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121.
An efficient new method is presented for the characterization of motional correlations derived from a set of protein structures without requiring the separation of overall and internal motion. In this method, termed isotropically distributed ensemble (IDE) analysis, each structure is represented by an ensemble of isotropically distributed replicas corresponding to the situation found in an isotropic protein solution. This leads to a covariance matrix of the cartesian atomic positions with elements proportional to the ensemble average of scalar products of the position vectors with respect to the center of mass. Diagonalization of the covariance matrix yields eigenmodes and amplitudes that describe concerted motions of atoms, including overall rotational and intramolecular dynamics. It is demonstrated that this covariance matrix naturally distinguishes between "rigid" and "mobile" parts without necessitating a priori selection of a reference structure and an atom set for the orientational alignment process. The method was applied to the analysis of a 5-ns molecular dynamics trajectory of native ubiquitin and a 40-ns trajectory of a partially folded state of ubiquitin. The results were compared with essential dynamics analysis. By taking advantage of the spherical symmetry of the IDE covariance matrix, more than a 10-fold speed up is achieved for the computation of eigenmodes and mode amplitudes. IDE analysis is particularly suitable for studying the correlated dynamics of flexible and large molecules. 相似文献
122.
Lauren C. Balmert Jeanine M. Buchanich Janice L. Pringle Karl E. Williams Donald S. Burke Gary M. Marsh 《PloS one》2016,11(3)
IntroductionThe purpose of this study was to examine county and state-level accidental poisoning mortality trends in Pennsylvania from 1979 to 2014.MethodsCrude and age-adjusted death rates were formed for age group, race, sex, and county for accidental poisonings (ICD 10 codes X40-X49) from 1979 to 2014 for ages 15+ using the Mortality and Population Data System housed at the University of Pittsburgh. Rate ratios were calculated comparing rates from 1979 to 2014, overall and by sex, age group, and race. Joinpoint regression was used to detect statistically significant changes in trends of age-adjusted mortality rates.ResultsRate ratios for accidental poisoning mortality in Pennsylvania increased more than 14-fold from 1979 to 2014. The largest rate ratios were among 35–44 year olds, females, and White adults. The highest accidental poisoning mortality rates were found in the counties of Southwestern Pennsylvania, those surrounding Philadelphia, and those in Northeast Pennsylvania near Scranton.ConclusionsThe patterns and locations of accidental poisoning mortality by race, sex, and age group provide direction for interventions and policy makers. In particular, this study found the highest rate ratios in PA among females, whites, and the age group 35–44. 相似文献
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124.
Marian Beekman Hélène Blanché Markus Perola Anti Hervonen Vladyslav Bezrukov Ewa Sikora Friederike Flachsbart Lene Christiansen Anton J. M. De Craen Tom B. L. Kirkwood Irene Maeve Rea Michel Poulain Jean‐Marie Robine Silvana Valensin Maria Antonietta Stazi Giuseppe Passarino Luca Deiana Efstathios S. Gonos Lavinia Paternoster Thorkild I. A. Sørensen Qihua Tan Quinta Helmer Erik B. van den Akker Joris Deelen Francesca Martella Heather J. Cordell Kristin L. Ayers James W. Vaupel Outi Törnwall Thomas E. Johnson Stefan Schreiber Mark Lathrop Axel Skytthe Rudi G. J. Westendorp Kaare Christensen Jutta Gampe Almut Nebel Jeanine J. Houwing‐Duistermaat Pieternella Eline Slagboom Claudio Franceschi the GEHA consortium 《Aging cell》2013,12(2):184-193
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome‐wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12‐q22 (LOD = 2.95), chromosome 19p13.3‐p13.11 (LOD = 3.76), and chromosome 19q13.11‐q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed‐effect meta‐analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P‐value = 9.6 × 10?8). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11‐q13.32 with P‐value = 0.02 and P‐value = 1.0 × 10?5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12‐q22, and 19p13.3‐p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity. 相似文献
125.
Massa SI Pearson GA Aires T Kube M Olsen JL Reinhardt R Serrão EA Arnaud-Haond S 《Marine Genomics》2011,4(3):181-188
Predicted global climate change threatens the distributional ranges of species worldwide. We identified genes expressed in the intertidal seagrass Zostera noltii during recovery from a simulated low tide heat-shock exposure. Five Expressed Sequence Tag (EST) libraries were compared, corresponding to four recovery times following sub-lethal temperature stress, and a non-stressed control. We sequenced and analyzed 7009 sequence reads from 30 min, 2 h, 4 h and 24 h after the beginning of the heat-shock (AHS), and 1585 from the control library, for a total of 8594 sequence reads. Among 51 Tentative UniGenes (TUGs) exhibiting significantly different expression between libraries, 19 (37.3%) were identified as ‘molecular chaperones’ and were over-expressed following heat-shock, while 12 (23.5%) were ‘photosynthesis TUGs’ generally under-expressed in heat-shocked plants. A time course analysis of expression showed a rapid increase in expression of the molecular chaperone class, most of which were heat-shock proteins; which increased from 2 sequence reads in the control library to almost 230 in the 30 min AHS library, followed by a slow decrease during further recovery. In contrast, ‘photosynthesis TUGs’ were under-expressed 30 min AHS compared with the control library, and declined progressively with recovery time in the stress libraries, with a total of 29 sequence reads 24 h AHS, compared with 125 in the control. A total of 4734 TUGs were screened for EST-Single Sequence Repeats (EST-SSRs) and 86 microsatellites were identified. 相似文献
126.
Jeanine F. Amacher Patrick R. Cushing Christopher D. Bahl Tobias Beck Dean R. Madden 《The Journal of biological chemistry》2013,288(7):5114-5126
PDZ (PSD-95/Dlg/ZO-1) binding domains often serve as cellular traffic engineers, controlling the localization and activity of a wide variety of binding partners. As a result, they play important roles in both physiological and pathological processes. However, PDZ binding specificities overlap, allowing multiple PDZ proteins to mediate distinct effects on shared binding partners. For example, several PDZ domains bind the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), an epithelial ion channel mutated in CF. Among these binding partners, the CFTR-associated ligand (CAL) facilitates post-maturational degradation of the channel and is thus a potential therapeutic target. Using iterative optimization, we previously developed a selective CAL inhibitor peptide (iCAL36). Here, we investigate the stereochemical basis of iCAL36 specificity. The crystal structure of iCAL36 in complex with the CAL PDZ domain reveals stereochemical interactions distributed along the peptide-binding cleft, despite the apparent degeneracy of the CAL binding motif. A critical selectivity determinant that distinguishes CAL from other CFTR-binding PDZ domains is the accommodation of an isoleucine residue at the C-terminal position (P0), a characteristic shared with the Tax-interacting protein-1. Comparison of the structures of these two PDZ domains in complex with ligands containing P0 Leu or Ile residues reveals two distinct modes of accommodation for β-branched C-terminal side chains. Access to each mode is controlled by distinct residues in the carboxylate-binding loop. These studies provide new insights into the primary sequence determinants of binding motifs, which in turn control the scope and evolution of PDZ interactomes. 相似文献
127.
Differential effects of short- and long-term high-fat diet feeding on hepatic fatty acid metabolism in rats 总被引:1,自引:0,他引:1
Ciapaite J van den Broek NM Te Brinke H Nicolay K Jeneson JA Houten SM Prompers JJ 《Biochimica et biophysica acta》2011,1811(7-8):441-451
Imbalance in the supply and utilization of fatty acids (FA) is thought to contribute to intrahepatic lipid (IHL) accumulation in obesity. The aim of this study was to determine the time course of changes in the liver capacity to oxidize and store FA in response to high-fat diet (HFD). Adult male Wistar rats were fed either normal chow or HFD for 2.5weeks (short-term) and 25weeks (long-term). Short-term HFD feeding led to a 10% higher palmitoyl-l-carnitine-driven ADP-stimulated (state 3) oxygen consumption rate in isolated liver mitochondria indicating up-regulation of β-oxidation. This adaptation was insufficient to cope with the dietary FA overload, as indicated by accumulation of long-chain acylcarnitines, depletion of free carnitine and increase in FA content in the liver, reflecting IHL accumulation. The latter was confirmed by in vivo((1))H magnetic resonance spectroscopy and Oil Red O staining. Long-term HFD feeding caused further up-regulation of mitochondrial β-oxidation (24% higher oxygen consumption rate in state 3 with palmitoyl-l-carnitine as substrate) and stimulation of mitochondrial biogenesis as indicated by 62% higher mitochondrial DNA copy number compared to controls. These adaptations were paralleled by a partial restoration of free carnitine levels and a decrease in long-chain acylcarnitine content. Nevertheless, there was a further increase in IHL content, accompanied by accumulation of lipid peroxidation and protein oxidation products. In conclusion, partially effective adaption of hepatic FA metabolism to long-term HFD feeding came at a price of increased oxidative stress, caused by a combination of higher FA oxidation capacity and oversupply of FA. 相似文献
128.
Asma Ben Ammar Payam Soltanzadeh Stéphanie Bauché Pascale Richard Evelyne Goillot Ruth Herbst Karen Gaudon Caroline Huzé Laurent Schaeffer Yuji Yamanashi Osamu Higuchi Antoine Taly Jeanine Koenig Jean-Paul Leroy Fay?al Hentati Hossein Najmabadi Kimia Kahrizi Manouchehr Ilkhani Michel Fardeau Bruno Eymard Daniel Hanta? 《PloS one》2013,8(1)
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient’s biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation. 相似文献
129.
Alexander Jueterbock Lennert Tyberghein Heroen Verbruggen James A. Coyer Jeanine L. Olsen Galice Hoarau 《Ecology and evolution》2013,3(5):1356-1373
The North-Atlantic has warmed faster than all other ocean basins and climate change scenarios predict sea surface temperature isotherms to shift up to 600 km northwards by the end of the 21st century. The pole-ward shift has already begun for many temperate seaweed species that are important intertidal foundation species. We asked the question: Where will climate change have the greatest impact on three foundational, macroalgal species that occur along North-Atlantic shores: Fucus serratus, Fucus vesiculosus, and Ascophyllum nodosum? To predict distributional changes of these key species under three IPCC (Intergovernmental Panel on Climate Change) climate change scenarios (A2, A1B, and B1) over the coming two centuries, we generated Ecological Niche Models with the program MAXENT. Model predictions suggest that these three species will shift northwards as an assemblage or “unit” and that phytogeographic changes will be most pronounced in the southern Arctic and the southern temperate provinces. Our models predict that Arctic shores in Canada, Greenland, and Spitsbergen will become suitable for all three species by 2100. Shores south of 45° North will become unsuitable for at least two of the three focal species on both the Northwest- and Northeast-Atlantic coasts by 2200. If these foundational species are unable to adapt to the rising temperatures, they will lose their centers of genetic diversity and their loss will trigger an unpredictable shift in the North-Atlantic intertidal ecosystem. 相似文献
130.
Wen-Yuan Lin Shin-Li Tsai Jeanine B. Albu Cheng-Chieh Lin Tsai-Chung Li F. Xavier Pi-Sunyer Pei-Kun Sung Kuo-Chin Huang 《CMAJ》2011,183(6):E329-E336