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101.
GA Thun I Ferrarotti M Imboden T Rochat M Gerbase F Kronenberg PO Bridevaux E Zemp M Zorzetto S Ottaviani EW Russi M Luisetti NM Probst-Hensch 《PloS one》2012,7(8):e42728
Background
Severe alpha1-antitrypsin (AAT) deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi) S or Z allele (PiMS and PiMZ) on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study.Methodology and Principal Findings
The SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP), were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (ΔFEF25-75%) of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p = 0.03). Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM) vs. 108.2 ml (PiMZ), p = 0.005). Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio.Conclusions
We suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation. 相似文献102.
Laura Pizzuti Maddalena Barba Diana Giannarelli Domenico Sergi Claudio Botti Paolo Marchetti Michele Anzà Marcello Maugeri‐Saccà Clara Natoli Simona Di Filippo Teresa Catenaro Federica Tomao Antonella Amodio Silvia Carpano Letizia Perracchio Marcella Mottolese Luigi Di Lauro Giuseppe Sanguineti Anna Di Benedetto Antonio Giordano Patrizia Vici 《Journal of cellular physiology》2016,231(11):2541-2547
To report the results of the DECT trial, a phase II study of locally advanced or operable HER2‐positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA‐IIIB HER2‐positive BC, 18–75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m2 intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3‐weekly cycles of epirubicin 120 mg/m2 and cyclophosphamide, 600 mg/m2, plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8–78). Four‐year recurrence‐free survival was 74.7% (95%CI, 58.2–91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541–2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. 相似文献
103.
Association between a school‐based intervention and adiposity outcomes in adolescents: The Italian “EAT” project 下载免费PDF全文
104.
Peng Zhang James C. Weaver Gang Chen Julia Beretov Tatsuya Atsumi Miao Qi Ravinay Bhindi Jian C. Qi Michele C. Madigan Bill Giannakopoulos Steven A. Krilis 《PloS one》2016,11(3)
Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI. 相似文献
105.
Buckmelter AJ Ren L Laird ER Rast B Miknis G Wenglowsky S Schlachter S Welch M Tarlton E Grina J Lyssikatos J Brandhuber BJ Morales T Randolph N Vigers G Martinson M Callejo M 《Bioorganic & medicinal chemistry letters》2011,21(4):1248-1252
Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf. 相似文献
106.
The distribution of residues in a polypeptide sequence is a determinant of aggregation optimized by evolution 下载免费PDF全文
Monsellier E Ramazzotti M de Laureto PP Tartaglia GG Taddei N Fontana A Vendruscolo M Chiti F 《Biophysical journal》2007,93(12):4382-4391
It has been shown that the propensity of a protein to form amyloid-like fibrils can be predicted with high accuracy from the knowledge of its amino acid sequence. It has also been suggested, however, that some regions of the sequences are more important than others in determining the aggregation process. Here, we have addressed this issue by constructing a set of “sequence scrambled” variants of the first 29 residues of horse heart apomyoglobin (apoMb1-29), in which the sequence was modified while maintaining the same amino acid composition. The clustering of the most amyloidogenic residues in one region of the sequence was found to cause a marked increase of the elongation rate (kagg) and a remarkable shortening of the lag phase (tlag) of the fibril growth, as determined by far-UV circular dichroism and thioflavin T fluorescence. We also show that taking explicitly into consideration the presence of aggregation-promoting regions in the predictive methods results in a quantitative agreement between the theoretical and observed kagg and tlag values of the apoMb1-29 variants. These results, together with a comparison between homologous segments from the family of globins, indicate the existence of a negative selection against the clustering of highly amyloidogenic residues in one or few regions of polypeptide sequences. 相似文献
107.
Light acclimation involves dynamic re‐organization of the pigment–protein megacomplexes in non‐appressed thylakoid domains 下载免费PDF全文
Marjaana Suorsa Marjaana Rantala Fikret Mamedov Maija Lespinasse Andrea Trotta Michele Grieco Eerika Vuorio Mikko Tikkanen Sari Järvi Eva‐Mari Aro 《The Plant journal : for cell and molecular biology》2015,84(2):360-373
Thylakoid energy metabolism is crucial for plant growth, development and acclimation. Non‐appressed thylakoids harbor several high molecular mass pigment–protein megacomplexes that have flexible compositions depending upon the environmental cues. This composition is important for dynamic energy balancing in photosystems (PS) I and II. We analysed the megacomplexes of Arabidopsis wild type (WT) plants and of several thylakoid regulatory mutants. The stn7 mutant, which is defective in phosphorylation of the light‐harvesting complex (LHC) II, possessed a megacomplex composition that was strikingly different from that of the WT. Of the nine megacomplexes in total for the non‐appressed thylakoids, the largest megacomplex in particular was less abundant in the stn7 mutant under standard growth conditions. This megacomplex contains both PSI and PSII and was recently shown to allow energy spillover between PSII and PSI (Nat. Commun., 6, 2015, 6675). The dynamics of the megacomplex composition was addressed by exposing plants to different light conditions prior to thylakoid isolation. The megacomplex pattern in the WT was highly dynamic. Under darkness or far red light it showed low levels of LHCII phosphorylation and resembled the stn7 pattern; under low light, which triggers LHCII phosphorylation, it resembled that of the tap38/pph1 phosphatase mutant. In contrast, solubilization of the entire thylakoid network with dodecyl maltoside, which efficiently solubilizes pigment–protein complexes from all thylakoid compartments, revealed that the pigment–protein composition remained stable despite the changing light conditions or mutations that affected LHCII (de)phosphorylation. We conclude that the composition of pigment–protein megacomplexes specifically in non‐appressed thylakoids undergoes redox‐dependent changes, thus facilitating maintenance of the excitation balance between the two photosystems upon changes in light conditions. 相似文献
108.
Andrea Madeo Paolo Piras Federica Re Stefano Gabriele Paola Nardinocchi Luciano Teresi Concetta Torromeo Claudia Chialastri Michele Schiariti Geltrude Giura Antonietta Evangelista Tania Dominici Valerio Varano Elisabetta Zachara Paolo Emilio Puddu 《PloS one》2015,10(4)
The assessment of left ventricular shape changes during cardiac revolution may be a new step in clinical cardiology to ease early diagnosis and treatment. To quantify these changes, only point registration was adopted and neither Generalized Procrustes Analysis nor Principal Component Analysis were applied as we did previously to study a group of healthy subjects. Here, we extend to patients affected by hypertrophic cardiomyopathy the original approach and preliminarily include genotype positive/phenotype negative individuals to explore the potential that incumbent pathology might also be detected. Using 3D Speckle Tracking Echocardiography, we recorded left ventricular shape of 48 healthy subjects, 24 patients affected by hypertrophic cardiomyopathy and 3 genotype positive/phenotype negative individuals. We then applied Generalized Procrustes Analysis and Principal Component Analysis and inter-individual differences were cleaned by Parallel Transport performed on the tangent space, along the horizontal geodesic, between the per-subject consensuses and the grand mean. Endocardial and epicardial layers were evaluated separately, different from many ecocardiographic applications. Under a common Principal Component Analysis, we then evaluated left ventricle morphological changes (at both layers) explained by first Principal Component scores. Trajectories’ shape and orientation were investigated and contrasted. Logistic regression and Receiver Operating Characteristic curves were used to compare these morphometric indicators with traditional 3D Speckle Tracking Echocardiography global parameters. Geometric morphometrics indicators performed better than 3D Speckle Tracking Echocardiography global parameters in recognizing pathology both in systole and diastole. Genotype positive/phenotype negative individuals clustered with patients affected by hypertrophic cardiomyopathy during diastole, suggesting that incumbent pathology may indeed be foreseen by these methods. Left ventricle deformation in patients affected by hypertrophic cardiomyopathy compared to healthy subjects may be assessed by modern shape analysis better than by traditional 3D Speckle Tracking Echocardiography global parameters. Hypertrophic cardiomyopathy pathophysiology was unveiled in a new manner whereby also diastolic phase abnormalities are evident which is more difficult to investigate by traditional ecocardiographic techniques. 相似文献
109.
Bello C Dal Bello G Cea M Nahimana A Aubry D Garuti A Motta G Moran E Fruscione F Pronzato P Grossi F Patrone F Ballestrero A Dupuis M Sordat B Zimmermann K Loretan J Wartmann M Duchosal MA Nencioni A Vogel P 《Bioorganic & medicinal chemistry》2011,19(24):7720-7727
New derivatives of 1,4-dideoxy-1,4-imino-d-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-d-ribitol (13, IC50 ∼2 μM) and its C18-analogues (IC50 <10 μM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC50 ∼8 μM) growth of JURKAT cells. 相似文献
110.
Laeyendecker O Church JD Oliver AE Mwatha A Owen SM Donnell D Brookmeyer R Musoke P Jackson JB Guay L Nakabiito C Quinn TC Eshleman SH 《PloS one》2010,5(10):e13259