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101.
102.
Protein engineering of the colony-stimulating factor-1 receptor kinase domain for structural studies
Schalk-Hihi C Ma HC Struble GT Bayoumy S Williams R Devine E Petrounia IP Mezzasalma T Zeng L Schubert C Grasberger B Springer BA Deckman IC 《The Journal of biological chemistry》2007,282(6):4085-4093
A parallel approach to designing crystallization constructs for the c-FMS kinase domain was implemented, resulting in proteins suitable for structural studies. Sequence alignment and limited proteolysis were used to identify and eliminate unstructured and surface-exposed domains. A small library of chimeras was prepared in which the kinase insert domain of FMS was replaced with the kinase insert domain of previously crystallized receptor-tyrosine kinases. Characterization of the newly generated FMS constructs by enzymology and thermoshift assays demonstrated similar activities and compound binding to the FMS full-length cytoplasmic domain. Two chimeras were evaluated for crystallization in the presence and absence of a variety of ligands resulting in crystal structures, and leading to a successful structure-based drug design project for this important inflammation target. 相似文献
103.
Sean M. Gibbons Tara Schwartz Jennifer Fouquier Michelle Mitchell Naseer Sangwan Jack A. Gilbert Scott T. Kelley 《Applied and environmental microbiology》2015,81(2):765-773
Human-associated bacteria dominate the built environment (BE). Following decontamination of floors, toilet seats, and soap dispensers in four public restrooms, in situ bacterial communities were characterized hourly, daily, and weekly to determine their successional ecology. The viability of cultivable bacteria, following the removal of dispersal agents (humans), was also assessed hourly. A late-successional community developed within 5 to 8 h on restroom floors and showed remarkable stability over weeks to months. Despite late-successional dominance by skin- and outdoor-associated bacteria, the most ubiquitous organisms were predominantly gut-associated taxa, which persisted following exclusion of humans. Staphylococcus represented the majority of the cultivable community, even after several hours of human exclusion. Methicillin-resistant Staphylococcus aureus (MRSA)-associated virulence genes were found on floors but were not present in assembled Staphylococcus pan-genomes. Viral abundances, which were predominantly enterophages, human papilloma virus, and herpesviruses, were significantly correlated with bacterial abundances and showed an unexpectedly low virus-to-bacterium ratio in surface-associated samples, suggesting that bacterial hosts are mostly dormant on BE surfaces. 相似文献
104.
Susanne Wegmann Eduardo A Maury Molly J Kirk Lubna Saqran Allyson Roe Sarah L DeVos Samantha Nicholls Zhanyun Fan Shuko Takeda Ozge Cagsal‐Getkin Christopher M William Tara L Spires‐Jones Rose Pitstick George A Carlson Amy M Pooler Bradley T Hyman 《The EMBO journal》2015,34(24):3028-3041
In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion‐like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans‐synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau‐overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau‐null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein. 相似文献
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107.
Robinson RP Bartlett JA Bertinato P Bessire AJ Cosgrove J Foley PM Manion TB Minich ML Ramos B Reese MR Schmahai TJ Swick AG Tess DA Vaz A Wolford A 《Bioorganic & medicinal chemistry letters》2011,21(14):4150-4154
Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4′-alkyl and 4′-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies. 相似文献
108.
Burke JE Vadas O Berndt A Finegan T Perisic O Williams RL 《Structure (London, England : 1993)》2011,19(8):1127-1137
Phosphoinositide 3-kinase δ is upregulated in lymphocytic leukemias. Because the p85-regulatory subunit binds to any class IA subunit, it was assumed there is a single universal p85-mediated regulatory mechanism; however, we find isozyme-specific inhibition by p85α. Using deuterium exchange mass spectrometry (DXMS), we mapped regulatory interactions of p110δ with p85α. Both nSH2 and cSH2 domains of p85α contribute to full inhibition of p110δ, the nSH2 by contacting the helical domain and the cSH2 via the C terminus of p110δ. The cSH2 inhibits p110β and p110δ, but not p110α, implying that p110α is uniquely poised for oncogenic mutations. Binding RTK phosphopeptides disengages the SH2 domains, resulting in exposure of the catalytic subunit. We find that phosphopeptides greatly increase the affinity of the heterodimer for PIP2-containing membranes measured by FRET. DXMS identified regions decreasing exposure at membranes and also regions gaining exposure, indicating loosening of interactions within the heterodimer at membranes. 相似文献
109.
Franco C Sell TK 《Biosecurity and bioterrorism : biodefense strategy, practice, and science》2011,9(2):117-137
Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series have analyzed civilian biodefense funding by the federal government for fiscal years (FY) 2001 through proposed funding for FY2011. This article updates those figures with budgeted amounts for FY2012, specifically analyzing the budgets and allocations for biodefense at the Departments of Health and Human Services, Defense, Homeland Security, Agriculture, Commerce, and State; the Environmental Protection Agency; and the National Science Foundation. This article also includes an updated assessment of the proportion of biodefense funding provided for programs that address multiple scientific, public health, healthcare, national security, and international security issues in addition to biodefense. The FY2012 federal budget for civilian biodefense totals $6.42 billion. Of that total, $5.78 billion (90%) is budgeted for programs that have both biodefense and nonbiodefense goals and applications, and $637.6 million (10%) is budgeted for programs that have objectives solely related to biodefense. 相似文献
110.
Karsenti E Acinas SG Bork P Bowler C De Vargas C Raes J Sullivan M Arendt D Benzoni F Claverie JM Follows M Gorsky G Hingamp P Iudicone D Jaillon O Kandels-Lewis S Krzic U Not F Ogata H Pesant S Reynaud EG Sardet C Sieracki ME Speich S Velayoudon D Weissenbach J Wincker P;Tara Oceans Consortium 《PLoS biology》2011,9(10):e1001177
The structure, robustness, and dynamics of ocean plankton ecosystems remain poorly understood due to sampling, analysis, and computational limitations. The Tara Oceans consortium organizes expeditions to help fill this gap at the global level. 相似文献