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1.
J A Martignetti A A Aqeel W A Sewairi C E Boumah M Kambouris S A Mayouf K V Sheth W A Eid O Dowling J Harris M J Glucksman S Bahabri B F Meyer R J Desnick 《Nature genetics》2001,28(3):261-265
The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion. 相似文献
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Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis 总被引:1,自引:0,他引:1
Zaph C Troy AE Taylor BC Berman-Booty LD Guild KJ Du Y Yost EA Gruber AD May MJ Greten FR Eckmann L Karin M Artis D 《Nature》2007,446(7135):552-556
Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation. 相似文献
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Bos KI Schuenemann VJ Golding GB Burbano HA Waglechner N Coombes BK McPhee JB DeWitte SN Meyer M Schmedes S Wood J Earn DJ Herring DA Bauer P Poinar HN Krause J 《Nature》2011,478(7370):506-510
Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections. 相似文献
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Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits. 相似文献
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Spatio-temporal transcriptome of the human brain 总被引:1,自引:0,他引:1
8.
Annette Burkhart Thomas Lars Andresen Achim Aigner Louiza Bohn Thomsen Torben Moos 《Cellular and molecular life sciences : CMLS》2017,74(13):2467-2485
Treatment of chronic disorders affecting the central nervous system (CNS) is complicated by the inability of drugs to cross the blood–brain barrier (BBB). Non-viral gene therapy applied to brain capillary endothelial cells (BCECs) denotes a novel approach to overcome the restraints in this passage, as turning BCECs into recombinant protein factories by transfection could result in protein secretion further into the brain. The present study aims to investigate the possibility of transfecting primary rat brain endothelial cells (RBECs) for recombinant protein synthesis and secretion of the neuroprotective protein erythropoietin (EPO). We previously showed that 4% of RBECs with BBB properties can be transfected without disrupting the BBB integrity in vitro, but it can be questioned whether this is sufficient to enable protein secretion at therapeutic levels. The present study examined various transfection vectors, with regard to increasing the transfection efficiency without disrupting the BBB integrity. Lipofectamine 3000? was the most potent vector compared to polyethylenimine (PEI) and Turbofect. When co-cultured with astrocytes, the genetically modified RBECs secreted recombinant EPO into the cell culture medium both luminally and abluminally, and despite lower levels of EPO reaching the abluminal chamber, the amount of recombinant EPO was sufficient to evolve a biological effect on astrocytes cultured at the abluminal side in terms of upregulated gene expression of brain-derived neurotropic factor (BDNF). In conclusion, non-viral gene therapy to RBECs leads to protein secretion and signifies a method for therapeutic proteins to target cells inside the CNS otherwise omitted due to the BBB. 相似文献
9.
Penstemon palmeri is a short-lived perennial herb colonizing disturbed sites in semiarid habitats in the western USA. In this study seed was harvested from six native and four seeded populations during two consecutive years. In laboratory germination trials at constant 15 C, considerable between-lot variation in primary dormancy and light requirement was observed. Four weeks of moist chilling (1 C) induced secondary dormancy at 15 C. Cold-induced secondary dormancy was reversed by one week of dark incubation at 30 C. This warm incubation treatment also reduced the light requirement of unchilled, after-ripened seed. Fluctuations in dormancy and light requirement of buried seeds have been linked to seasonal changes in soil temperature. Penstemon palmeri germination responses to temperature appear to be similar to those of facultative winter annuals. 相似文献
10.
Effect of conditioned media on nerve cell differentiation 总被引:2,自引:0,他引:2
M. Sensenbrenner G. G. Jaros G. Moonen B. J. Meyer 《Cellular and molecular life sciences : CMLS》1980,36(6):660-662
Summary Glial conditioned medium strongly stimulates the morphological maturation of cultured neuronal cells, while fibroblast and meningeal conditioned media have weaker effects.Acknowledgment. We acknowledge the expert technical assistance of Mrs M.F. Knoetgen. 相似文献