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31.
32.
Divakara S. S. M. Uppu Goutham B. Manjunath Venkateswarlu Yarlagadda Jyothi E. Kaviyil Raju Ravikumar Krishnamoorthy Paramanandham Bibek R. Shome Jayanta Haldar 《PloS one》2015,10(3)
Gram-negative ‘superbugs’ such as New Delhi metallo-beta-lactamase-1 (bla
NDM-1) producing pathogens have become world’s major public health threats. Development of molecular strategies that can rehabilitate the ‘old antibiotics’ and halt the antibiotic resistance is a promising approach to target them. We report membrane-active macromolecules (MAMs) that restore the antibacterial efficacy (enhancement by >80-1250 fold) of tetracycline antibiotics towards bla
NDM-1
Klebsiella pneumonia and bla
NDM-1
Escherichia coli clinical isolates. Organismic studies showed that bacteria had an increased and faster uptake of tetracycline in the presence of MAMs which is attributed to the mechanism of re-sensitization. Moreover, bacteria did not develop resistance to MAMs and MAMs stalled the development of bacterial resistance to tetracycline. MAMs displayed membrane-active properties such as dissipation of membrane potential and membrane-permeabilization that enabled higher uptake of tetracycline in bacteria. In-vivo toxicity studies displayed good safety profiles and preliminary in-vivo antibacterial efficacy studies showed that mice treated with MAMs in combination with antibiotics had significantly decreased bacterial burden compared to the untreated mice. This report of re-instating the efficacy of the antibiotics towards bla
NDM-1 pathogens using membrane-active molecules advocates their potential for synergistic co-delivery of antibiotics to combat Gram-negative superbugs. 相似文献
33.
Kristina Kirschner Shamith A. Samarajiwa Jonathan M. Cairns Suraj Menon Pedro A. Pérez-Mancera Kosuke Tomimatsu Camino Bermejo-Rodriguez Yoko Ito Tamir Chandra Masako Narita Scott K. Lyons Andy G. Lynch Hiroshi Kimura Tetsuya Ohbayashi Simon Tavaré Masashi Narita 《PLoS genetics》2015,11(3)
The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms. 相似文献
34.
Chinnapaka Somaiah Atul Kumar Darilang Mawrie Amit Sharma Suraj Dasharath Patil Jina Bhattacharyya Rajaram Swaminathan Bithiah Grace Jaganathan 《PloS one》2015,10(12)
Mesenchymal stem cells (MSC) can differentiate into several cell types and are desirable candidates for cell therapy and tissue engineering. However, due to poor cell survival, proliferation and differentiation in the patient, the therapy outcomes have not been satisfactory. Although several studies have been done to understand the conditions that promote proliferation, differentiation and migration of MSC in vitro and in vivo, still there is no clear understanding on the effect of non-cellular bio molecules. Of the many factors that influence the cell behavior, the immediate cell microenvironment plays a major role. In this context, we studied the effect of extracellular matrix (ECM) proteins in controlling cell survival, proliferation, migration and directed MSC differentiation. We found that collagen promoted cell proliferation, cell survival under stress and promoted high cell adhesion to the cell culture surface. Increased osteogenic differentiation accompanied by high active RHOA (Ras homology gene family member A) levels was exhibited by MSC cultured on collagen. In conclusion, our study shows that collagen will be a suitable matrix for large scale production of MSC with high survival rate and to obtain high osteogenic differentiation for therapy. 相似文献
35.
Reto Guler Suraj P. Parihar Suzana Savvi Erin Logan Anita Schwegmann Sugata Roy Natalie E. Nieuwenhuizen Mumin Ozturk Sebastian Schmeier Harukazu Suzuki Frank Brombacher 《PloS one》2015,10(3)
Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild-type (WT) and LysMcreIL-4Rα-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb-infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow-derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Rα driven pathway. Together, these results suggest that IL-4Rα-macrophages do not play a central role in TB disease progression. 相似文献
36.
37.
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the most devastating bacterial diseases to affect humans. M. tuberculosis is a robust pathogen that has evolved the capacity to survive and grow inside macrophage phagosomes. A cocktail of antibiotics has long been successfully used against M. tuberculosis but is becoming less effective owing to the emergence of multidrug resistance. The only available preventive vaccine, using Mycobacterium bovis bacille Calmette-Guérin, is considered to be ineffective against adult pulmonary TB, the most prevalent form of the disease. Here, we review the potential use of biodegradable nanoparticle-based anti-TB drug delivery systems that have been shown to be more effective against M. tuberculosis in animal models than conventional antibiotic treatment regimens. This technology also has substantial potential for vaccination and other therapeutic strategies against TB and other infectious diseases. 相似文献
38.
Tannert A Kurz A Erlemann KR Müller K Herrmann A Schiller J Töpfer-Petersen E Manjunath P Müller P 《European biophysics journal : EBJ》2007,36(4-5):461-475
The bovine seminal plasma protein PDC-109 modulates the maturation of bull sperm cells by removing lipids, mainly phosphatidylcholine
and cholesterol, from their cellular membrane. Here, we have characterized the process of extraction of endogenous phospholipids
and of their respective analogues. By measuring the PDC-109-mediated release of fluorescent phospholipid analogues from lipid
vesicles and from biological membranes (human erythrocytes, bovine epididymal sperm cells), we showed that PDC-109 extracts
phospholipids with a phosphorylcholine headgroup mainly from the outer leaflet of these membranes. The ability of PDC-109
to extract endogenous phospholipids from epididymal sperm cells was followed by mass spectrometry, which allowed us to characterize
the fatty acid pattern of the released lipids. From these cells, PDC-109 extracted phosphatidylcholine and sphingomyelin that
contained an enrichment of mono- and di-unsaturated fatty acids as well as short-chain and lyso-phosphatidylcholine species.
Based on the results, a model explaining the phospholipid specificity of PDC-109-mediated lipid release is presented.
Astrid Tannert and Anke Kurz have contributed equally to this work.
Dedicated to Prof. K. Arnold on the occasion of his 65th birthday. 相似文献
39.
Lucio Marcello Suraj Menon Pauline Ward Jonathan M Wilkes Nicola G Jones Mark Carrington J David Barry 《BMC bioinformatics》2007,8(1):143
Background
Trypanosomes are coated with a variant surface glycoprotein (VSG) that is so densely packed that it physically protects underlying proteins from effectors of the host immune system. Periodically cells expressing a distinct VSG arise in a population and thereby evade immunity. The main structural feature of VSGs are two long α-helices that form a coiled coil, and sets of relatively unstructured loops that are distal to the plasma membrane and contain most or all of the protective epitopes. The primary structure of different VSGs is highly variable, typically displaying only ~20% identity with each other. The genome has nearly 2000 VSG genes, which are located in subtelomeres. Only one VSG gene is expressed at a time, and switching between VSGs primarily involves gene conversion events. The archive of silent VSGs undergoes diversifying evolution rapidly, also involving gene conversion. The VSG family is a paradigm for α helical coiled coil structures, epitope variation and GPI-anchor signals. At the DNA level, the genes are a paradigm for diversifying evolutionary processes and for the role of subtelomeres and recombination mechanisms in generation of diversity in multigene families. To enable ready availability of VSG sequences for addressing these general questions, and trypanosome-specific questions, we have created VSGdb, a database of all known sequences. 相似文献40.
The purpose of this research was to study whether the bioavailability of lovastatin could be improved by administering lovastatin
solid lipid nanoparticles (SLN) duodenally to rats. Lovastatin SLN were developed using triglycerides by hot homogenization
followed by ultrasonication. Particle size and zeta potential were measured by photon correlation spectroscopy. The solid
state of the drug in the SLN and lipid modification were characterized. Bioavailability studies were conducted in male Wistar
rats after intraduodenal administration of lovastatin suspension and SLN. Stable lovastatin SLN having a mean size range of
60 to 119 nm and a zeta potential range of −16 to −21 mV were developed. More than 99% of the lovastatin was entrapped in
the SLN. Lovastatin was dispersed in an amorphous state, and triglycerides were in {ieE162-1} form in the SLN. In vitro stability
studies showed the slow release and stability of lovastatin SLN. The relative bioavailabilities of lovastatin and lovastatin
hydroxy acid of SLN were increased by ∼173% and 324%, respectively, compared with the reference lovastatin suspension.
Published: March 23, 2007 相似文献