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121.
Amit Kaura Adam Hartley Vasileios Panoulas Ben Glampson Anoop S. V. Shah Jim Davies Abdulrahim Mulla Kerrie Woods Joe Omigie Anoop D. Shah Mark R. Thursz Paul Elliott Harry Hemmingway Bryan Williams Folkert W. Asselbergs Michael OSullivan Graham M. Lord Adam Trickey Jonathan AC Sterne Dorian O. Haskard Narbeh Melikian Darrel P. Francis Wolfgang Koenig Ajay M. Shah Rajesh Kharbanda Divaka Perera Riyaz S. Patel Keith M. Channon Jamil Mayet Ramzi Khamis 《PLoS medicine》2022,19(2)
BackgroundThere is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS.Methods and findingsWe conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (<2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin.Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP <2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957), and 10 to 15 mg/L (n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, the exclusion of those with abnormal WCC or hsCRP levels >15 mg/L makes it unlikely that sepsis was a major contributor.ConclusionsThese multicentre, real-world data from a large cohort of patients with suspected ACS suggest that mildly elevated hsCRP (up to 15 mg/L) may be a clinically meaningful prognostic marker beyond troponin and point to its potential utility in selecting patients for novel treatments targeting inflammation.Trial registrationClinicalTrials.gov - Amit Kaura and colleagues investigate whether mildly elevated high sensitivity C-reactive protein is associated with mortality risk in patients with suspected acute coronary syndromes. NCT03507309相似文献
122.
Kerrie M. Jones Michael J. McPherson Andrew J. Baron Iain W. Mattaj Claudia L. Riordan John C. Wootton 《Molecular genetics and genomics : MGG》1993,240(2):286-289
gdhA1 is a spontaneous mutant of Escherichia coli that causes complete loss of activity of the NADP-specific glutamate dehydrogenase (GDH) encoded by the gdhA gene. The gdhA1 mutational site has been identified by recombinational mapping, polymerase chain reaction (PCR) amplification and DNA sequencing, as an A to G transition at nucleotide 274 of the gdhA coding sequence, resulting in an amino acid change of lysine 92 to glutamic acid. The mutant enzyme forms hybrid hexamers with a wild-type GDH, providing a useful system for analysis of conformational integrity of mutational variants. 相似文献
123.
Charles Robin Robyn J. Russell Kerrie M. Medveczky John G. Oakeshott 《Journal of molecular evolution》1996,43(3):241-252
The α-esterase cluster of D. melanogaster contains 11 esterase genes dispersed over 60 kb. Embedded in the cluster are two unrelated open reading frames that have
sequence similarity with genes encoding ubiquitin-conjugating enzyme and tropomyosin. The esterase amino acid sequences show
37–66% identity with one another and all but one have all the motifs characteristic of functional members of the carboxyl/cholinesterase
multigene family. The exception has several frameshift mutations and appears to be a pseudogene. Patterns of amino acid differences
among cluster members in relation to generic models of carboxyl/cholinesterase protein structure are broadly similar to those
among other carboxyl/cholinesterases sequenced to date. However the α-esterases differ from most other members of the family
in: their lack of a signal peptide; the lack of conservation in cysteines involved in disulfide bridges; and in four indels,
two of which occur in or adjacent to regions that align with proposed substrate-binding sites of other carboxyl/cholinesterases.
Phylogenetic analyses clearly identify three simple gene duplication events within the cluster. The most recent event involved
the pseudogene which is located in an intron of another esterase gene. However, relative rate tests suggest that the pseudogene
remained functional after the duplication event and has become inactive relatively recently. The distribution of indels also
suggests a deeper node in the gene phylogeny that separates six genes at the two ends of the cluster from a block of five
in the middle.
Received: 18 January 1996 / Accepted: 12 March 1996 相似文献
124.
Denley A Wang CC McNeil KA Walenkamp MJ van Duyvenvoorde H Wit JM Wallace JC Norton RS Karperien M Forbes BE 《Molecular endocrinology (Baltimore, Md.)》2005,19(3):711-721
We have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val44Met IGF-I). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val44Met IGF-I to provide a molecular basis for the phenotype observed. Val44Met IGF-I exhibits a 90-fold decrease in type 1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val44Met IGF-I to signal via the extracellular signal-regulated kinase 1/2 and Akt/protein kinase B pathways and to stimulate DNA synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val44Met IGF-I binds IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance confirms retention of near-native structure with only local side-chain disruptions despite the significant loss of function. To our knowledge, our results provide the first structural study of a naturally occurring mutant human IGF-I associated with growth and developmental abnormalities and identifies Val44 as an essential residue involved in the IGF-IGF-1R interaction. 相似文献
125.
While the role of C2-ceramide in the induction of programmed cell death (PCD) in animal systems has been well documented, little is known of its role in plant cells. Here we show that C2-ceramide induces PCD in Arabidopsis suspension cultures, which is preceded by the generation of a calcium transient and an increase in reactive oxygen species (ROS). Inhibition of the calcium transient prevented cell death, whereas inhibition of ROS had no effect on cell survival. These observations suggest that calcium signalling plays a role in ceramide-induced PCD but is independent of the generation of ROS. 相似文献
126.
Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium 总被引:3,自引:0,他引:3
He Z Way KJ Arikawa E Chou E Opland DM Clermont A Isshiki K Ma RC Scott JA Schoen FJ Feener EP King GL 《The Journal of biological chemistry》2005,280(16):15719-15726
Protein kinase C (PKC) and angiotensin II (AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor (CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin-induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15-fold, which was completely inhibited by co-infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform-dependent action was further studied using adenoviral vector-mediated gene transfer of dominant negative (dn) PKC or wild type PKC isoforms. Expression of dnPKCalpha, -epsilon, and -zeta isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKCdelta significantly increased AngII-induced CTGF expression, whereas expression of wild type PKCdelta inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKCdelta (deltaTg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation-mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy. 相似文献
127.
Dietary cholesterol alters Na+/K+ selectivity at intracellular Na+/K+ pump sites in cardiac myocytes 总被引:1,自引:0,他引:1
Buhagiar KA Hansen PS Kong BY Clarke RJ Fernandes C Rasmussen HH 《American journal of physiology. Cell physiology》2004,286(2):C398-C405
A modest diet-induced increase in serum cholesterol in rabbits increases the sensitivity of the sarcolemmal Na+/K+ pump to intracellular Na+, whereas a large increase in cholesterol levels decreases the sensitivity to Na+. To examine the mechanisms, we isolated cardiac myocytes from controls and from rabbits with diet-induced increases in serum cholesterol. The myocytes were voltage clamped with the use of patch pipettes that contained osmotically balanced solutions with Na+ in a concentration of 10 mM and K+ in concentrations ([K+]pip) ranging from 0 to 140 mM. There was no effect of dietary cholesterol on electrogenic Na+/K+ current (Ip) when pipette solutions were K+ free. A modest increase in serum cholesterol caused a [K+]pip-dependent increase in Ip, whereas a large increase caused a [K+]pip-dependent decrease in Ip. Modeling suggested that pump stimulation with a modest increase in serum cholesterol can be explained by a decrease in the microscopic association constant KK describing the backward reaction E1 + 2K+ E2(K+)2, whereas pump inhibition with a large increase in serum cholesterol can be explained by an increase in KK. Because hypercholesterolemia upregulates angiotensin II receptors and because angiotensin II regulates the Na+/K+ pump in cardiac myocytes in a [K+]pip-dependent manner, we blocked angiotensin synthesis or angiotensin II receptors in vivo in cholesterol-fed rabbits. This abolished cholesterol-induced pump inhibition. Because the -isoform of protein kinase C (PKC) mediates effects of angiotensin II on the pump, we included specific PKC-blocking peptide in patch pipette filling solutions. The peptide reversed cholesterol-induced pump inhibition. partial reactions; protein kinase C; angiotensin converting enzyme inhibitors; arteriosclerosis; insulin resistance 相似文献
128.
Overwintering populations of Mesodinium rubrum (Ciliophora: Haptorida) in lakes of the Vestfold Hills, East Antarctica 总被引:1,自引:0,他引:1
J. A. E. Gibson Kerrie M. Swadling Tracey M. Pitman Harry R. Burton 《Polar Biology》1997,17(2):175-179
The autotrophic ciliate Mesodinium rubrum Lohmann was observed during winter and spring in saline lakes ranging in salinity from 2 to 78‰ in the Vestfold Hills, Antarctica.
The ciliate remained active during winter, and contained chlorophyll even though the level of light available for photosynthesis
was minimal. No evidence of encystment as a means of survival during winter was observed. A seasonal study in one of the lakes,
Ace Lake, revealed that M. rubrum was present throughout the year at abundances ranging from 1×104 to 3.5×105 cells l-1. During the winter period, when little light penetrated the lake’s ice cover, cells were most common immediately under the
ice at 2 m, where cell numbers were typically 8×104 cells l-1.
Received: 3 January 1996/Accepted: 21 April 1996 相似文献
129.
Katherine L. Yates Phil J. Bouchet M. Julian Caley Kerrie Mengersen Christophe F. Randin Stephen Parnell Alan H. Fielding Andrew J. Bamford Stephen Ban A. Márcia Barbosa Carsten F. Dormann Jane Elith Clare B. Embling Gary N. Ervin Rebecca Fisher Susan Gould Roland F. Graf Edward J. Gregr Ana M.M. Sequeira 《Trends in ecology & evolution》2018,33(10):790-802
130.
Kerrie L. Mengersen Christopher C. Drovandi Christian P. Robert David B. Pyne Christopher J. Gore 《PloS one》2016,11(4)
The aim of this paper is to provide a Bayesian formulation of the so-called magnitude-based inference approach to quantifying and interpreting effects, and in a case study example provide accurate probabilistic statements that correspond to the intended magnitude-based inferences. The model is described in the context of a published small-scale athlete study which employed a magnitude-based inference approach to compare the effect of two altitude training regimens (live high-train low (LHTL), and intermittent hypoxic exposure (IHE)) on running performance and blood measurements of elite triathletes. The posterior distributions, and corresponding point and interval estimates, for the parameters and associated effects and comparisons of interest, were estimated using Markov chain Monte Carlo simulations. The Bayesian analysis was shown to provide more direct probabilistic comparisons of treatments and able to identify small effects of interest. The approach avoided asymptotic assumptions and overcame issues such as multiple testing. Bayesian analysis of unscaled effects showed a probability of 0.96 that LHTL yields a substantially greater increase in hemoglobin mass than IHE, a 0.93 probability of a substantially greater improvement in running economy and a greater than 0.96 probability that both IHE and LHTL yield a substantially greater improvement in maximum blood lactate concentration compared to a Placebo. The conclusions are consistent with those obtained using a ‘magnitude-based inference’ approach that has been promoted in the field. The paper demonstrates that a fully Bayesian analysis is a simple and effective way of analysing small effects, providing a rich set of results that are straightforward to interpret in terms of probabilistic statements. 相似文献