全文获取类型
收费全文 | 730篇 |
免费 | 37篇 |
出版年
2022年 | 7篇 |
2021年 | 22篇 |
2020年 | 8篇 |
2019年 | 19篇 |
2018年 | 17篇 |
2017年 | 11篇 |
2016年 | 31篇 |
2015年 | 36篇 |
2014年 | 34篇 |
2013年 | 45篇 |
2012年 | 68篇 |
2011年 | 54篇 |
2010年 | 26篇 |
2009年 | 22篇 |
2008年 | 47篇 |
2007年 | 39篇 |
2006年 | 50篇 |
2005年 | 32篇 |
2004年 | 28篇 |
2003年 | 26篇 |
2002年 | 24篇 |
2001年 | 9篇 |
2000年 | 3篇 |
1999年 | 9篇 |
1998年 | 4篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1987年 | 3篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1980年 | 2篇 |
1979年 | 5篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1973年 | 3篇 |
1970年 | 4篇 |
1969年 | 2篇 |
1968年 | 4篇 |
1966年 | 6篇 |
1965年 | 3篇 |
1964年 | 6篇 |
1960年 | 2篇 |
1958年 | 3篇 |
1957年 | 3篇 |
1956年 | 2篇 |
排序方式: 共有767条查询结果,搜索用时 187 毫秒
51.
Icksoo Lee Alena Pecinova Petr Pecina Benjamin G. Neel Toshiyuki Araki Raju Kucherlapati Amy E. Roberts Maik Hüttemann 《生物化学与生物物理学报:疾病的分子基础》2010,1802(2):275-283
Noonan syndrome (NS) is an autosomal dominant disorder, and a main feature is congenital heart malformation. About 50% of cases are caused by gain-of-function mutations in the tyrosine phosphatase SHP2/PTPN11, a downstream regulator of ERK/MAPK. Recently it was reported that SHP2 also localizes to the mitochondrial intercristae/intermembrane space (IMS), but the role of SHP2 in mitochondria is unclear. The mitochondrial oxidative phosphorylation (OxPhos) system provides the vast majority of cellular energy and produces reactive oxygen species (ROS). Changes in ROS may interfere with organ development such as that observed in NS patients. Several phosphorylation sites have been found in OxPhos components including cytochrome c oxidase (CcO) and cytochrome c (Cytc), and we hypothesized that OxPhos complexes may be direct or indirect targets of SHP2. We analyzed mitochondrial function using mouse fibroblasts from wild-types, SHP2 knockdowns, and D61G SHP2 mutants leading to constitutively active SHP2, as found in NS patients. Levels of OxPhos complexes were similar except for CcO and Cytc, which were 37% and 28% reduced in the D61G cells. However, CcO activity was significantly increased, as we also found for two lymphoblast cell lines from NS patients with two independent mutations in PTPN11. D61G cells showed lower mitochondrial membrane potential and 30% lower ATP content compared to controls. ROS were significantly increased; aconitase activity, a marker for ROS-induced damage, was decreased; and catalase activity was increased in D61G cells. We propose that decreased energy levels and/or increased ROS may explain, at least in part, some of the clinical features in NS that overlap with children with mitochondrial disorders. 相似文献
52.
Sefcáková A Katina S Velemínski J Brůzek J Velemínský P Thurzo M 《Anthropologischer Anzeiger; Bericht über die biologisch-anthropologische Literatur》2010,68(2):221-237
In this study we estimate sex and population affinity of Gravettian Predmostí (P) skulls using linear and geometric discriminant analysis (DA), and compare them with results of 2D geometric morphometrics (GM). We used the measurements of P3 and P9 males, P4 and P10 females, as originally estimated by Matiegka (1934), as well as two databases--the recent skull database of Howells and the fossil data of Henke. DA classifies the P skulls as robust and belonging to the "male" region, loosing the sensitivity of inter-population differences influenced by size factor. That is why this approach could not be applied. The geographic inter-population differences according to DA do not define P skull shapes as extreme. The influence of geographic variability could be stronger than the inter-sexual differences. Despite the chronological differences between databases and Gravettian skulls, these differences are a component of regional inter-population variability. According to our results, GM is more successful methodological approach than DA. Our previous sex estimation of P skulls with help of GM is completely in accordance with the classical morphoscopic estimation. However, an appropriate reference database is necessary in both the GM and DA approaches. For the sexing of skull with unknown population affinity, and with absence of appropriate reference database, we suggest to use the application of more subjective visual scoring methods. 相似文献
53.
Monika Martiniaková Radoslav Omelka Birgit Grosskopf Alena Jančová 《Acta veterinaria Scandinavica》2010,52(1):58
Background
Free-living wild rodents are often used as zoomonitors of environmental contamination. In the present study, accumulation of cadmium (Cd), copper (Cu), iron (Fe), and zinc (Zn) in critical organs of yellow-necked mice (Apodemus flavicollis) and bank voles (Myodes glareolus) trapped in a polluted area in Nováky, Slovakia was investigated. 相似文献54.
We administered recombinant SV40-derived viral vectors (rSV40s) intravenously to mice with or without prior intraperitoneal injection of mannitol to deliver transgenes to the central nervous system (CNS). We detected transgene-expressing cells (mainly neurons) most prominently in the cortex and spinal cord; prior intraperitoneal mannitol injection increased CNS gene delivery tenfold. Intravenous injection of rSV40s, particularly with mannitol pretreatment, resulted in extensive expression of multiple transgenes throughout the CNS. 相似文献
55.
Rescue and production of vaccine and therapeutic adenovirus vectors expressing inhibitory transgenes
Gall JG Lizonova A EttyReddy D McVey D Zuber M Kovesdi I Aughtman B King CR Brough DE 《Molecular biotechnology》2007,35(3):263-273
Expression of certain transgenes from an adenovirus vector can be deleterious to its own replication. This can result in the
inhibition of virus rescue, reduced viral yields, or, in the worst case, make it impossible to construct a vector expressing
the inhibiting transgene product. A gene regulation system based on the tet operon was used to allow the rescue and efficient growth of adenovectors that express transgenes to high levels. A key advantage
to this system is that repression of transgene expression is mediated by the packaging cell line, thus, expression of regulatory
products from the adenovector are not required. This provides a simple, broadly applicable system wherein transgene repression
is constitutive during vector rescue and growth and there is no effect on adenovector-mediated expression of gene products
in transduced cells. Several high-level expression vectors based on first- and second-generation adenovectors were rescued
and produced to high titer that otherwise could not be grown. Yields of adenovectors expressing inhibitory transgene products
were increased, and the overgrowth of cultures by adenovectors with nonfunctional expression cassettes was prevented. The
gene regulation system is a significant advancement for the development of adenovirus vectors for vaccine and other gene transfer
applications. 相似文献
56.
Lenco J Hubálek M Larsson P Fucíková A Brychta M Macela A Stulík J 《FEMS microbiology letters》2007,269(1):11-21
Francisella tularensis is a highly virulent, facultative intracellular pathogen that causes tularemia in humans and animals. Although it is one of the most infectious bacterial pathogens, little is known about its virulence mechanisms. In this study, the response of F. tularensis live vaccine strain to iron depletion, which simulates the environment within the host, was investigated. In order to detect alterations in protein synthesis, metabolic labeling, followed by 2D-PAGE analysis was used. Globally, 141 protein spots were detected whose levels were significantly altered in the iron-restricted medium. About 65% of the spots were successfully identified using mass spectrometric approaches. Importantly, among the proteins produced at an increased level during iron-limited growth, three proteins were found encoded by the igl operon, located in the F. tularensis pathogenicity island I (FPI). Of these, the IglC and IglA proteins were previously reported to be necessary for full virulence of F. tularensis. These results, obtained at the proteome level, support and confirm recently published data showing that the igl operon genes are transcribed in response to iron limitation. 相似文献
57.
Background
The problem of protein structure prediction consists of predicting the functional or native structure of a protein given its linear sequence of amino acids. This problem has played a prominent role in the fields of biomolecular physics and algorithm design for over 50 years. Additionally, its importance increases continually as a result of an exponential growth over time in the number of known protein sequences in contrast to a linear increase in the number of determined structures. Our work focuses on the problem of searching an exponentially large space of possible conformations as efficiently as possible, with the goal of finding a global optimum with respect to a given energy function. This problem plays an important role in the analysis of systems with complex search landscapes, and particularly in the context of ab initio protein structure prediction. 相似文献58.
Background
The ab initio protein folding problem consists of predicting protein tertiary structure from a given amino acid sequence by minimizing an energy function; it is one of the most important and challenging problems in biochemistry, molecular biology and biophysics. The ab initio protein folding problem is computationally challenging and has been shown to be -hard even when conformations are restricted to a lattice. In this work, we implement and evaluate the replica exchange Monte Carlo (REMC) method, which has already been applied very successfully to more complex protein models and other optimization problems with complex energy landscapes, in combination with the highly effective pull move neighbourhood in two widely studied Hydrophobic Polar (HP) lattice models. 相似文献59.
Higher genetic diversity in recolonized areas than in refugia of Alnus glutinosa triggered by continent‐wide lineage admixture
下载免费PDF全文
![点击此处可从《Molecular ecology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Alena Havrdová Jan Douda Karol Krak Petr Vít Věroslava Hadincová Petr Zákravský Bohumil Mandák 《Molecular ecology》2015,24(18):4759-4777
Genetic admixture is supposed to be an important trigger of species expansions because it can create the potential for selection of genotypes suitable for new climatic conditions. Up until now, however, no continent‐wide population genetic study has performed a detailed reconstruction of admixture events during natural species expansions. To fill this gap, we analysed the postglacial history of Alnus glutinosa, a keystone species of European swamp habitats, across its entire distribution range using two molecular markers, cpDNA and nuclear microsatellites. CpDNA revealed multiple southern refugia located in the Iberian, Apennine, Balkan and Anatolian Peninsulas, Corsica and North Africa. Analysis of microsatellites variation revealed three main directions of postglacial expansion: (i) from the northern part of the Iberian Peninsula to Western and Central Europe and subsequently to the British Isles, (ii) from the Apennine Peninsula to the Alps and (iii) from the eastern part of the Balkan Peninsula to the Carpathians followed by expansion towards the Northern European plains. This challenges the classical paradigm that most European populations originated from refugial areas in the Carpathians. It has been shown that colonizing lineages have met several times and formed secondary contact zones with unexpectedly high population genetic diversity in Central Europe and Scandinavia. On the contrary, limited genetic admixture in southern refugial areas of A. glutinosa renders rear‐edge populations in the Mediterranean region more vulnerable to extinction due to climate change. 相似文献
60.
Gibson TM Brennan P Han S Karami S Zaridze D Janout V Kollarova H Bencko V Navratilova M Szeszenia-Dabrowska N Mates D Slamova A Pfeiffer RM Stolzenberg-Solomon RZ Mayne ST Yeager M Chanock S Rothman N Chow WH Rosenberg PS Boffetta P Moore LE 《PloS one》2011,6(10):e26165