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51.
Joel S. Schwartz 《Annals of science》2013,70(6):631-637
While Charles Darwin wrote his Observations on South America, he often sought the advice and help of other scientists in solving specific problems. Three letters that the Cambridge geologist and mathematician William Hopkins wrote to Darwin exemplify such aid. In these letters Hopkins was able to show Darwin how he could calculate the position of the sedimentary beds on the Chonos Archipelago, which Darwin had visited. In his first letter Hopkins sent a solution, part of which eluded Darwin. Darwin's letters to Hopkins have not yet been found, but two additional letters gave Darwin the solution he was looking for. 相似文献
52.
Schwartz D 《Nature》2006,444(7115):1 p preceding 122
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Thomas JW Touchman JW Blakesley RW Bouffard GG Beckstrom-Sternberg SM Margulies EH Blanchette M Siepel AC Thomas PJ McDowell JC Maskeri B Hansen NF Schwartz MS Weber RJ Kent WJ Karolchik D Bruen TC Bevan R Cutler DJ Schwartz S Elnitski L Idol JR Prasad AB Lee-Lin SQ Maduro VV Summers TJ Portnoy ME Dietrich NL Akhter N Ayele K Benjamin B Cariaga K Brinkley CP Brooks SY Granite S Guan X Gupta J Haghighi P Ho SL Huang MC Karlins E Laric PL Legaspi R Lim MJ Maduro QL Masiello CA Mastrian SD 《Nature》2003,424(6950):788-793
The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding and conserved non-coding regions, including regulatory elements, and provide insight into the forces that have rendered modern-day genomes. As a complement to whole-genome sequencing efforts, we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non-coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates. 相似文献
56.
The ability of an animal to respond to a given antigenic peptide depends on its major histocompatibility complex (MHC) type. Some peptides are not immunogenic when combined with a particular form of the MHC-encoded molecule. This non-responsiveness is regulated by immune response (Ir) genes and is thought to arise by one of two distinct mechanisms. Either the MHC-encoded molecules physically fail to interact with the antigen, preventing the activation of T cells with appropriate receptors, or they limit the expressed repertoire of T cell clones so that no T cells are available to be activated by existing complexes of MHC-encoded molecules and antigen. Experimental evidence has been generated to support both mechanisms. However, the relative importance of each has not been clearly established. In this study we started with a peptide that was immunogenic in B10 mice; it was thus known to be able to interact with the MHC molecule, and T cells existed which could recognise the peptide-MHC complex. Based on previous experiments, we then changed only those parts of the peptide that we thought interacted with the T-cell receptor. All the new analogues created were still immunogenic, confirming that the amino-acid substitutions that we had made did not prevent productive interactions with the MHC-encoded molecule. No limitations ('holes') in the T-cell repertoire were found. The experiments demonstrate the vast potential of the T-cell population to recognize many different analogues, each in a unique way, and suggest that constraints on the diversity of the T-cell repertoire may not be a major explanation for Ir gene defects. 相似文献
57.
Differential expression of two distinct T-cell receptors during thymocyte development 总被引:10,自引:0,他引:10
D M Pardoll B J Fowlkes J A Bluestone A Kruisbeek W L Maloy J E Coligan R H Schwartz 《Nature》1987,326(6108):79-81
The product of the T-cell receptor (TCR) gamma-gene has recently been found to be expressed on a subset of both peripheral cells and thymocytes. As an initial approach to understanding the role of this gamma-chain of TCR (TCR gamma) in T-cell development, we have studied the ontogeny of TCR expression at the protein level in the developing murine thymus. We show here that the first T3-associated TCR to be expressed in the developing thymus is a disulphide-linked heterodimer composed of a gamma-chain of relative molecular mass 35,000 (Mr 35K) and a 45K partner (termed TCR delta). This TCR gamma delta is first detected approximately two days before the appearance of cell-surface TCR alpha beta heterodimers. We report that N-glycosidase digestions reveal that all of the gamma-protein expressed on fetal thymocytes, as in adult CD4-8-(L3T4-, Lyt2-) thymocytes, bear N-linked carbohydrate side chains. The major gamma-gene transcribed in mature, alpha beta-bearing T cells (V gamma 1.2C gamma 2)encodes no N-linked glycosylation site so these results suggest that the fetal gamma delta receptor defines a distinct T-cell lineage whose development in the thymus precedes classical alpha beta-bearing cells. 相似文献
58.
Deletion of self-reactive thymocytes occurs at a CD4+8+ precursor stage 总被引:34,自引:0,他引:34
As T cells develop in the thymus, they become tolerant of self-antigens. A major advance in the understanding of how this process occurs was the direct demonstration that cells bearing autoreactive T-cell receptors (TCRs) are physically eliminated from the population of functionally mature T cells present in both the thymus and periphery. We have sought to determine the developmental stage at which autoreactive T cells are eliminated by examining the expression of V beta 17a anti-I-E TCRs under various experimental conditions. In vivo antibody blockage of the CD4 molecule on developing thymocytes of I-E+ C57BR mice was found to inhibit the deletion of V beta 17a-bearing cells from the CD4-8+ single positive thymocyte subset. This result provides strong evidence that deletion of potentially autoreactive T cells occurs at a CD4+8+ precursor stage, that the non-clonally distributed accessory molecules (CD4, CD8) are significant participants in the self-recognition process that leads to clonal elimination, and that thymic class II major histocompatibility complex (MHC) molecules can influence the repertoire of CD4-8+ cells. 相似文献
59.
Fairhurst RM Baruch DI Brittain NJ Ostera GR Wallach JS Hoang HL Hayton K Guindo A Makobongo MO Schwartz OM Tounkara A Doumbo OK Diallo DA Fujioka H Ho M Wellems TE 《Nature》2005,435(7045):1117-1121
Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature. 相似文献
60.
Pocai A Lam TK Gutierrez-Juarez R Obici S Schwartz GJ Bryan J Aguilar-Bryan L Rossetti L 《Nature》2005,434(7036):1026-1031
Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis. The medial hypothalamus is a major integrator of nutritional and hormonal signals, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance and glucose metabolism. Here we show that activation of ATP-sensitive potassium (K(ATP)) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a K(ATP) blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the K(ATP) channel are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic K(ATP) channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia. 相似文献