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Jagadish Vangipurapu Alena Stan?áková Teemu Kuulasmaa Johanna Kuusisto Markku Laakso 《PloS one》2015,10(4)
Background
Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin.Methods
Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m2) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated.Results
Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations.Conclusion
Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes. 相似文献64.
Ribosome profiling identifies ribosome positions on translated mRNAs. A prominent feature of published datasets is the near complete absence of ribosomes in 3′ untranslated regions (3′UTR) although substantial ribosome density can be observed on non-coding RNAs. Here we perform ribosome profiling in cultured Drosophila and human cells and show that different features of translation are revealed depending on the nuclease and the digestion conditions used. Most importantly, we observe high abundance of ribosome protected fragments in 3′UTRs of thousands of genes without manipulation of translation termination. Affinity purification of ribosomes indicates that the 3′UTR reads originate from ribosome protected fragments. Association of ribosomes with the 3′UTR may be due to ribosome migration through the stop codon or 3′UTR mRNA binding to ribosomes on the coding sequence. This association depends primarily on the relative length of the 3′UTR and may be related to translational regulation or ribosome recycling, for which the efficiency is known to inversely correlate with 3′UTR length. Together our results indicate that ribosome profiling is highly dependent on digestion conditions and that ribosomes commonly associate with the 3′UTR, which may have a role in translational regulation. 相似文献
65.
Kei Asayama Lutgarde Thijs Jana Brguljan-Hitij Teemu J. Niiranen Atsushi Hozawa José Boggia Lucas S. Aparicio Azusa Hara Jouni K. Johansson Takayoshi Ohkubo Christophe Tzourio George S. Stergiou Edgardo Sandoya Ichiro Tsuji Antti M. Jula Yutaka Imai Jan A. Staessen for the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome investigators 《PLoS medicine》2014,11(1)
Background
The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).Methods and Findings
This meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120–129/80–84; high-normal, 130–139/85–89; mild hypertension, 140–159/90–99; and severe hypertension, ≥160/≥100.Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01–1.62) and 1.22 (1.00–1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03–1.49) and 1.20 (1.06–1.37), respectively, for all cardiovascular events and 1.33 (1.07–1.65) and 1.30 (1.09–1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p≥0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP≥130 mm Hg systolic or ≥85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5–3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.Conclusions
HBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings. Please see later in the article for the Editors'' Summary 相似文献66.
El-Najjar N Ketola RA Nissilä T Mauriala T Antopolsky M Jänis J Gali-Muhtasib H Urtti A Vuorela H 《Journal of chemical biology》2011,4(3):97-107
Thymoquinone (TQ), an active component of Nigella sativa L., is known to have anti-cancer and anti-inflammatory effects; however, no studies on its analytical detection in serum
and its protein binding have been published. Using high performance liquid chromatography analysis, we show that the average
recovery of TQ from serum is 2.5% at 10 μg/ml of TQ and 72% at 100 μg/ml. The low recovery of TQ from serum is due to its
extensive binding to plasma proteins, as more than 99% of TQ was bound within 30 min of incubation. The binding of TQ to the
major plasma proteins, bovine serum albumin (BSA) and alpha −1 acid glycoprotein (AGP), was studied and found to be 94.5 ± 1.7%
for BSA and 99.1 ± 0.1% for AGP. Mass spectrometric analysis revealed that TQ was bound covalently to BSA, specifically on
Cyst-34. Using WST-1 proliferation assay, we showed that BSA plays a protective role against TQ-induced cell death; pre-incubation
with BSA prevented TQ from exerting its anti-proliferative effects against DLD-1 and HCT-116 human colon cancer cells. On
the other hand, binding of TQ to AGP did not alter its anti-proliferative activity against both cell lines. When TQ was pre-incubated
with AGP prior to the addition of BSA, the activity of TQ against DLD-1 was maintained, suggesting that AGP prevented the
binding of TQ to BSA. This is the first time the covalent binding and inhibitory effect of BSA on TQ is documented. These
data offer new grounds for TQ future pharmacokinetic analysis in vivo. 相似文献
67.
Protein diffusion in mammalian cell cytoplasm 总被引:1,自引:0,他引:1
Kühn T Ihalainen TO Hyväluoma J Dross N Willman SF Langowski J Vihinen-Ranta M Timonen J 《PloS one》2011,6(8):e22962
We introduce a new method for mesoscopic modeling of protein diffusion in an entire cell. This method is based on the construction of a three-dimensional digital model cell from confocal microscopy data. The model cell is segmented into the cytoplasm, nucleus, plasma membrane, and nuclear envelope, in which environment protein motion is modeled by fully numerical mesoscopic methods. Finer cellular structures that cannot be resolved with the imaging technique, which significantly affect protein motion, are accounted for in this method by assigning an effective, position-dependent porosity to the cell. This porosity can also be determined by confocal microscopy using the equilibrium distribution of a non-binding fluorescent protein. Distinction can now be made within this method between diffusion in the liquid phase of the cell (cytosol/nucleosol) and the cytoplasm/nucleoplasm. Here we applied the method to analyze fluorescence recovery after photobleach (FRAP) experiments in which the diffusion coefficient of a freely-diffusing model protein was determined for two different cell lines, and to explain the clear difference typically observed between conventional FRAP results and those of fluorescence correlation spectroscopy (FCS). A large difference was found in the FRAP experiments between diffusion in the cytoplasm/nucleoplasm and in the cytosol/nucleosol, for all of which the diffusion coefficients were determined. The cytosol results were found to be in very good agreement with those by FCS. 相似文献
68.
Johanna Tahvanainen Minna K. Kyl?niemi Kartiek Kanduri Bhawna Gupta Hanna L?hteenm?ki Teemu Kallonen Anna Rajavuori Omid Rasool P?ivi J. Koskinen Kanury V. S. Rao Harri L?hdesm?ki Riitta Lahesmaa 《The Journal of biological chemistry》2013,288(5):3048-3058
The differentiation of human primary T helper 1 (Th1) cells from naïve precursor cells is regulated by a complex, interrelated signaling network. The identification of factors regulating the early steps of Th1 cell polarization can provide important insight in the development of therapeutics for many inflammatory and autoimmune diseases. The serine/threonine-specific proviral integration site for Moloney murine leukemia virus (PIM) kinases PIM1 and PIM2 have been implicated in the cytokine-dependent proliferation and survival of lymphocytes. We have established that the third member of this family, PIM3, is also expressed in human primary Th cells and identified a new function for the entire PIM kinase family in T lymphocytes. Although PIM kinases are expressed more in Th1 than Th2 cells, we demonstrate here that these kinases positively influence Th1 cell differentiation. Our RNA interference results from human primary Th cells also suggest that PIM kinases promote the production of IFNγ, the hallmark cytokine produced by Th1 cells. Consistent with this, they also seem to be important for the up-regulation of the critical Th1-driving factor, T box expressed in T cells (T-BET), and the IL-12/STAT4 signaling pathway during the early Th1 differentiation process. In summary, we have identified PIM kinases as new regulators of human primary Th1 cell differentiation, thus providing new insights into the mechanisms controlling the selective development of human Th cell subsets. 相似文献
69.
Einari A. Niskanen Olli Kalliolinna Teemu O. Ihalainen Milla H?kkinen Maija Vihinen-Ranta 《Journal of virology》2013,87(21):11762-11774
The multifunctional replication protein of autonomous parvoviruses, NS1, is vital for viral genome replication and for the control of viral protein production. Two DNA-interacting domains of NS1, the N-terminal and helicase domains, are necessary for these functions. In addition, the N and C termini of NS1 are required for activation of viral promoter P38. By comparison with the structural and biochemical data from other parvoviruses, we identified potential DNA-interacting amino acid residues from canine parvovirus NS1. The role of the identified amino acids in NS1 binding dynamics was studied by mutagenesis, fluorescence recovery after photobleaching, and computer simulations. Mutations in the predicted DNA-interacting amino acids of the N-terminal and helicase domains increased the intranuclear binding dynamics of NS1 dramatically. A substantial increase in binding dynamics was also observed for NS1 mutants that targeted the metal ion coordination site in the N terminus. Interestingly, contrary to other mutants, deletion of the C terminus resulted in slower binding dynamics of NS1. P38 transactivation was severely reduced in both N-terminal DNA recognition and in C-terminal deletion mutants. These data suggest that the intranuclear dynamics of NS1 are largely characterized by its sequence-specific and -nonspecific binding to double-stranded DNA. Moreover, binding of NS1 is equally dependent on the N-terminal domain and conserved β-loop of the helicase domain. 相似文献
70.
Yawu Liu Jussi Mattila Miguel ángel Mu?oz Ruiz Teemu Paajanen Juha Koikkalainen Mark van Gils Sanna-Kaisa Herukka Gunhild Waldemar Jyrki L?tj?nen Hilkka Soininen for The Alzheimer’s Disease Neuroimaging Initiative 《PloS one》2013,8(2)