全文获取类型
收费全文 | 6849篇 |
免费 | 219篇 |
国内免费 | 49篇 |
专业分类
化学 | 4271篇 |
晶体学 | 25篇 |
力学 | 276篇 |
数学 | 1406篇 |
物理学 | 1054篇 |
综合类 | 85篇 |
出版年
2023年 | 34篇 |
2022年 | 127篇 |
2021年 | 145篇 |
2020年 | 145篇 |
2019年 | 118篇 |
2018年 | 114篇 |
2017年 | 88篇 |
2016年 | 246篇 |
2015年 | 188篇 |
2014年 | 230篇 |
2013年 | 399篇 |
2012年 | 450篇 |
2011年 | 469篇 |
2010年 | 242篇 |
2009年 | 274篇 |
2008年 | 415篇 |
2007年 | 411篇 |
2006年 | 347篇 |
2005年 | 325篇 |
2004年 | 314篇 |
2003年 | 242篇 |
2002年 | 189篇 |
2001年 | 88篇 |
2000年 | 69篇 |
1999年 | 65篇 |
1998年 | 65篇 |
1997年 | 73篇 |
1996年 | 105篇 |
1995年 | 50篇 |
1994年 | 65篇 |
1993年 | 44篇 |
1992年 | 66篇 |
1991年 | 48篇 |
1990年 | 44篇 |
1989年 | 48篇 |
1988年 | 40篇 |
1987年 | 37篇 |
1986年 | 38篇 |
1985年 | 55篇 |
1984年 | 53篇 |
1983年 | 52篇 |
1982年 | 57篇 |
1981年 | 31篇 |
1980年 | 44篇 |
1979年 | 30篇 |
1978年 | 35篇 |
1977年 | 30篇 |
1976年 | 27篇 |
1974年 | 19篇 |
1973年 | 19篇 |
排序方式: 共有7117条查询结果,搜索用时 15 毫秒
931.
Alberto Seeger 《Integral Equations and Operator Theory》2006,54(2):279-300
Let H be an infinite dimensional Hilbert space. Denote by Λ (E, F) the set of all
for which the multivalued system 0 ∈ (F − λ E) (x) admits a nonzero solution x ∈ H. One says that Λ (E, F) is the point spectrum of the pair (E, F). It is well known that Λ (E, F) does not behave in a stable manner with respect to perturbations in the argument (E, F). The purpose of this note is to study the outer-semicontinuous hull (or graph-closure) of the mapping Λ. 相似文献
932.
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer 总被引:1,自引:0,他引:1
Misale S Yaeger R Hobor S Scala E Janakiraman M Liska D Valtorta E Schiavo R Buscarino M Siravegna G Bencardino K Cercek A Chen CT Veronese S Zanon C Sartore-Bianchi A Gambacorta M Gallicchio M Vakiani E Boscaro V Medico E Weiser M Siena S Di Nicolantonio F Solit D Bardelli A 《Nature》2012,486(7404):532-536
A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. 相似文献
933.
Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control. 相似文献
934.
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR 总被引:1,自引:0,他引:1
Prahallad A Sun C Huang S Di Nicolantonio F Salazar R Zecchin D Beijersbergen RL Bardelli A Bernards R 《Nature》2012,483(7387):100-103
Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors. 相似文献
935.
Fritz JH Rojas OL Simard N McCarthy DD Hapfelmeier S Rubino S Robertson SJ Larijani M Gosselin J Ivanov II Martin A Casellas R Philpott DJ Girardin SE McCoy KD Macpherson AJ Paige CJ Gommerman JL 《Nature》2012,481(7380):199-203
The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells. 相似文献
936.
Demonstrations of the possibility of obtaining functional information from the spinal cord in humans using functional magnetic resonance imaging (fMRI) have been growing in number and sophistication, but the technique and the results that it provides are still perceived by the scientific community with a greater degree of scepticism than fMRI investigations of brain function. Here we review the literature on spinal fMRI in humans during voluntary movements and somatosensory stimulation. Particular attention is given to study design, acquisition and statistical analysis of the images, and to the agreement between the obtained results and existing knowledge regarding spinal cord anatomy and physiology. 相似文献
937.
Piero Boraschi Francescamaria Donati Roberto Gigoni Simonetta Salemi Carlo Bartolozzi Fabio Falaschi 《Magnetic resonance imaging》2010
Purpose
To evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in the differentiation of cystic pancreatic lesions.Materials and Methods
Institutional review board approval was obtained, and written informed consent was taken from all enrolled subjects. Fifty-four patients with cystic pancreatic lesions of at least 1 cm in diameter (range:10–96 mm) at ultrasonography and/or computed tomography and 10 normal subjects underwent MRI at 1.5 T. These subjects included thirty-four patients with intraductal papillary mucinous tumors (IPMTs), 10 with pseudocysts, 5 with serous cystoadenoma and 5 with mucinous cystoadenoma. The MR protocol included axial T1w and T2w sequences and coronal MR cholangiopancreatography images. DW-MRI was performed using a breath-hold single-shot echo-planar sequence with a b gradient factor value of 500 s/mm2 in the three orthogonal axes. Apparent diffusion coefficient (ADC) was calculated for cerebrospinal fluid, normal pancreatic parenchyma, and for each focal pancreatic lesion. Imaging results were correlated with endoscopic retrograde cholangiopancreatography, endoscopic ultrasound-guided fine needle aspiration, surgery and/or imaging follow-up.Results
Mean ADC value was 4.1×10−3 mm2/s for cerebrospinal fluid, 1.73×10−3 mm2/s for normal pancreatic parenchyma, 4.09×10−3 mm2/s for IPMT, 3.89×10−3 mm2/s for mucinous cystoadenoma, 3.65×10−3 mm2/s for serous cystoadenoma and 2.83×10−3 mm2/s for pseudocyst. Mean ADC values of each of the different types of pancreatic lesions were statistically different (P<.05).Conclusion
DW-MRI may be helpful in the differential diagnosis of cystic pancreatic lesions. 相似文献938.
Marta Balietti Belinda Giorgetti Giuseppina Di Stefano Tiziana Casoli Daniela Platano Moreno Solazzi Carlo Bertoni-Freddari Giorgio Aicardi Fabrizia Lattanzio Patrizia Fattoretti 《Micron (Oxford, England : 1993)》2010,41(2):143-148
Ketogenic diets (KDs) have been applied in the therapy of paediatric epilepsy for nearly a century. Recently, beneficial results have also been reported on metabolic disorders and neurodegeneration, designating aged individuals as possible recipients. However, KDs efficacy decrease after the suckling period, and very little is known about their impact on the aging brain. In the present study, the effect on the neuronal energetic supply of a KD containing 20% of medium chain triglycerides (MCT) was investigated in Purkinje cells of the cerebellar vermis of late-adult (19-month-old) rats. The animals were fed with the KD for 8 weeks, and succinic dehydrogenase (SDH) activity was cytochemically determined. The following parameters of SDH-positive mitochondria were evaluated by the use of a computer-assisted image analysis system connected to a transmission electron microscope: numeric density (Nv), average volume (V), volume density (Vv), and cytochemical precipitate area/mitochondrial area (R). Young, age-matched, and old animals fed with a standard chow were used as controls. We found significantly higher Nv in MCT-KD-fed rats vs. all the control groups, in young vs. late-adult and old controls, and in late-adult vs. old controls. V and Vv showed no significant differences among the groups. R was significantly higher in MCT-KD-fed rats vs. all the control animals, and in old vs. young and late-adult controls. Present data indicate that the ketogenic treatment counteracted age-related decrease in numeric density of SDH-positive mitochondria, and enhanced their metabolic efficiency. Given the central role of mitochondrial impairment in age-related physio-pathological changes of the brain, these findings may represent a starting point to examine novel potentialities for KDs. 相似文献
939.
Tuned mass sampers (TMDs) are widely used strategies for vibration control in many engineering applications, so that many TMD optimization criteria have been proposed till now. However, they normally consider only TMD stiffness and damping as design variables and assume that the tuned mass is a pre-selected value. In this work a more complete approach is proposed and then also TMD mass ratio is optimized. A standard single degree of freedom system is investigated to evaluate TMD protection efficiency in case of excitation at the support. More precisely, this model is used to develop two different optimizations criteria which minimize the main system displacement or the inertial acceleration. Different environmental conditions described by various characterizations of the input, here modelled by a stationary filtered stochastic process, are considered. Results show that all solutions obtained considering also the mass of the TMD as design variable are more efficient if compared with those obtained without it. However, in many cases these solutions are inappropriate because the optimal TMD mass is greater than real admissible values in practical technical applications for civil and mechanical engineering. Anyway, one can deduce that there are some interesting indications for applications in some actual contexts. In fact, the results show that there are some ranges of environmental parameters ranges where results attained by the displacement criterion are compatible with real applications requiring some percent of main system mass. Finally, the present research gives promising indications for complete TMD optimization application in emerging technical contexts, as micromechanical devices and nano resonant beams. 相似文献
940.
Carlo Bianca Caterina Mogno 《Mathematical and Computer Modelling of Dynamical Systems: Methods, Tools and Applications in Engineering and Related Sciences》2018,24(2):207-235
This paper deals with the modelling of pedestrian dynamics at the entry of a metro station by means of the thermostatted kinetic theory framework. Specifically, the model depicts the time evolution of the pedestrian dynamics at the turnstiles under no panic conditions. The modelling of the microscopic interactions is based on the stochastic game theory and reflects the decision dynamics of the turnstiles pursued by pedestrians. A qualitative analysis is addressed to the equilibrium solutions by means of the classical stability theory of perturbations. Numerical simulations aim at showing the emerging behaviours captured by the model. In particular the model validation is obtained by performing a sensitivity analysis on the parameters and on the initial conditions. Further refinements and research perspective, including the modelling under panic conditions, are discussed in the last section of the paper. 相似文献