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排序方式: 共有232条查询结果,搜索用时 15 毫秒
181.
Schreiner PR Reisenauer HP Pickard FC Simmonett AC Allen WD Mátyus E Császár AG 《Nature》2008,453(7197):906-909
Singlet carbenes exhibit a divalent carbon atom whose valence shell contains only six electrons, four involved in bonding to two other atoms and the remaining two forming a non-bonding electron pair. These features render singlet carbenes so reactive that they were long considered too short-lived for isolation and direct characterization. This view changed when it was found that attaching the divalent carbon atom to substituents that are bulky and/or able to donate electrons produces carbenes that can be isolated and stored. N-heterocyclic carbenes are such compounds now in wide use, for example as ligands in metathesis catalysis. In contrast, oxygen-donor-substituted carbenes are inherently less stable and have been less studied. The pre-eminent case is hydroxymethylene, H-C-OH; although it is the key intermediate in the high-energy chemistry of its tautomer formaldehyde, has been implicated since 1921 in the photocatalytic formation of carbohydrates, and is the parent of alkoxycarbenes that lie at the heart of transition-metal carbene chemistry, all attempts to observe this species or other alkoxycarbenes have failed. However, theoretical considerations indicate that hydroxymethylene should be isolatable. Here we report the synthesis of hydroxymethylene and its capture by matrix isolation. We unexpectedly find that H-C-OH rearranges to formaldehyde with a half-life of only 2 h at 11 K by pure hydrogen tunnelling through a large energy barrier in excess of 30 kcal mol(-1). 相似文献
182.
Hung RJ McKay JD Gaborieau V Boffetta P Hashibe M Zaridze D Mukeria A Szeszenia-Dabrowska N Lissowska J Rudnai P Fabianova E Mates D Bencko V Foretova L Janout V Chen C Goodman G Field JK Liloglou T Xinarianos G Cassidy A McLaughlin J Liu G Narod S Krokan HE Skorpen F Elvestad MB Hveem K Vatten L Linseisen J Clavel-Chapelon F Vineis P Bueno-de-Mesquita HB Lund E Martinez C Bingham S Rasmuson T Hainaut P Riboli E Ahrens W Benhamou S Lagiou P Trichopoulos D Holcátová I Merletti F Kjaerheim K 《Nature》2008,452(7187):633-637
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets. 相似文献
183.
184.
Martin Michaelis Christina Paulus Nadine Löschmann Stephanie Dauth Elisabeth Stange Hans Wilhelm Doerr Michael Nevels Jindrich CinatlJr. 《Cellular and molecular life sciences : CMLS》2011,68(6):1079-1090
Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer
kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant
strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early
promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib
with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently
of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced
IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV
IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated
for the first time that Raf activation is involved in HCMV IEA expression. 相似文献
185.
Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome 总被引:1,自引:0,他引:1
Koolen DA Kramer JM Neveling K Nillesen WM Moore-Barton HL Elmslie FV Toutain A Amiel J Malan V Tsai AC Cheung SW Gilissen C Verwiel ET Martens S Feuth T Bongers EM de Vries P Scheffer H Vissers LE de Brouwer AP Brunner HG Veltman JA Schenck A Yntema HG de Vries BB 《Nature genetics》2012,44(6):639-641
We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes. 相似文献
186.
Model‐based SKU‐level forecasts are often adjusted by experts. In this paper we propose a statistical methodology to test whether these expert forecasts improve on model forecasts. Application of the methodology to a very large database concerning experts in 35 countries who adjust SKU‐level forecasts for pharmaceutical products in seven distinct categories leads to the general conclusion that expert forecasts are equally good at best, but are more often worse than model‐based forecasts. We explore whether this is due to experts putting too much weight on their contribution, and this indeed turns out to be the case. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
187.
Cízková A Stránecký V Mayr JA Tesarová M Havlícková V Paul J Ivánek R Kuss AW Hansíková H Kaplanová V Vrbacký M Hartmannová H Nosková L Honzík T Drahota Z Magner M Hejzlarová K Sperl W Zeman J Houstek J Kmoch S 《Nature genetics》2008,40(11):1288-1290
We carried out whole-genome homozygosity mapping, gene expression analysis and DNA sequencing in individuals with isolated mitochondrial ATP synthase deficiency and identified disease-causing mutations in TMEM70. Complementation of the cell lines of these individuals with wild-type TMEM70 restored biogenesis and metabolic function of the enzyme complex. Our results show that TMEM70 is involved in mitochondrial ATP synthase biogenesis in higher eukaryotes. 相似文献
188.
Spinazzola A Viscomi C Fernandez-Vizarra E Carrara F D'Adamo P Calvo S Marsano RM Donnini C Weiher H Strisciuglio P Parini R Sarzi E Chan A DiMauro S Rötig A Gasparini P Ferrero I Mootha VK Tiranti V Zeviani M 《Nature genetics》2006,38(5):570-575
The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice. 相似文献
189.
McKay JD Hung RJ Gaborieau V Boffetta P Chabrier A Byrnes G Zaridze D Mukeria A Szeszenia-Dabrowska N Lissowska J Rudnai P Fabianova E Mates D Bencko V Foretova L Janout V McLaughlin J Shepherd F Montpetit A Narod S Krokan HE Skorpen F Elvestad MB Vatten L Njølstad I Axelsson T Chen C Goodman G Barnett M Loomis MM Lubiñski J Matyjasik J Lener M Oszutowska D Field J Liloglou T Xinarianos G Cassidy A;EPIC Study Vineis P Clavel-Chapelon F Palli D Tumino R Krogh V Panico S González CA 《Nature genetics》2008,40(12):1404-1406
We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology. 相似文献
190.
Hennies HC Kornak U Zhang H Egerer J Zhang X Seifert W Kühnisch J Budde B Nätebus M Brancati F Wilcox WR Müller D Kaplan PB Rajab A Zampino G Fodale V Dallapiccola B Newman W Metcalfe K Clayton-Smith J Tassabehji M Steinmann B Barr FA Nürnberg P Wieacker P Mundlos S 《Nature genetics》2008,40(12):1410-1412
Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues. 相似文献