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191.
Michael K. E. Schäfer Peter Altevogt 《Cellular and molecular life sciences : CMLS》2010,67(14):2425-2437
Research over the last 25 years on the cell adhesion molecule L1 has revealed its pivotal role in nervous system function.
Mutations of the human L1CAM gene have been shown to cause neurodevelopmental disorders such as X-linked hydrocephalus, spastic paraplegia and mental
retardation. Impaired L1 function has been also implicated in the aetiology of fetal alcohol spectrum disorders, defective
enteric nervous system development and malformations of the renal system. Importantly, aberrant expression of L1 has emerged
as a critical factor in the development of human carcinomas, where it enhances cell proliferation, motility and chemoresistance.
This discovery promoted collaborative work between tumour biologists and neurobiologists, which has led to a substantial expansion
of the basic knowledge about L1 function and regulation. Here we provide an overview of the pathological conditions caused
by L1 malfunction. We further discuss how the available data on gene regulation, molecular interactions and posttranslational
processing of L1 may contribute to a better understanding of associated neurological and cancerous diseases. 相似文献
192.
193.
Matthias Samereier Otto Baumann Irene Meyer Ralph Gräf 《Cellular and molecular life sciences : CMLS》2011,68(2):275-287
We have localized TACC to the microtubule-nucleating centrosomal corona and to microtubule plus ends. Using RNAi we proved
that Dictyostelium TACC promotes microtubule growth during interphase and mitosis. For the first time we show in vivo that both TACC and XMAP215
family proteins can be differentially localized to microtubule plus ends during interphase and mitosis and that TACC is mainly
required for recruitment of an XMAP215-family protein to interphase microtubule plus ends but not for recruitment to centrosomes
and kinetochores. Moreover, we have now a marker to study dynamics and behavior of microtubule plus ends in living Dictyostelium cells. In a combination of live cell imaging of microtubule plus ends and fluorescence recovery after photobleaching (FRAP)
experiments of GFP-α-tubulin cells we show that Dictyostelium microtubules are dynamic only in the cell periphery, while they remain stable at the centrosome, which also appears to harbor
a dynamic pool of tubulin dimers. 相似文献
194.
Svenja D. Steinbrink Carlo Pergola Ulrike Bühring Sven George Julia Metzner Astrid S. Fischer Ann-Kathrin Häfner Joanna M. Wisniewska Gerd Geisslinger Oliver Werz Dieter Steinhilber Thorsten J. Maier 《Cellular and molecular life sciences : CMLS》2010,67(5):797-806
Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug’s chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC50 ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC50 = 18.7 μM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC50 of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy. 相似文献
195.
Saikiran K. Sedimbi Thomas Hägglöf Mikael C. I. Karlsson 《Cellular and molecular life sciences : CMLS》2013,70(24):4795-4808
Inflammation serves as the first line of defense in response to tissue injury, guiding the immune system to ensure preservation of the host. The inflammatory response can be divided into a quick initial phase mediated mainly by innate immune cells including neutrophils and macrophages, followed by a late phase that is dominated by lymphocytes. Early in the new millennium, a key component of the inflammatory reaction was discovered with the identification of a number of cytosolic sensor proteins (Nod-like receptors) that assembled into a common structure, the ‘inflammasome’. This structure includes an enzyme, caspase-1, which upon activation cleaves pro-forms of cytokines leading to subsequent release of active IL-1 and IL-18. This review focuses on the role of IL-18 in inflammatory responses with emphasis on autoimmune diseases. 相似文献
196.
197.
Stylianos Michalakis Karin Schäferhoff Isabella Spiwoks-Becker Nawal Zabouri Susanne Koch Fred Koch Michael Bonin Martin Biel Silke Haverkamp 《Cellular and molecular life sciences : CMLS》2013,70(10):1831-1847
In the mammalian retina, light signals generated in photoreceptors are passed to bipolar and horizontal cells via synaptic contacts. In various pathological conditions, these second-order neurons extend neurites into the outer nuclear layer (ONL). However, the molecular events associated with this neurite outgrowth are not known. Here, we characterized the morphological synaptic changes in the CNGA3/CNGB1 double-knockout (A3B1) mouse, a model of retinitis pigmentosa. In these mice, horizontal cells looked normal until postnatal day (p) 11, but started growing neurites into the ONL 1 day later. At p28, the number of sprouting processes decreased, but the remaining sprouts developed synapse-like contacts at rod cell bodies, with an ultrastructural appearance reminiscent of ribbon synapses. Hence, neurite outgrowth and ectopic synaptogenesis in the A3B1 retina were precisely timed events starting at p12 and p28, respectively. We therefore performed microarray analysis of retinal gene expression in A3B1 and wild-type mice at those ages to evaluate the genomic response underlying these two events. This analysis identified 163 differentially regulated genes in the A3B1 retina related to neurite outgrowth or plasticity of synapses. The global changes in gene expression in the A3B1 retina were consistent with activation of signaling pathways related to Tp53, Smad, and Stat3. Moreover, key molecules of these signaling pathways could be localized at or in close proximity to outgrowing neurites. We therefore propose that Tp53, Smad, and Stat3 signaling pathways contribute to the synaptic plasticity in the A3B1 retina. 相似文献
198.
A radiation hybrid map of the zebrafish genome. 总被引:12,自引:0,他引:12
R Geisler G J Rauch H Baier F van Bebber L Bross M P Dekens K Finger C Fricke M A Gates H Geiger S Geiger-Rudolph D Gilmour S Glaser L Gnügge H Habeck K Hingst S Holley J Keenan A Kirn H Knaut D Lashkari F Maderspacher U Martyn S Neuhauss C Neumann T Nicolson F Pelegri R Ray J M Rick H Roehl T Roeser H E Schauerte A F Schier U Sch?nberger H B Sch?nthaler S Schulte-Merker C Seydler W S Talbot C Weiler C Nüsslein-Volhard P Haffter 《Nature genetics》1999,23(1):86-89
Recent large-scale mutagenesis screens have made the zebrafish the first vertebrate organism to allow a forward genetic approach to the discovery of developmental control genes. Mutations can be cloned positionally, or placed on a simple sequence length polymorphism (SSLP) map to match them with mapped candidate genes and expressed sequence tags (ESTs). To facilitate the mapping of candidate genes and to increase the density of markers available for positional cloning, we have created a radiation hybrid (RH) map of the zebrafish genome. This technique is based on somatic cell hybrid lines produced by fusion of lethally irradiated cells of the species of interest with a rodent cell line. Random fragments of the donor chromosomes are integrated into recipient chromosomes or retained as separate minichromosomes. The radiation-induced breakpoints can be used for mapping in a manner analogous to genetic mapping, but at higher resolution and without a need for polymorphism. Genome-wide maps exist for the human, based on three RH panels of different resolutions, as well as for the dog, rat and mouse. For our map of the zebrafish genome, we used an existing RH panel and 1,451 sequence tagged site (STS) markers, including SSLPs, cloned candidate genes and ESTs. Of these, 1,275 (87.9%) have significant linkage to at least one other marker. The fraction of ESTs with significant linkage, which can be used as an estimate of map coverage, is 81.9%. We found the average marker retention frequency to be 18.4%. One cR3000 is equivalent to 61 kb, resulting in a potential resolution of approximately 350 kb. 相似文献
199.
The early large birefringence signal and mechanical activity were studied together in isolated single fibres of frog skeletal muscle with double stimulation at short stimulus intervals (2-60 msec) at room temperature and at 4--6 degrees C. In all fibres tested, extra tension and additional birefringence signal in response to the second stimulus appeared simultaneously and suddenly upon increasing the stimulus interval. The shape of the stimulus-interval versus tension-development curve makes it highly improbable that subthreshold calcium release occurs at shorter stimulus intervals; therefore, tension development reliably reflects Ca-release in these experiments. In contrast to the report by Suarez-Kurtz and Partker, birefringence signal and calcium release are shown not to be dissociated by double stimulation. This result supports the hypothesis that the early large birefringence signal is an intrinsic indicator of calcium release from the sr during EC-coupling in skeletal muscle. 相似文献
200.
Carlsson F Stålhammar-Carlemalm M Flärdh K Sandin C Carlemalm E Lindahl G 《Nature》2006,442(7105):943-946
All living cells require specific mechanisms that target proteins to the cell surface. In eukaryotes, the first part of this process involves recognition in the endoplasmic reticulum of amino-terminal signal sequences and translocation through Sec translocons, whereas subsequent targeting to different surface locations is promoted by internal sorting signals. In bacteria, N-terminal signal sequences promote translocation across the cytoplasmic membrane, which surrounds the entire cell, but some proteins are nevertheless secreted in one part of the cell by poorly understood mechanisms. Here we analyse localized secretion in the Gram-positive pathogen Streptococcus pyogenes, and show that the signal sequences of two surface proteins, M protein and protein F (PrtF), direct secretion to different subcellular regions. The signal sequence of M protein promotes secretion at the division septum, whereas that of PrtF preferentially promotes secretion at the old pole. Our work therefore shows that a signal sequence may contain information that directs the secretion of a protein to one subcellular region, in addition to its classical role in promoting secretion. This finding identifies a new level of complexity in protein translocation and emphasizes the potential of bacterial systems for the analysis of fundamental cell-biological problems. 相似文献