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. In the present study, the effects of several drug treatments were assessed using a progressive ratio (PROG)/chow feeding concurrent choice task. With this task, rats can lever press on a PROG schedule reinforced by a preferred high-carbohydrate food pellet, or alternatively approach and consume the less-preferred but concurrently available laboratory chow. Rats pass through each ratio level 15 times, after which the ratio requirement is incremented by one additional response. The DA D2 antagonist haloperidol (0.025–0.1 mg/kg) reduced number of lever presses and highest ratio achieved but did not reduce chow intake. In contrast, the adenosine A2A antagonist MSX-3 increased lever presses and highest ratio achieved, but decreased chow consumption. The cannabinoid CB1 inverse agonist and putative appetite suppressant AM251 decreased lever presses, highest ratio achieved, and chow intake; this effect was similar to that produced by pre-feeding. Furthermore, DA-related signal transduction activity (pDARPP-32(Thr34) expression) was greater in nucleus accumbens core of high responders (rats with high lever pressing output) compared to low responders. Thus, the effects of DA antagonism differed greatly from those produced by pre-feeding or reduced CB1 transmission, and it appears unlikely that haloperidol reduces PROG responding because of a general reduction in primary food motivation or the unconditioned reinforcing properties of food. Furthermore, accumbens core signal transduction activity is related to individual differences in work output. 相似文献
193.
Javaid Nauman Stian Thoresen Aspenes Tom Ivar Lund Nilsen Lars J. Vatten Ulrik Wisl?ff 《PloS one》2012,7(9)
Objectives
We assessed the prospective association of resting heart rate (RHR) at baseline with peak oxygen uptake (VO2peak) 23 years later, and evaluated whether physical activity (PA) could modify this association.Background
Both RHR and VO2peak are strong and independent predictors of cardiovascular morbidity and mortality. However, the association of RHR with VO2peak and modifying effect of PA have not been prospectively assessed in population studies.Methods
In 807 men and 810 women free from cardiovascular disease both at baseline (1984–86) and follow-up 23 years later, RHR was recorded at both occasions, and VO2peak was measured by ergospirometry at follow-up. We used Generalized Linear Models to assess the association of baseline RHR with VO2peak, and to study combined effects of RHR and self-reported PA on later VO2peak.Results
There was an inverse association of RHR at baseline with VO2peak (p<0.01). Men and women with baseline RHR greater than 80 bpm had 4.6 mL·kg−1·min−1 (95% confidence interval [CI], 2.8 to 6.3) and 1.4 mL·kg−1·min−1 (95% CI, −0.4 to 3.1) lower VO2peak at follow-up compared with men and women with RHR below 60 bpm at baseline. We found a linear association of change in RHR with VO2peak (p = 0.03), suggesting that a decrease in RHR over time is likely to be beneficial for cardiovascular fitness. Participants with low RHR and high PA at baseline had higher VO2peak than inactive people with relatively high RHR. However, among participants with relatively high RHR and high PA at baseline, VO2peak was similar to inactive people with relatively low RHR.Conclusion
RHR is an important predictor of VO2peak, and serial assessments of RHR may provide useful and inexpensive information on cardiovascular fitness. The results suggest that high levels of PA may compensate for the lower VO2peak associated with a high RHR. 相似文献194.
Rakel Brendsdal Forthun Tanima SenGupta Hanne Kim Skjeldam Jessica Margareta Lindvall Emmet McCormack Bj?rn Tore Gjertsen Hilde Nilsen 《PloS one》2012,7(11)
The mechanisms of successful epigenetic reprogramming in cancer are not well characterized as they involve coordinated removal of repressive marks and deposition of activating marks by a large number of histone and DNA modification enzymes. Here, we have used a cross-species functional genomic approach to identify conserved genetic interactions to improve therapeutic effect of the histone deacetylase inhibitor (HDACi) valproic acid, which increases survival in more than 20% of patients with advanced acute myeloid leukemia (AML). Using a bidirectional synthetic lethality screen revealing genes that increased or decreased VPA sensitivity in C. elegans, we identified novel conserved sensitizers and synthetic lethal interactors of VPA. One sensitizer identified as a conserved determinant of therapeutic success of HDACi was UTX (KDM6A), which demonstrates a functional relationship between protein acetylation and lysine-specific methylation. The synthetic lethal screen identified resistance programs that compensated for the HDACi-induced global hyper-acetylation, and confirmed MAPKAPK2, HSP90AA1, HSP90AB1 and ACTB as conserved hubs in a resistance program for HDACi that are drugable in human AML cell lines. Hence, these resistance hubs represent promising novel targets for refinement of combinatorial epigenetic anti-cancer therapy. 相似文献
195.
Objective
Hyperuricemia is associated with an increased risk of metabolic and cardiovascular diseases. There are pronounced sex differences in the levels of uric acid. It is largely unknown whether or not reproductive parameters which induce hormonal changes are responsible for this. We examined if there are associations between reproductive parameters and uric acid levels in a female population-based sample.Methods
In this cross-sectional analysis, data of 1530 women aged 32 to 81 years participating in the KORA F4 study, conducted between 2006 and 2008 in Southern Germany were used. Reproductive parameters were obtained by standardized interviews. Uric acid levels were tested by the uricase method. The whole study sample and stratified in pre- and postmenopausal women was analyzed.Results
Menopausal status and earlier age at menarche were associated with higher serum uric acid levels (age-adjusted: p-values 0.003, <0.001 respectively; after multivariable adjustment, including BMI: p-values 0.002, 0.036). A history of oral contraceptive use showed an association with uric acid levels only after multivariable adjustment (p-value 0.009). Hot flushes showed an association with uric acid levels only after age-adjustment (p-value 0.038), but lost significance after adding other confounders. Other reproductive factors, including parity, current or ever use of hormone replacement therapy, current use of oral contraceptives, hysterectomy, bilateral oophorectomy, or depressive mood related to menopausal transition were not associated with uric acid levels.Conclusions
Postmenopausal status, earlier age at menarche and a history of oral contraceptive use were independently associated with higher serum uric acid concentrations in women from the general population. Further studies, especially longitudinal population-based studies investigating the relationship of female reproductive parameters with uric acid levels are necessary to confirm our findings. 相似文献196.
PA Naesgaard RA León De La Fuente ST Nilsen L Woie T Aarsland C Brede H Staines DW Nilsen 《PloS one》2012,7(9):e43228
Background
Several studies have shown an association between vitamin D deficiency and cardiovascular risk. Vitamin D status is assessed by determination of 25-hydroxyvitamin D [25(OH)D] in serum.Methods
We assessed the prognostic utility of 25(OH)D in 982 chest-pain patients with suspected acute coronary syndrome (ACS) from Salta, Northern Argentina. 2-year follow-up data including all-cause mortality, cardiac death and sudden cardiac death were analyzed in quartiles of 25(OH)D, applying univariate and multivariate analysis.Results
There were statistically significant changes in seasonal 25(OH)D levels. At follow-up, 119 patients had died. The mean 25(OH)D levels were significantly lower among patients dying than in long-term survivors, both in the total population and in patients with a troponin T (TnT) release (n = 388). When comparing 25(OH)D in the highest quartile to the lowest quartile in a multivariable Cox regression model for all-cause mortality, the hazard ratio (HR) for cardiac death and sudden cardiac death in the total population was 0.37 (95% CI, 0.19–0.73), p = 0.004, 0.23 (95% CI, 0.08–0.67), p = 0.007, and 0.32 (95% CI, 0.11–0.94), p = 0.038, respectively. In patients with TnT release, the respective HR was 0.24 (95% CI, 0.10–0.54), p = 0.001, 0.18 (95% CI, 0.05–0.60), p = 0.006 and 0.25 (95% CI, 0.07–0.89), p = 0.033. 25(OH)D had no prognostic value in patients with no TnT release.Conclusion
Vitamin D was shown to be a useful biomarker for prediction of mortality when obtained at admission in chest pain patients with suspected ACS.Trial registration
ClinicalTrials.gov NCT01377402相似文献197.
Christ A Christa A Kur E Lioubinski O Bachmann S Willnow TE Hammes A 《Developmental cell》2012,22(2):268-278
Sonic hedgehog (SHH) is a regulator of forebrain development that acts through its receptor, patched 1. However, little is known about cellular mechanisms at neurulation, whereby SHH from the prechordal plate governs specification of the rostral diencephalon ventral midline (RDVM), a major forebrain organizer. We identified LRP2, a member of the LDL receptor gene family, as a component of the SHH signaling machinery in the RDVM. LRP2 acts as an apical SHH-binding protein that sequesters SHH in its target field and controls internalization and cellular trafficking of SHH/patched 1 complexes. Lack of LRP2 in mice and in cephalic explants results in failure to respond to SHH, despite functional expression of patched 1 and smoothened, whereas overexpression of LRP2 variants in cells increases SHH signaling capacity. Our data identify a critical role for LRP2 in SHH signaling and reveal the molecular mechanism underlying forebrain anomalies in mice and patients with Lrp2 defects. 相似文献
198.
Henrik Br?seth Erlend B. Nilsen Hans C. Pedersen 《European Journal of Wildlife Research》2012,58(5):797-802
Theoretical models have shown that the effect of removing a given proportion of the population can be profoundly different if the harvest takes place late in the season compared to early. We explore the effect of these differences using theoretical models based on the concept of demographic value and empirical data on seasonal patterns of natural mortality risk in two contrasting populations of willow ptarmigan in Norway. Based on the theoretical models, we found that changes in the timing of harvest have a much stronger effect in populations with relatively low annual survival compared to populations characterized by longevity typical for species with slow life histories. Also, the timing of harvest is more influential in cases with constant mortality hazards compared to a situation with density-dependent natural mortality. Empirical data from two study populations of willow ptarmigan showed large deviations from the theoretical predictions of models with both constant and density-dependent mortality hazards. There were also large differences in both the temporal pattern and magnitude of annual survival between the two ptarmigan populations (54 vs 26% annual survival). Site differences illustrate the importance of knowledge of both the magnitude and temporal pattern of natural mortality hazard to be able to correctly predict the effect of changing the timing of harvest in a population. In the two ptarmigan populations, we show how harvest quotas can be adjusted in accordance to the empirical estimates of natural mortality risk and how this determines the effects of shifting from harvesting early to late in the annual cycle. 相似文献
199.
M Soudi M Zamocky C Jakopitsch PG Furtmüller C Obinger 《Chemistry & biodiversity》2012,9(9):1776-1793
Peroxidasins represent the subfamily 2 of the peroxidase-cyclooxygenase superfamily and are closely related to chordata peroxidases (subfamily 1) and peroxinectins (subfamily 3). They are multidomain proteins containing a heme peroxidase domain with high homology to human lactoperoxidase that mediates one- and two-electron oxidation reactions. Additional domains of the secreted and glycosylated metalloproteins are type C-like immunoglobulin domains, typical leucine-rich repeats, as well as a von Willebrand factor C module. These are typical motifs of extracellular proteins that mediate protein-protein interactions. We have reconstructed the phylogeny of this new family of oxidoreductases and show the presence of four invertebrate clades as well as one vertebrate clade that includes also two different human representatives. The variability of domain assembly in the various clades was analyzed, as was the occurrence of relevant catalytic residues in the peroxidase domain based on the knowledge of catalysis of the mammalian homologues. Finally, the few reports on expression, localization, enzymatic activity, and physiological roles in the model organisms Drosophila melanogaster, Caenorhabditis elegans, and Homo sapiens are critically reviewed. Roles attributed to peroxidasins include antimicrobial defense, extracellular matrix formation, and consolidation at various developmental stages. Many research questions need to be solved in future, including detailed biochemical/physical studies and elucidation of the three dimensional structure of a model peroxidasin as well as the relation and interplay of the domains and the in vivo functions in various organisms including man. 相似文献
200.
In cerebrospinal fluid (CSF) analysis, hematology analyzers (HAs) Sysmex? XT-4000i and XE-5000, equipped with flow cytometry (FCM), were used to count cells and differentiate leukocytes into mononuclear and polymorphonuclear cells (MNCs, PMCs) applying body fluid mode. FCM was evaluated with 20 DGKL CSF controls containing viable human leukocytes and erythrocytes. HA values were compared with reference values by Passing/Bablok regression analysis to reveal conformity. Conformity of white blood cells (WBCs) was obtained with native leukocytes, counted in calibrated Fuchs-Rosenthal chamber as reference; red blood cell counts proved inaccurate. CV <40% with WBC counts <20 per μL impairs accuracy. Reference WBC differentiation was assayed using FACS Canto II? and FC-500 SN with anti-CD45, anti-CD14, anti-CD16, anti-CD16/56 [Becton Dickinson (BD); Beckman Coulter (BC)]. BD FACS lysing solution?-no-wash-procedure was applied. BC pretreatment with Versalyse lysing solution was not recommended. MNCs (lymphocytes + monocytes) were significantly lower (~14%) on both HAs; PMCs (granulocytes or sum of neutrophils + eosinophils + basophils: range 1-86 M/L) were significantly higher (~2.2-fold). WBC HA differentiation is not reliable because MNC/PMC differentiation yielded lower and higher values than FACS-FCM references, respectively. This is attributed to incorrect discrimination of leukocytes with rounded/nonrounded nuclei; adding leukocytes with nonrounded nuclei to too low HA MNCs (about 40% not-activated) yielded P/B conformity; subtraction of leukocytes with nonrounded nuclei from elevated HA PMCs showed conformity (about 85% activated). Nucleus/activation state of leukocytes was assessed using microhistology. Sysmex XT-4000i and XE-5000 HAs systems are inappropriate for complete CSF cell analysis. 相似文献