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971.
Gilmore BF Carson L McShane LL Quinn D Coulter WA Walker B 《Biochemical and biophysical research communications》2006,347(1):373-379
In this study, we report on the synthesis, kinetic characterisation, and application of a novel biotinylated and active site-directed inactivator of dipeptidyl peptidase IV (DPP-IV). Thus, the dipeptide-derived proline diphenyl phosphonate NH(2)-Glu(biotinyl-PEG)-Pro(P)(OPh)(2) has been prepared by a combination of classical solution- and solid-phase methodologies and has been shown to be an irreversible inhibitor of porcine DPP-IV, exhibiting an over all second-order rate constant (k(i)/K(i)) for inhibition of 1.57 x 10(3) M(-1) min(-1). This value compares favourably with previously reported rates of inactivation of DPP-IV by dipeptides containing a P(1) proline diphenyl phosphonate grouping [B. Boduszek, J. Oleksyszyn, C.M. Kam, J. Selzler, R.E. Smith, J.C. Powers, Dipeptide phophonates as inhibitors of dipeptidyl peptidase IV, J. Med. Chem. 37 (1994) 3969-3976; B.F. Gilmore, J.F. Lynas, C.J. Scott, C. McGoohan, L. Martin, B. Walker, Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha), Biochem, Biophys. Res. Commun. 346 (2006) 436-446.], thus demonstrating that the incorporation of the side-chain modified (N-biotinyl-3-(2-(2-(3-aminopropyloxy)-ethoxy)-ethoxy)-propyl) glutamic acid residue at the P(2) position is compatible with inhibitor efficacy. The utilisation of this probe for the detection of both purified dipeptidyl peptidase IV and the disclosure of a dipeptidyl peptidase IV-like activity from a clinical isolate of Porphyromonas gingivalis, using established electrophoretic and Western blotting techniques previously developed by our group, is also demonstrated. 相似文献
972.
BACKGROUND: Some plants hyperaccumulate the toxic element selenium (Se) to extreme levels, up to 1% of dry weight. The function of this intriguing phenomenon is obscure. RESULTS: Here, we show that the Se in the hyperaccumulator prince's plume (Stanleya pinnata) protects it from caterpillar herbivory because of deterrence and toxicity. In its natural habitat, however, a newly discovered variety of the invasive diamondback moth (Plutella xylostella) has disarmed this elemental defense. It thrives on plants containing highly toxic Se levels and shows no oviposition or feeding deterrence, in contrast to related varieties. Interestingly, a Se-tolerant wasp (Diadegma insulare) was found to parasitize the tolerant moth. The insect's Se tolerance mechanism was revealed by X-ray absorption spectroscopy and liquid chromatography-mass spectroscopy, which showed that the Se-tolerant moth and its parasite both accumulate methylselenocysteine, the same form found in the hyperaccumulator plant, whereas related sensitive moths accumulate selenocysteine. The latter is toxic because of its nonspecific incorporation into proteins. Indeed, the Se-tolerant diamondback moth incorporated less Se into protein. Additionally, the tolerant variety sequestered Se in distinct abdominal areas, potentially involved in detoxification and larval defense to predators. CONCLUSIONS: Although Se hyperaccumulation protects plants from herbivory by some invertebrates, it can give rise to the evolution of unique Se-tolerant herbivores and thus provide a portal for Se into the local ecosystem. In a broader context, this study provides insight into the possible ecological implications of using Se-enriched crops as a source of anti-carcinogenic selenocompounds and for the remediation of Se-polluted environments. 相似文献
973.
Characterization of the twin-arginine translocase secretion system of Mycobacterium smegmatis 下载免费PDF全文
The twin-arginine translocation (TAT) system secretes fully folded proteins that contain a twin-arginine motif within their signal sequence across the cytoplasmic membrane in bacteria. Using a green fluorescent protein fused with a TAT signal sequence, we demonstrated that Mycobacterium smegmatis contains a TAT system. By inactivating individual genes, we showed that three genes (tatA, tatB, and tatC) are required for a functional TAT system in M. smegmatis. The tat mutants exhibited a decreased growth rate and altered colony morphology compared to the parent strain. Comparison of the secreted proteins of the deltatatC and parent strain by two-dimensional polyacrylamide gel electrophoresis revealed an alteration in the secretion of at least five proteins, and one of the major TAT-dependent secreted proteins was identified as beta-lactamase (BlaS). The genome of M. smegmatis was analyzed with the TATFIND program, and 49 putative TAT substrates were identified, including the succinate transporter DctP. Because disruption of the TAT secretion system has a direct effect on the physiology of M. smegmatis and homologs of the TAT proteins are also present in the genome of Mycobacterium tuberculosis, the TAT secretion system or its substrates may be good candidates for drug or vaccine development. 相似文献
974.
Quinn P. Peterson David R. Goode Diana C. West Joy J.Y. Lee 《Journal of molecular biology》2009,388(1):144-50
The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key “executioner” caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds. 相似文献
975.
Vaags AK Lionel AC Sato D Goodenberger M Stein QP Curran S Ogilvie C Ahn JW Drmic I Senman L Chrysler C Thompson A Russell C Prasad A Walker S Pinto D Marshall CR Stavropoulos DJ Zwaigenbaum L Fernandez BA Fombonne E Bolton PF Collier DA Hodge JC Roberts W Szatmari P Scherer SW 《American journal of human genetics》2012,90(1):133-141
The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses. 相似文献
976.
Phylogenetic analysis is becoming an increasingly important tool for biological research. Applications include epidemiological
studies, drug development, and evolutionary analysis. Phylogenetic search is a known NP-Hard problem. The size of the data
sets which can be analyzed is limited by the exponential growth in the number of trees that must be considered as the problem
size increases. A better understanding of the problem space could lead to better methods, which in turn could lead to the
feasible analysis of more data sets. We present a definition of phylogenetic tree space and a visualization of this space
that shows significant exploitable structure. This structure can be used to develop search methods capable of handling much
larger data sets. 相似文献
977.
Steven J. Reynolds Cissy Kityo Claire W. Hallahan Geoffrey Kabuye Diana Atwiine Frank Mbamanya Francis Ssali Robin Dewar Marybeth Daucher Richard T. Davey Jr Peter Mugyenyi Anthony S. Fauci Thomas C. Quinn Mark R. Dybul 《PloS one》2010,5(4)
Background
Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.Methods
A 72 week, non-inferiority trial enrolled one hundred forty six HIV positive persons receiving ART (CD4+ cell count ≥125 cells/mm3 and HIV RNA plasma levels <50 copies/ml) in one of three arms: continuous, 7 days on/7 days off and 5 days on/2 days off treatment. Primary endpoint was ART treatment failure determined by plasma HIV RNA level, CD4+ cell count decrease, death attributed to study participation, or opportunistic infection.Results
Following enrollment of 32 participants, the 7 days on/7 days off arm was closed because of a failure rate of 31%. Six of 52 (11.5%) participants in the 5 days on/2 days off arm failed. Five had virologic failure and one participant had immunologic failure. Eleven of 51 (21.6%) participants in the continuous treatment arm failed. Nine had virologic failure with 1 death (lactic acidosis) and 1 clinical failure (extra-pulmonary TB). The upper 97.5% confidence boundary for the difference between the percent of non-failures in the 5 days on/2 days off arm (88.5% non-failure) compared to continuous treatment (78.4% non failure) was 4.8% which is well within the preset non-inferiority margin of 15%. No significant difference was found in time to failure in the 2 study arms (p = 0.39).Conclusions
Short cycle 5 days on/2 days off intermittent ART was at least as effective as continuous therapy.Trial Registration
ClinicalTrials.gov NCT00339456相似文献978.
Full field strain measurements of biological tissue during loading are often limited to the quantification of fiduciary marker displacements on the tissue surface. These marker measurements can lack the necessary spatial resolution to characterize non-uniform deformation and may not represent the deformation of the load-bearing collagen microstructure. To overcome these potential limitations, a method was developed to track the deformation of the collagen fiber microstructure in ligament tissue. Using quantitative polarized light imaging, fiber alignment maps incorporating both direction and alignment strength at each pixel were generated during facet capsular ligament loading. A grid of virtual markers was superimposed over the tissue in the alignment maps, and the maximization of a vector correlation calculation between fiber alignment maps was used to track marker displacement. Tracking error was quantified through comparisons to the displacements of excised ligament tissue (n=3); separate studies applied uniaxial tension to isolated facet capsular ligament tissue (n=4) to evaluate tracking capabilities during large tissue deformations. The average difference between virtual marker and tissue displacements was 0.07±0.06 pixels. This error in marker location produced principal strain measurements of 1.2±1.6% when markers were spaced 4 pixels apart. During tensile tissue loading, substantial inhomogeneity was detected in the strain field using vector correlation tracking, and the location of maximum strain differed from that produced by standard tracking techniques using coarser meshes. These findings provide a method to directly measure fiber network strains using quantitative fiber alignment data, enabling a better understanding of structure–function relationships in tissues at different length scales. 相似文献
979.
Ryan K. Quinn Amelia L. Cianci Jennifer A. Beaudoin Bianca R. Sculimbrene 《Bioorganic & medicinal chemistry letters》2010,20(15):4382-4385
The alkene peptide isostere for the d-Ala-d-Ala dipeptide was synthesized via a convergent approach utilizing olefin cross-metathesis. The new isostere was then evaluated for binding to the last resort antibiotic, vancomycin. The alkene isostere exhibited a KD = 90 μM in comparison to the native peptide (KD = 2.3 μM) and Lac mutant (KD = 2300 μM). This study demonstrates that loss of binding in vancomycin resistant strains as a result of a d-Ala to d-Lac mutation is from both the loss of a crucial hydrogen bond and introduction of a repulsive lone pair interaction. 相似文献
980.
Stephen D. Goble Liping Wang K. Lulu Howell Alka Bansal Richard Berger Linda Brockunier Jerry DiSalvo Scott Feighner Bart Harper Jiafang He Amanda Hurley Donna Hreniuk Emma Parmee Michael Robbins Gino Salituro Anthony Sanfiz Eric Streckfuss Eloisa Watkins Ann E. Weber Mary Struthers Scott D. Edmondson 《Bioorganic & medicinal chemistry letters》2010,20(6):1895-1899
A series of amide derived β3-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation β3-AR agonists for the treatment of overactive bladder. 相似文献