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931.
Bachmann M Horn K Rudloff I Goren I Holdener M Christen U Darsow N Hunfeld KP Koehl U Kind P Pfeilschifter J Kraiczy P Mühl H 《PLoS pathogens》2010,6(10):e1001144
If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection. 相似文献
932.
Miko?aj S?abicki Mirko Theis Dragomir B. Krastev Sergey Samsonov Emeline Mundwiller Magno Junqueira Maciej Paszkowski-Rogacz Joan Teyra Anne-Kristin Heninger Ina Poser Fabienne Prieur Jérémy Truchetto Christian Confavreux Cécilia Marelli Alexandra Durr Jean Philippe Camdessanche Alexis Brice Andrej Shevchenko M. Teresa Pisabarro Giovanni Stevanin Frank Buchholz 《PLoS biology》2010,8(6)
DNA repair is essential to maintain genome integrity, and genes with roles in DNA repair are frequently mutated in a variety of human diseases. Repair via homologous recombination typically restores the original DNA sequence without introducing mutations, and a number of genes that are required for homologous recombination DNA double-strand break repair (HR-DSBR) have been identified. However, a systematic analysis of this important DNA repair pathway in mammalian cells has not been reported. Here, we describe a genome-scale endoribonuclease-prepared short interfering RNA (esiRNA) screen for genes involved in DNA double strand break repair. We report 61 genes that influenced the frequency of HR-DSBR and characterize in detail one of the genes that decreased the frequency of HR-DSBR. We show that the gene KIAA0415 encodes a putative helicase that interacts with SPG11 and SPG15, two proteins mutated in hereditary spastic paraplegia (HSP). We identify mutations in HSP patients, discovering KIAA0415/SPG48 as a novel HSP-associated gene, and show that a KIAA0415/SPG48 mutant cell line is more sensitive to DNA damaging drugs. We present the first genome-scale survey of HR-DSBR in mammalian cells providing a dataset that should accelerate the discovery of novel genes with roles in DNA repair and associated medical conditions. The discovery that proteins forming a novel protein complex are required for efficient HR-DSBR and are mutated in patients suffering from HSP suggests a link between HSP and DNA repair. 相似文献
933.
934.
Statistical multivariate metabolite profiling for aiding biomarker pattern detection and mechanistic interpretations in GC/MS based metabolomics 总被引:1,自引:0,他引:1
Elin Pohjanen Elin Thysell Johan Lindberg Ina Schuppe-Koistinen Thomas Moritz Pär Jonsson Henrik Antti 《Metabolomics : Official journal of the Metabolomic Society》2006,2(4):257-268
A strategy for robust and reliable mechanistic statistical modelling of metabolic responses in relation to drug induced toxicity
is presented. The suggested approach addresses two cases commonly occurring within metabonomic toxicology studies, namely;
1) A pre-defined hypothesis about the biological mechanism exists and 2) No such hypothesis exists. GC/MS data from a liver
toxicity study consisting of rat urine from control rats and rats exposed to a proprietary AstraZeneca compound were resolved
by means of hierarchical multivariate curve resolution (H-MCR) generating 287 resolved chromatographic profiles with corresponding
mass spectra. Filtering according to significance in relation to drug exposure rendered in 210 compound profiles, which were
subjected to further statistical analysis following correction to account for the control variation over time. These dose
related metabolite traces were then used as new observations in the subsequent analyses. For case 1, a multivariate approach,
named Target Batch Analysis, based on OPLS regression was applied to correlate all metabolite traces to one or more key metabolites
involved in the pre-defined hypothesis. For case 2, principal component analysis (PCA) was combined with hierarchical cluster
analysis (HCA) to create a robust and interpretable framework for unbiased mechanistic screening. Both the Target Batch Analysis
and the unbiased approach were cross-verified using the other method to ensure that the results did match in terms of detected
metabolite traces. This was also the case, implying that this is a working concept for clustering of metabolites in relation
to their toxicity induced dynamic profiles regardless if there is a pre-existing hypothesis or not. For each of the methods
the detected metabolites were subjected to identification by means of data base comparison as well as verification in the
raw data. The proposed strategy should be seen as a general approach for facilitating mechanistic modelling and interpretations
in metabolomic studies. 相似文献
935.
Background
Signal transduction pathways are usually modelled using classical quantitative methods, which are based on ordinary differential equations (ODEs). However, some difficulties are inherent in this approach. On the one hand, the kinetic parameters involved are often unknown and have to be estimated. With increasing size and complexity of signal transduction pathways, the estimation of missing kinetic data is not possible. On the other hand, ODEs based models do not support any explicit insights into possible (signal-) flows within the network. Moreover, a huge amount of qualitative data is available due to high-throughput techniques. In order to get information on the systems behaviour, qualitative analysis techniques have been developed. Applications of the known qualitative analysis methods concern mainly metabolic networks. Petri net theory provides a variety of established analysis techniques, which are also applicable to signal transduction models. In this context special properties have to be considered and new dedicated techniques have to be designed. 相似文献936.
Crina Rusu Simona Racasan Diana Moldovan Ina Maria Kacso Alina Potra Cosmina Ioana Bondor 《Biomarkers》2017,22(3-4):232-238
Context: Soluble CD40 ligand (sCD40l) can predict cardiovascular events (CVE) and mortality in haemodialysis (HD) patients (short-, medium-term follow-up studies).
Objective: To evaluate the relationship between sCD40l and survival, CVE and mortality in HD patients on long-term follow-up.
Methods: We registered 46?HD patients’ baseline characteristics, mortality and CVE for 108 months.
Results: SCD40l correlated positively with C-reactive protein, was higher in survivors, but had no impact on survival and was not predictive for CVE or CV mortality.
Conclusion: The levels of sCD40l have no influence on survival or CVE and mortality in HD patients in a long-term follow-up. 相似文献
937.
Wisarut Payoungkiattikun Seiji Okazaki Atsutoshi Ina Aran H-Kittikun Yasuhisa Asano 《Journal of industrial microbiology & biotechnology》2017,44(4-5):677-685
α-Amino-ε-caprolactam (ACL) racemizing activity was detected in a putative dialkylglycine decarboxylase (EC 4.1.1.64) from Citreicella sp. SE45. The encoding gene of the enzyme was cloned and transformed in Escherichia coli BL21 (DE3). The molecular mass of the enzyme was shown to be 47.4 kDa on SDS–polyacrylamide gel electrophoresis. The enzymatic properties including pH and thermal optimum and stabilities were determined. This enzyme acted on a broad range of amino acid amides, particularly unbranched amino acid amides including l-alanine amide and l-serine amide with a specific activity of 17.5 and 21.6 U/mg, respectively. The K m and V max values for d- and l-ACL were 5.3 and 2.17 mM, and 769 and 558 μmol/min.mg protein, respectively. Moreover, the turn over number (K cat) and catalytic efficiency (K cat/K m ) of purified ACL racemase from Citreicella sp. SE45 using l-ACL as a substrate were 465 S?1 and 214 S?1mM?1, respectively. The new ACL racemase from Citreicella sp. SE45 has a potential to be used as the biocatalytic application. 相似文献
938.
Risk of suicide,deliberate self‐harm and psychiatric illness after the loss of a close relative: A nationwide cohort study
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Mai‐Britt Guldin Maiken Ina Siegismund Kjaersgaard Morten Fenger‐Grøn Erik Thorlund Parner Jiong Li Anders Prior Mogens Vestergaard 《World psychiatry》2017,16(2):193-199
The loss of a close relative is a common event, yet it is associated with increased risk of serious mental health conditions. No large‐scale study has explored up to now the importance of the bereaved person's relation to the deceased while accounting for gender and age. We performed a nationwide Danish cohort study using register information from 1995 through 2013 on four sub‐cohorts including all persons aged ≥18 years exposed to the loss of a child, spouse, sibling or parent. We identified 1,445,378 bereaved persons, and each was matched by gender, age and family composition to five non‐bereaved persons. Cumulative incidence proportions were calculated to estimate absolute differences in suicide, deliberate self‐harm and psychiatric illness. Cox proportional hazard regression was used to calculate hazard ratios while adjusting for potential confounders. Results revealed that the risk of suicide, deliberate self‐harm and psychiatric illness was increased in the bereaved cohorts for at least 10 years after the loss, particularly during the first year. During that year, the risk difference was 18.9 events in 1,000 persons after loss of a child (95% CI: 17.6‐20.1) and 16.0 events in 1,000 persons after loss of the spouse (95% CI: 15.4‐16.6). Hazard ratios were generally highest after loss of a child, in younger persons, and after sudden loss by suicide, homicide or accident. One in three persons with a previous psychiatric diagnosis experienced suicide, deliberate self‐harm or psychiatric illness within the first year of bereavement. In conclusion, this study shows that the risk of suicide, deliberate self‐harm and psychiatric illness is high after the loss of a close relative, especially in susceptible subgroups. This suggests the need for early identification of high‐risk persons displaying adjustment problems after loss of a close family member, in order to reduce the risk of serious mental health outcomes. 相似文献
939.
The matrix protein M of Borna disease virus (BDV) is a constituent of the viral envelope covering the inner leaflet of the lipid bilayer. BDV-M was expressed as recombinant protein in Escherichia coli, purified to homogeneity and structurally analyzed. Recombinant M (i) forms non-covalently bound multimers with a Stoke's radius of 35 Angstroms estimated by size exclusion chromatography, (ii) consists of tetramers detected by analytical ultracentrifugation, and (iii) appears by electron microscopy studies as tetramers with the tendency to assemble into high molecular mass lattice-like complexes. The structural features suggest that BDV-M possesses a dominant driving force for virus particle formation. 相似文献
940.
Lind C Gerdes R Hamnell Y Schuppe-Koistinen I von Löwenhielm HB Holmgren A Cotgreave IA 《Archives of biochemistry and biophysics》2002,406(2):229-240
Redox modification of proteins is proposed to play a central role in regulating cellular function. However, high-throughput techniques for the analysis of the redox status of individual proteins in complex mixtures are lacking. The aim was thus to develop a suitable technique to rapidly identify proteins undergoing oxidation of critical thiols by S-glutathionylation. The method is based on the specific reduction of mixed disulfides by glutaredoxin, their reaction with N-ethylmaleimide-biotin, affinity purification of tagged proteins, and identification by proteomic analysis. The method unequivocally identified 43 mostly novel cellular protein substrates for S-glutathionylation. These include protein chaperones, cytoskeletal proteins, cell cycle regulators, and enzymes of intermediate metabolism. Comparisons of the patterns of S-glutathionylated proteins extracted from cells undergoing diamide-induced oxidative stress and during constitutive metabolism reveal both common protein substrates and substrates failing to undergo enhanced S-glutathionylation during oxidative stress. The ability to chemically tag, select, and identify S-glutathionylated proteins, particularly during constitutive metabolism, will greatly enhance efforts to establish posttranslational redox modification of cellular proteins as an important biochemical control mechanism in coordinating cellular function. 相似文献