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101.
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103.
Phage shock proteins (Psp) and their homologues are found in species from the three domains of life: Bacteria, Archaea and
Eukarya (e.g. higher plants). In enterobacteria, the Psp response helps to maintain the proton motive force (PMF) of the cell
when the inner membrane integrity is impaired. The presumed ability of ArcB to sense redox changes in the cellular quinone
pool and the strong decrease of psp induction in ΔubiG or ΔarcAB backgrounds suggest a link between the Psp response and the quinone pool. The authors now provide evidence indicating that
the physiological signal for inducing psp by secretin-induced stress is neither the quinone redox state nor a drop in PMF. Neither the loss of the H+-gradient nor the dissipation of the electrical potential alone is sufficient to induce the Psp response. A set of electron
transport mutants differing in their redox states due to the lack of a NADH dehydrogenase and a quinol oxidase, but retaining
a normal PMF displayed low levels of psp induction inversely related to oxidised ubiquinone levels under microaerobic growth and independent of PMF. In contrast,
cells displaying higher secretin induced psp expression showed increased levels of ubiquinone. Taken together, this study suggests that not a single but likely multiple
signals are needed to be integrated to induce the Psp response. 相似文献
104.
Zembe L Burgers WA Jaspan HB Bekker LG Bredell H Stevens G Gilmour J Cox JH Fast P Hayes P Vardas E Williamson C Gray CM 《PloS one》2011,6(10):e26096
The genetic diversity of HIV-1 across the globe is a major challenge for developing an HIV vaccine. To facilitate immunogen design, it is important to characterize clusters of commonly targeted T-cell epitopes across different HIV clades. To address this, we examined 39 HIV-1 clade C infected individuals for IFN-γ Gag-specific T-cell responses using five sets of overlapping peptides, two sets matching clade C vaccine candidates derived from strains from South Africa and China, and three peptide sets corresponding to consensus clades A, B, and D sequences. The magnitude and breadth of T-cell responses against the two clade C peptide sets did not differ, however clade C peptides were preferentially recognized compared to the other peptide sets. A total of 84 peptides were recognized, of which 19 were exclusively from clade C, 8 exclusively from clade B, one peptide each from A and D and 17 were commonly recognized by clade A, B, C and D. The entropy of the exclusively recognized peptides was significantly higher than that of commonly recognized peptides (p = 0.0128) and the median peptide processing scores were significantly higher for the peptide variants recognized versus those not recognized (p = 0.0001). Consistent with these results, the predicted Major Histocompatibility Complex Class I IC50 values were significantly lower for the recognized peptide variants compared to those not recognized in the ELISPOT assay (p<0.0001), suggesting that peptide variation between clades, resulting in lack of cross-clade recognition, has been shaped by host immune selection pressure. Overall, our study shows that clade C infected individuals recognize clade C peptides with greater frequency and higher magnitude than other clades, and that a selection of highly conserved epitope regions within Gag are commonly recognized and give rise to cross-clade reactivities. 相似文献
105.
Satish Keshav Tomá? Vaňásek Yaron Niv Robert Petryka Stephanie Howaldt Mauro Bafutto István Rácz David Hetzel Ole Haagen Nielsen Séverine Vermeire Walter Reinisch Per Karlén Stefan Schreiber Thomas J. Schall Pirow Bekker the Prospective Randomized Oral-Therapy Evaluation in Crohn’s Disease Trial- Study Group 《PloS one》2013,8(3)
CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease.
Trial Registration
ClinicalTrials.gov . NCT00306215相似文献106.
Yasuyoshi Oka Hanne Varmark Kristoffer Vitting‐Seerup Petra Beli Johannes Waage Anna Hakobyan Martin Mistrik Chunaram Choudhary Mikkel Rohde Simon Bekker‐Jensen Niels Mailand 《EMBO reports》2014,15(9):956-964
UBL5 is an atypical ubiquitin‐like protein, whose function in metazoans remains largely unexplored. We show that UBL5 is required for sister chromatid cohesion maintenance in human cells. UBL5 primarily associates with spliceosomal proteins, and UBL5 depletion decreases pre‐mRNA splicing efficiency, leading to globally enhanced intron retention. Defective sister chromatid cohesion is a general consequence of dysfunctional pre‐mRNA splicing, resulting from the selective downregulation of the cohesion protection factor Sororin. As the UBL5 yeast orthologue, Hub1, also promotes spliceosome functions, our results show that UBL5 plays an evolutionary conserved role in pre‐mRNA splicing, the integrity of which is essential for the fidelity of chromosome segregation. 相似文献
107.
Marques Alexandra Robuchon Marine Hellweg Stefanie Newbold Tim Beher Jutta Bekker Sebastian Essl Franz Ehrlich Daniele Hill Samantha Jung Martin Marquardt Sandra Rosa Francesca Rugani Benedetto Suárez-Castro Andrés F. Silva André P. Williams David R Dubois Grégoire Sala Serenella 《The International Journal of Life Cycle Assessment》2021,26(2):238-243
The International Journal of Life Cycle Assessment - 相似文献
108.
Proteasome immunosubunits protect against the development of CD8 T cell-mediated autoimmune diseases
Zaiss DM Bekker CP Gröne A Lie BA Sijts AJ 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(5):2302-2309
Exposure of cells to inflammatory cytokines induces the expression of three proteasome immunosubunits, two of which are encoded in the MHC class II region. The induced subunits replace their constitutive homologs in newly formed "so-called" immunoproteasomes. Immunosubunit incorporation enhances the proteasome's proteolytic activity and modifies the proteasome's cleavage-site preferences, which improves the generation of many MHC class I-presented peptides and shapes the fine specificity of pathogen-specific CD8 T cell responses. In this article, we report on a second effect of immunoproteasome formation on CD8 T cell responses. We show that mice deficient for the immunosubunits β5i/low molecular mass polypeptide (LMP7) and β2i/multicatalytic endopeptidase complex-like-1 develop early-stage multiorgan autoimmunity following irradiation and bone marrow transplantation. Disease symptoms are caused by CD8 T cells and are transferable into immunosubunit-deficient, RAG1-deficient mice. Moreover, using the human Type 1 Diabetes Genetics Consortium MHC dataset, we identified two single nucleotide polymorphisms within the β5i/LMP7-encoding gene sequences, which were in strong linkage disequilibrium, as independent genetic risk factors for type 1 diabetes development in humans. Strikingly, these single nucleotide polymorphisms significantly enhanced the risk conferred by HLA haplotypes that were previously shown to predispose for type 1 diabetes. These data suggested that inflammation-induced immunosubunit expression in peripheral tissues constitutes a mechanism that prevents the development of CD8 T cell-mediated autoimmune diseases. 相似文献
109.
Eugene T. Richardson Carl D. Morrow Darryl B. Kalil Linda-Gail Bekker Robin Wood 《PloS one》2014,9(5)
Background
Despite an improvement in the overall TB cure rate from 40–74% between 1995 and 2011, TB incidence in South Africa continues to increase. The epidemic is notably disquieting in schools because the vulnerable population is compelled to be present. Older learners (age 15–19) are at particular risk given a smear-positive rate of 427 per 100,000 per year and the significant amount of time they spend indoors. High schools are therefore important locations for potential TB infection and thus prevention efforts.Methods and Findings
Using portable carbon dioxide monitors, we measured CO2 in classrooms under non-steady state conditions. The threshold for tuberculosis transmission was estimated using a carbon dioxide-based risk equation. We determined a critical rebreathed fraction of carbon dioxide () of 1·6%, which correlates with an indoor CO2 concentration of 1000 ppm. These values correspond with a ventilation rate of 8·6 l/s per person or 12 air exchanges per hour (ACH) for standard classrooms of 180 m3.Conclusions
Given the high smear positive rate of high-school adolescents in South Africa, the proposal to achieve CO2 levels of 1000ppm through natural ventilation (in the amount 12 ACH) will not only help achieve WHO guidelines for providing children with healthy indoor environments, it will also provide a low-cost intervention for helping control the TB epidemic in areas of high prevalence. 相似文献110.
Thesla Palanee-Phillips Katie Schwartz Elizabeth R. Brown Vaneshree Govender Nyaradzo Mgodi Flavia Matovu Kiweewa Gonasagrie Nair Felix Mhlanga Samantha Siva Linda-Gail Bekker Nitesha Jeenarain Zakir Gaffoor Francis Martinson Bonus Makanani Sarita Naidoo Arendevi Pather Jessica Phillip Marla J. Husnik Ariane van der Straten Lydia Soto-Torres Jared Baeten 《PloS one》2015,10(6)