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排序方式: 共有229条查询结果,搜索用时 31 毫秒
181.
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
182.
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
183.
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
184.
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
185.
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
186.
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
187.
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
188.
Bicknell LS Bongers EM Leitch A Brown S Schoots J Harley ME Aftimos S Al-Aama JY Bober M Brown PA van Bokhoven H Dean J Edrees AY Feingold M Fryer A Hoefsloot LH Kau N Knoers NV Mackenzie J Opitz JM Sarda P Ross A Temple IK Toutain A Wise CA Wright M Jackson AP 《Nature genetics》2011,43(4):356-359
Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1?3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities. 相似文献
189.
We analyze the behavior of experts who quote forecasts for monthly SKU‐level sales data, where we compare data before and after the moment that experts received different kinds of feedback on their behavior. We have data for 21 experts located in as many countries who make SKU‐level forecasts for a variety of pharmaceutical products for October 2006 to September 2007. We study the behavior of the experts by comparing their forecasts with those from an automated statistical program, and we report the forecast accuracy over these 12 months. In September 2007 these experts were given feedback on their behavior and they received training at the headquarters office, where specific attention was given to the ins and outs of the statistical program. Next, we study the behavior of the experts for the 3 months after the training session, i.e. October 2007 to December 2007. Our main conclusion is that in the second period the experts’ forecasts deviated less from the statistical forecasts and that their accuracy improved substantially. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
190.
Philip Hans Franses 《Journal of forecasting》1996,15(2):83-95
A periodically integrated (PI) time series process assumes that the stochastic trend can be removed using a seasonally varying differencing filter. In this paper the multi-step forecast error variances are derived for a quarterly PI time series when low-order periodic autoregressions adequately describe the data. The forecast error variances display seasonal variation, indicating that observations in some seasons can be forecast more precise than those in others. Two examples illustrate the empirical relevance of calculating forecast error variances. A by-product of the analysis is an expression for the seasonally varying impact of the stochastic trend. 相似文献