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901.
Humbert O Davis L Maizels N 《Critical reviews in biochemistry and molecular biology》2012,47(3):264-281
Many devastating human diseases are caused by mutations in a single gene that prevent a somatic cell from carrying out its essential functions, or by genetic changes acquired as a result of infectious disease or in the course of cell transformation. Targeted gene therapies have emerged as potential strategies for treatment of such diseases. These therapies depend upon rare-cutting endonucleases to cleave at specific sites in or near disease genes. Targeted gene correction provides a template for homology-directed repair, enabling the cell's own repair pathways to erase the mutation and replace it with the correct sequence. Targeted gene disruption ablates the disease gene, disabling its function. Gene targeting can also promote other kinds of genome engineering, including mutation, insertion, or gene deletion. Targeted gene therapies present significant advantages compared to approaches to gene therapy that depend upon delivery of stably expressing transgenes. Recent progress has been fueled by advances in nuclease discovery and design, and by new strategies that maximize efficiency of targeting and minimize off-target damage. Future progress will build on deeper mechanistic understanding of critical factors and pathways. 相似文献
902.
Duminil J Kenfack D Viscosi V Grumiau L Hardy OJ 《Molecular phylogenetics and evolution》2012,62(1):275-285
Plant species delimitation within tropical ecosystems is often difficult because of the lack of diagnostic morphological characters that are clearly visible. The development of an integrated approach, which utilizes several different types of markers (both morphological and molecular), would be extremely useful in this context. Here we have addressed species delimitation of sympatric tropical tree species that belong to Carapa spp. (Meliaceae) in Central Africa. We adopted a population genetics approach, sampling numerous individuals from three locations where sympatric Carapa species are known to exist. Comparisons between morphological markers (the presence or absence of characters, leaf-shape traits) and molecular markers (chloroplast sequences, ribosomal internal transcribed spacer region (ITS) sequences, and nuclear microsatellites) demonstrated the following: (i) a strong correlation between morphological and nuclear markers; (ii) despite substantial polymorphism, the inability of chloroplast DNA to discriminate between species, suggesting that cytoplasmic markers represent ineffective DNA barcodes; (iii) lineage sorting effects when using ITS sequences; and (iv) a complex evolutionary history within the genus Carapa, which includes frequent inter-specific gene flow. Our results support the use of a population genetics approach, based on ultra-polymorphic markers, to address species delimitation within complex taxonomic groups. 相似文献
903.
Hanon C Bernard O Rabate M Claire T 《Journal of strength and conditioning research / National Strength & Conditioning Association》2012,26(6):1551-1557
The purpose of this study was to analyze 2 different long-sprint training programs (TPs) of equal total work load, completed either with short recovery (SR) or long recovery (LR) between sets and to compare the effects of 6 long-sprint training sessions (TSs) conducted over a 2-week period on a 300-m performance. Fourteen trained subjects performed 3 pretraining maximal sprints (50-, 100-, and 300-m), were paired according to their 300-m performance, and randomly allocated to an LR or SR group, which performed 6 TSs consisting of sets of 150, 200, or 250 m. The recovery in the LR group was double that of the SR group. During the third TS and the 300-m pretest and posttest, blood pH, bicarbonate concentration ([HCO??]), excess-base (EB), and lactate concentration were recorded. Compared with a similar TS performed with SR, the LR training tends to induce a greater alteration of the acid-base balance: pH: 7.09 ± 0.08 (LR) and 7.14 ± 0.05 (SR) (p = 0.10), [HCO??]: 7.8 ± 1.9 (LR) and 9.6 ± 2.7 (SR) (p = 0.04), and EB: -21.1 ± 3.8 (LR) and -17.7 ± 2.8 (SR) (p = 0.11). A significant improvement in the 300-m performance between pre-TP and post-TP (42.45 ± 2.64 vs. 41.52 ± 2.45, p = 0.01) and significant decreases in pH (p < 0.01), EB (p < 0.001) and increase in [La] (p < 0.001) have been observed post-TP compared with those pre-TP. Although sprint training with longer recovery induces higher metabolic disturbances, both sprint training regimens allow a similar 300-m performance improvement with no concomitant significant progress in the 50- and 100-m performance. 相似文献
904.
Girold S Jalab C Bernard O Carette P Kemoun G Dugué B 《Journal of strength and conditioning research / National Strength & Conditioning Association》2012,26(2):497-505
This study was undertaken to compare the effects of dry-land strength training vs. an electrical stimulation program on swimmers. Twenty-four national-level swimmers were randomly assigned to 3 groups: the dry-land strength training program (S), the electrical stimulation training program (ES), and the control (C) group. The training program lasted 4 weeks. The subjects were evaluated before the training, at the end of the training program, and 4 weeks later. The outcome values ascertained were peak torque during arm extension at different velocities (from -60 to 180°·s(-1)) using an isokinetic dynamometer and performance, stroke rate, and stroke length during a 50-m front crawl. A significant increase in swimming velocity and peak torque was observed for both S and ES at the end of the training and 4 weeks later. Stroke length increased in the S group but not in the ES group. However, no significant differences in swimming velocity between S and ES groups were observed. No significant changes occurred in the C group. Programs combining swimming training with dry-land strength or electrical stimulation programs led to a similar gain in sprint performance and were more efficient than swimming alone. 相似文献
905.
Boulter L Govaere O Bird TG Radulescu S Ramachandran P Pellicoro A Ridgway RA Seo SS Spee B Van Rooijen N Sansom OJ Iredale JP Lowell S Roskams T Forbes SJ 《Nature medicine》2012,18(4):572-579
During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted. 相似文献
906.
Patrick M Honore Rita Jacobs Olivier Joannes-Boyau Willem Boer Elisabeth De Waele Viola Van Gorp Jouke De Regt Herbert D Spapen 《Molecular medicine (Cambridge, Mass.)》2012,18(1):1363-1365
For almost three decades, researchers have invested in strategies that involved removal of excess inflammatory mediators from the circulation (that is, the “cytotoxic” approach). Blood purification techniques using an extracorporeal device can indeed non-specifically remove a wide array of inflammatory mediators from the circulation. In animal models, this multimediator targeting or pleiotropic approach was shown to downregulate systemic inflammation and to restore immune homeostasis. In this issue, Namas et al. seriously challenge this cytotoxic hypothesis and propose to replace it by a cytokinic approach. In a rodent model of sepsis, these authors elegantly demonstrate that hemoadsorption using a large surface-area polymer could reduce and, more importantly, relocalize and reprogram sepsis-induced acute inflammation, while simultaneously lowering infectious burden and liver damage. Although challenging, this new theory can be considered complementary to the existing cytotoxic hypotheses by coupling reduced endothelial damage at the interstitial level (cytotoxic approach) with the concept of reprogramming leucocytes and mediators toward infected tissue, thus emptying the bloodstream of important promoters of remote organ damages (cytokinic approach). 相似文献
907.
M Lutzmann C Grey S Traver O Ganier A Maya-Mendoza N Ranisavljevic F Bernex A Nishiyama N Montel E Gavois L Forichon B de Massy M Méchali 《Molecular cell》2012,47(4):523-534
We generated knockout mice for MCM8 and MCM9 and show that deficiency for these genes impairs homologous recombination (HR)-mediated DNA repair during gametogenesis and somatic cells cycles. MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I, and females have only arrested primary follicles and frequently develop ovarian tumors. MCM9(-/-) females also are sterile as ovaries are completely devoid of oocytes. In contrast, MCM9(-/-) testes produce spermatozoa, albeit in much reduced quantity. Mcm8(-/-) and Mcm9(-/-) embryonic fibroblasts show growth defects and chromosomal damage and cannot overcome a transient inhibition of replication fork progression. In these cells, chromatin recruitment of HR factors like Rad51 and RPA is impaired and HR strongly reduced. We further demonstrate that MCM8 and MCM9 form a complex and that they coregulate their stability. Our work uncovers essential functions of MCM8 and MCM9 in HR-mediated DSB repair during gametogenesis, replication fork maintenance, and DNA repair. 相似文献
908.
Laura S. Weyrich Olivier Y. Rolin Sarah J. Muse Jihye Park Nicholas Spidale Mary J. Kennett Sara E. Hester Chun Chen Edward G. Dudley Eric T. Harvill 《PloS one》2012,7(10)
Type VI Secretion Systems (T6SSs) have been identified in numerous Gram-negative pathogens, but the lack of a natural host infection model has limited analysis of T6SS contributions to infection and pathogenesis. Here, we describe disruption of a gene within locus encoding a putative T6SS in Bordetella bronchiseptica strain RB50, a respiratory pathogen that circulates in a broad range of mammals, including humans, domestic animals, and mice. The 26 gene locus encoding the B. bronchiseptica T6SS contains apparent orthologs to all known core genes and possesses thirteen novel genes. By generating an in frame deletion of clpV, which encodes a putative ATPase required for some T6SS-dependent protein secretion, we observe that ClpV contributes to in vitro macrophage cytotoxicity while inducing several eukaryotic proteins associated with apoptosis. Additionally, ClpV is required for induction of IL-1β, IL-6, IL-17, and IL-10 production in J774 macrophages infected with RB50. During infections in wild type mice, we determined that ClpV contributes to altered cytokine production, increased pathology, delayed lower respiratory tract clearance, and long term nasal cavity persistence. Together, these results reveal a natural host infection system in which to interrogate T6SS contributions to immunomodulation and pathogenesis. 相似文献
909.
Lynda Mezil Carole Berruyer-Pouyet Olivier Cabaud Emmanuelle Josselin Sébastien Combes Jean-Michel Brunel Patrice Viens Yves Collette Daniel Birnbaum Marc Lopez 《PloS one》2012,7(9)
Background
Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High-throughput approaches to identify new active and safe molecules with or without an “a priori” are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer.Methodology/Principal Findings
We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i) cell survival, ii) cell cycle, iii) extrinsic and intrinsic apoptotic pathways, iv) association with doxorubicin, docetaxel and lapatinib, v) cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN) and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine “primary” ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase-dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 µM to 12.5 µM).Conclusions/Significance
This is the first demonstration of the tumor selective cytotoxic action of a thiomorpholin hydroxamate compound. TMI-1 is a novel repositionable drug not only for the treatment of adverse prognosis breast cancers but also for other neoplasms. 相似文献910.
Enrique Casalino Bruno Bernot Olivier Bouchaud Chakib Alloui Christophe Choquet Elisabeth Bouvet Florence Damond Sandra Firmin Aurore Delobelle Beatrice Ename Nkoumazok Guillaume Der Sahakian Jean-Paul Viard Olivier Zak Dit Zbar Elisabeth Aslangul Anne Krivine Julie Zundel Jade Ghosn Patrice Nordmann Yann-Erick Claessens Tassadit Tahi Bruno Riou Agnès Gautheret-Dejean Christine Katlama Pierre Hausfater Fran?oise Brun-Vézinet Dominique Costagliola 《PloS one》2012,7(10)