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111.
Karolina Nemes Anna Sebestyén ágnes Márk Melinda Hajdu István Kenessey Tamás Sticz Eszter Nagy Gábor Barna Zsófia Váradi Gábor Kovács László Kopper Monika Csóka 《PloS one》2013,8(4)
Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments. 相似文献
112.
Eszter Deak Selwyn D. Wilson Elizabeth White Janice H. Carr S. Arunmozhi Balajee 《PloS one》2009,4(10)
Infection with Aspergillus terreus is more likely to result in invasive, disseminated disease when compared to other Aspergillus species; importantly this species appears to be less susceptible to the antifungal drug amphotericin B. Unique to this species is the ability to produce specialized structures denoted as accessory conidia (AC) directly on hyphae both in vitro and in vivo. With the hypothesis that production of AC by A. terreus may enhance virulence of this organism, we analyzed the phenotype, structure and metabolic potential of these conidia. Comparison of A. terreus phialidic conidia (conidia that arise from conidiophores, PC) and AC architecture by electron microscopy revealed distinct morphological differences between the two conidial forms; AC have a smoother, thicker outer cell surface with no apparent pigment-like layer. Further, AC germinated rapidly, had enhanced adherence to microspheres, and were metabolically more active compared to PC. Additionally, AC contained less cell membrane ergosterol, which correlated with decreased susceptibility to AMB as determined using a flow cytometry based analysis. Furthermore, AC exhibited surface patches of β1-3 glucan, suggestive of attachment scarring. Collectively, the findings of this study suggest a possible role for AC in A. terreus pathogenesis. 相似文献
113.
Harald Rouha Adriana Badarau Zehra C Visram Michael B Battles Bianka Prinz Zoltán Magyarics Gábor Nagy Irina Mirkina Lukas Stulik Manuel Zerbs Michaela J?gerhofer Barbara Maierhofer Astrid Teubenbacher Ivana Dolezilkova Karin Gross Srijib Banerjee Gerhild Zauner Stefan Malafa Jakub Zmajkovic Sabine Maier Robert Mabry Eric Krauland K Dane Wittrup Tillman U Gerngross Eszter Nagy 《MABS-AUSTIN》2015,7(1):243-254
Staphylococcus aureus is a major human pathogen associated with high mortality. The emergence of antibiotic resistance and the inability of antibiotics to counteract bacterial cytotoxins involved in the pathogenesis of S. aureus call for novel therapeutic approaches, such as passive immunization with monoclonal antibodies (mAbs). The complexity of staphylococcal pathogenesis and past failures with single mAb products represent considerable barriers for antibody-based therapeutics. Over the past few years, efforts have focused on neutralizing α-hemolysin. Recent findings suggest that the concerted actions of several cytotoxins, including the bi-component leukocidins play important roles in staphylococcal pathogenesis. Therefore, we aimed to isolate mAbs that bind to multiple cytolysins by employing high diversity human IgG1 libraries presented on the surface of yeast cells. Here we describe cross-reactive antibodies with picomolar affinity for α-hemolysin and 4 different bi-component leukocidins that share only ∼26% overall amino acid sequence identity. The molecular basis of cross-reactivity is the recognition of a conformational epitope shared by α-hemolysin and F-components of gamma-hemolysin (HlgAB and HlgCB), LukED and LukSF (Panton-Valentine Leukocidin). The amino acids predicted to form the epitope are conserved and known to be important for cytotoxic activity. We found that a single cross-reactive antibody prevented lysis of human phagocytes, epithelial and red blood cells induced by α-hemolysin and leukocidins in vitro, and therefore had superior effectiveness compared to α-hemolysin specific antibodies to protect from the combined cytolytic effect of secreted S. aureus toxins. Such mAb afforded high levels of protection in murine models of pneumonia and sepsis. 相似文献
114.
Tamás Garay István Kenessey Eszter Molnár éva Juhász Andrea Réti Viktória László Anita Rózsás Judit Dobos Balázs D?me Walter Berger Walter Klepetko József Tóvári József Tímár Balázs Heged?s 《PloS one》2015,10(2)
While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells. 相似文献
115.
RNA editing in plant mitochondria and plastids alters specific nucleotides from cytidine (C) to uridine (U) mostly in mRNAs. A number of PLS-class PPR proteins have been characterized as RNA recognition factors for specific RNA editing sites, all containing a C-terminal extension, the E domain, and some an additional DYW domain, named after the characteristic C-terminal amino acid triplet of this domain. Presently the recognition factors for more than 300 mitochondrial editing sites are still unidentified. In order to characterize these missing factors, the recently proposed computational prediction tool could be of use to assign target RNA editing sites to PPR proteins of yet unknown function. Using this target prediction approach we identified the nuclear gene MEF35 (Mitochondrial Editing Factor 35) to be required for RNA editing at three sites in mitochondria of Arabidopsis thaliana. The MEF35 protein contains eleven PPR repeats and E and DYW extensions at the C-terminus. Two T-DNA insertion mutants, one inserted just upstream and the other inside the reading frame encoding the DYW domain, show loss of editing at a site in each of the mRNAs for protein 16 in the large ribosomal subunit (site rpl16-209), for cytochrome b (cob-286) and for subunit 4 of complex I (nad4-1373), respectively. Editing is restored upon introduction of the wild type MEF35 gene in the reading frame mutant. The MEF35 protein interacts in Y2H assays with the mitochondrial MORF1 and MORF8 proteins, mutation of the latter also influences editing at two of the three MEF35 target sites. Homozygous mutant plants develop indistinguishably from wild type plants, although the RPL16 and COB/CYTB proteins are essential and the amino acids encoded after the editing events are conserved in most plant species. These results demonstrate the feasibility of the computational target prediction to screen for target RNA editing sites of E domain containing PLS-class PPR proteins. 相似文献
116.
Andrew R. H. Dalton Eszter P. Vamos Matthew J. Harris Gopalakrishnan Netuveli Robert M. Wachter Azeem Majeed Christopher Millett 《PloS one》2014,9(1)
Background
The Patient Protection and Affordable Care Act (ACA) galvanised debate in the United States (US) over universal health coverage. Comparison with countries providing universal coverage may illustrate whether the ACA can improve health outcomes and reduce disparities. We aimed to compare quality and disparities in hypertension management by socio-economic position in the US and England, the latter of which has universal health care.Method
We used data from the Health and Retirement Survey in the US, and the English Longitudinal Study for Aging from England, including non-Hispanic White respondents aged 50–64 years (US market-based v NHS) and >65 years (US-Medicare v NHS) with diagnosed hypertension. We compared blood pressure control to clinical guideline (140/90 mmHg) and audit (150/90 mmHg) targets; mean systolic and diastolic blood pressure and antihypertensive prescribing, and disparities in each by educational attainment, income and wealth, using regression models.Results
There were no significant differences in aggregate achievement of clinical targets aged 50 to 65 years (US market-based vs. NHS- 62.3% vs. 61.3% [p = 0.835]). There was, however, greater control in the US in patients aged 65 years and over (US Medicare vs. NHS- 53.5% vs. 58.2% [p = 0.043]). England had no significant socioeconomic disparity in blood pressure control (60.9% vs. 63.5% [p = 0.588], high and low wealth aged ≥65 years). The US had socioeconomic differences in the 50–64 years group (71.7% vs. 55.2% [p = 0.003], high and low wealth); these were attenuated but not abolished in Medicare beneficiaries.Conclusion
Moves towards universal health coverage in the US may reduce disparities in hypertension management. The current situation, providing universal coverage for residents aged 65 years and over, may not be sufficient for equality in care. 相似文献117.
In a previous experiment thyrotropin (TSH) increased the triiodothyronine (T3) production of Tetrahymena and chorionic gonadotropin (HCG) moderately overlapped the effect. At present the production of three amino acid type (histamine, serotonin, epinephrine) and one peptide (endorphin) hormones were studied under the effect of TSH or HCG, in tryptone-yeast (TY) or salt (Losina-Losinsky) medium. The duration of the effect was 10 min. TSH significantly (with almost 20%) decreased epinephrine production in TY medium and HCG similarly decreased epinephrine and increased histamine level. In salt solution TSH as well as HCG decreased the level of serotonin. The results show that at this low level of phylogeny TSH effect is not completely thyroxine-specific, however it is not general. HCG overlaps TSH effect on epinephrine and serotonin production, however its effect is broader. The experiments also demonstrate that the effect of pituitary trop-hormones can be bidirectional in Tetrahymena, as histamine level was increased and epinephrine level was decreased by HCG, in the same cells. 相似文献
118.
Zsila F Bikadi Z Malik D Hari P Pechan I Berces A Hazai E 《Bioinformatics (Oxford, England)》2011,27(13):1806-1813
MOTIVATION: Human serum albumin (HSA), the most abundant plasma protein is well known for its extraordinary binding capacity for both endogenous and exogenous substances, including a wide range of drugs. Interaction with the two principal binding sites of HSA in subdomain IIA (site 1) and in subdomain IIIA (site 2) controls the free, active concentration of a drug, provides a reservoir for a long duration of action and ultimately affects the ADME (absorption, distribution, metabolism, and excretion) profile. Due to the continuous demand to investigate HSA binding properties of novel drugs, drug candidates and drug-like compounds, a support vector machine (SVM) model was developed that efficiently predicts albumin binding. Our SVM model was integrated to a free, web-based prediction platform (http://albumin.althotas.com). Automated molecular docking calculations for prediction of complex geometry are also integrated into the web service. The platform enables the users (i) to predict if albumin binds the query ligand, (ii) to determine the probable ligand binding site (site 1 or site 2), (iii) to select the albumin X-ray structure which is complexed with the most similar ligand and (iv) to calculate complex geometry using molecular docking calculations. Our SVM model and the potential offered by the combined use of in silico calculation methods and experimental binding data is illustrated. 相似文献
119.
Tamás Garay Éva Juhász Eszter Molnár Maria Eisenbauer András Czirók Barbara Dekan Viktória László Mir Alireza Hoda Balázs Döme József Tímár Walter Klepetko Walter Berger Balázs Hegedűs 《Experimental cell research》2013,319(20):3094-3103
The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The “go or grow” hypothesis postulates that migration and proliferation spatiotemporally excludes each other.We evaluated this hypothesis on 35 cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility.We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive. 相似文献
120.
Thomas Cucchi Zsófia Eszter Kovács Rémi Berthon Annie Orth François Bonhomme Allowen Evin Roohollah Siahsarvie Jamshid Darvish Veli Bakhshaliyev Catherine Marro 《Biological journal of the Linnean Society. Linnean Society of London》2013,108(4):917-928
Transcaucasia comprises a key region for understanding the history of both the hybrid zone between house mouse lineages and the dispersal of the Neolithic way of life outside its Near Eastern cradle. The opportunity to document the colonization history of both men and mice in Transcaucasia was made possible by the discovery of mouse remains accumulated in pits from a 6000‐year‐old farming village in the Nakhchivan (Autonomous Republic of Nakhchivan, Azerbaijan). The present study investigated their taxonomy and most likely dispersal path through the identification of the Mus lineage to which they might belong using a geometric morphometric approach of dental traits distances between archaeological and modern populations of the different Mus lineages of South‐West Asia. We demonstrate that the mouse remains trapped in the deep storage pits of the dwelling belong to the Mus musculus domesticus from the Near East, with dental shapes similar to current populations in Northern Syria. These results strongly suggest that the domesticus lineage was dispersed into Transcaucasia from the upper Euphrates valley by Neolithic migration, some time between the 7th and 5th millennium BC, providing substantial evidence to back up the scenario featuring near‐eastern stimuli in the emergence of agriculture in the South Caucasus. The domesticus mitochondrial DNA signature of the current house mouse in the same location 5000 years later, as well as their turnover towards a subspecies musculus/castaneus phenotype, suggests that early domesticus colonizers hybridized with a later musculus (and maybe castaneus) dispersal originating from south of the Caspian Sea and/or Northern Caucasia. © 2013 The Linnean Society of London 相似文献