全文获取类型
收费全文 | 1886篇 |
免费 | 14篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 54篇 |
教育与普及 | 1篇 |
理论与方法论 | 23篇 |
现状及发展 | 1225篇 |
研究方法 | 91篇 |
综合类 | 434篇 |
自然研究 | 73篇 |
出版年
2020年 | 14篇 |
2018年 | 32篇 |
2017年 | 31篇 |
2016年 | 37篇 |
2015年 | 32篇 |
2014年 | 14篇 |
2013年 | 23篇 |
2012年 | 56篇 |
2011年 | 91篇 |
2010年 | 26篇 |
2009年 | 16篇 |
2008年 | 49篇 |
2007年 | 46篇 |
2006年 | 59篇 |
2005年 | 54篇 |
2004年 | 35篇 |
2003年 | 47篇 |
2002年 | 46篇 |
2001年 | 30篇 |
2000年 | 16篇 |
1999年 | 20篇 |
1992年 | 19篇 |
1991年 | 17篇 |
1985年 | 14篇 |
1984年 | 28篇 |
1983年 | 14篇 |
1982年 | 16篇 |
1981年 | 21篇 |
1979年 | 35篇 |
1978年 | 31篇 |
1977年 | 41篇 |
1976年 | 36篇 |
1975年 | 29篇 |
1974年 | 37篇 |
1973年 | 46篇 |
1972年 | 42篇 |
1971年 | 39篇 |
1970年 | 66篇 |
1969年 | 55篇 |
1968年 | 87篇 |
1967年 | 64篇 |
1966年 | 49篇 |
1965年 | 48篇 |
1964年 | 43篇 |
1963年 | 21篇 |
1962年 | 24篇 |
1961年 | 17篇 |
1959年 | 15篇 |
1958年 | 12篇 |
1957年 | 13篇 |
排序方式: 共有1901条查询结果,搜索用时 31 毫秒
81.
José Ramón Bertomeu-Sánchez 《Annals of science》2013,70(4):490-516
This paper analyses the development of three methods for detecting bloodstains during the first half of the nineteenth-century in France. After dealing with the main problems in detecting bloodstains, the paper describes the chemical tests introduced in the mid-1820s. Then the first uses of the microscope in the detection of bloodstains around 1827 are discussed. The most controversial method is then examined, the smell test introduced by Jean-Pierre Barruel in 1829, and the debates which took place in French academies and learned societies during ensuing years are surveyed. Moving to the courtrooms a review is conducted of how the different methods were employed in criminal trials. By reviewing these cases, the main arguments against Barruel's test during the 1830s are explored as well as the changes making possible the return of the microscope to legal medicine around 1840. By reconstructing the history of these three methods, the paper reveals how the senses of smell and vision (colours and microscopic images) were employed in order to produce convincing evidence in both academies and courts. The paper questions two linear master narratives that are organized in terms of progress and decline: the development of forensic science as a result of continued technological progress; and the supposed decline of smell in the history of the senses, particularly in the realm of chemistry and medicine. 相似文献
82.
Glaucia N. M. Hajj Camila P. Arantes Marcos Vinicios Salles Dias Martín Roffé Bruno Costa-Silva Marilene H. Lopes Isabel Porto-Carreiro Tatiana Rabachini Flávia R. Lima Flávio H. Beraldo Marco M. A. Prado Rafael Linden Vilma R. Martins 《Cellular and molecular life sciences : CMLS》2013,70(17):3211-3227
The co-chaperone stress-inducible protein 1 (STI1) is released by astrocytes, and has important neurotrophic properties upon binding to prion protein (PrPC). However, STI1 lacks a signal peptide and pharmacological approaches pointed that it does not follow a classical secretion mechanism. Ultracentrifugation, size exclusion chromatography, electron microscopy, vesicle labeling, and particle tracking analysis were used to identify three major types of extracellular vesicles (EVs) released from astrocytes with sizes ranging from 20–50, 100–200, and 300–400 nm. These EVs carry STI1 and present many exosomal markers, even though only a subpopulation had the typical exosomal morphology. The only protein, from those evaluated here, present exclusively in vesicles that have exosomal morphology was PrPC. STI1 partially co-localized with Rab5 and Rab7 in endosomal compartments, and a dominant-negative for vacuolar protein sorting 4A (VPS4A), required for formation of multivesicular bodies (MVBs), impaired EV and STI1 release. Flow cytometry and PK digestion demonstrated that STI1 localized to the outer leaflet of EVs, and its association with EVs greatly increased STI1 activity upon PrPC-dependent neuronal signaling. These results indicate that astrocytes secrete a diverse population of EVs derived from MVBs that contain STI1 and suggest that the interaction between EVs and neuronal surface components enhances STI1–PrPC signaling. 相似文献
83.
José M. Bravo-San Pedro Mireia Niso-Santano Rubén Gómez-Sánchez Elisa Pizarro-Estrella Ana Aiastui-Pujana Ana Gorostidi Vicente Climent Rakel López de Maturana Rosario Sanchez-Pernaute Adolfo López de Munain José M. Fuentes Rosa A. González-Polo 《Cellular and molecular life sciences : CMLS》2013,70(1):121-136
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of familial Parkinsonism, and the G2019S mutation of LRRK2 is one of the most prevalent mutations. The deregulation of autophagic processes in nerve cells is thought to be a possible cause of Parkinson’s disease (PD). In this study, we observed that G2019S mutant fibroblasts exhibited higher autophagic activity levels than control fibroblasts. Elevated levels of autophagic activity can trigger cell death, and in our study, G2019S mutant cells exhibited increased apoptosis hallmarks compared to control cells. LRRK2 is able to induce the phosphorylation of MAPK/ERK kinases (MEK). The use of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a highly selective inhibitor of MEK1/2, reduced the enhanced autophagy and sensibility observed in G2019S LRRK2 mutation cells. These data suggest that the G2019S mutation induces autophagy via MEK/ERK pathway and that the inhibition of this exacerbated autophagy reduces the sensitivity observed in G2019S mutant cells. 相似文献
84.
Fernando de Castro Ana Bribián Mª Cristina Ortega 《Cellular and molecular life sciences : CMLS》2013,70(22):4355-4368
Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). These cells originate from oligodendrocyte precursor cells (OPCs) during development, and they migrate extensively from oligodendrogliogenic niches along the neural tube to colonise the entire CNS. Like many other such events, this migratory process is precisely regulated by a battery of positional and signalling cues that act via their corresponding receptors and that are expressed dynamically by OPCs. Here, we will review the cellular and molecular basis of this important event during embryonic and postnatal development, and we will discuss the relevance of the substantial number of OPCs existing in the adult CNS. Similarly, we will consider the behaviour of OPCs in normal and pathological conditions, especially in animal models of demyelination and of the demyelinating disease, multiple sclerosis. The spontaneous remyelination observed after damage in demyelinating pathologies has a limited effect. Understanding the cellular and molecular mechanisms underlying the biology of OPCs, particularly adult OPCs, should help in the design of neuroregenerative strategies to combat multiple sclerosis and other demyelinating diseases. 相似文献
85.
Kozyrev SV Abelson AK Wojcik J Zaghlool A Linga Reddy MV Sanchez E Gunnarsson I Svenungsson E Sturfelt G Jönsen A Truedsson L Pons-Estel BA Witte T D'Alfonso S Barizzone N Barrizzone N Danieli MG Gutierrez C Suarez A Junker P Laustrup H González-Escribano MF Martin J Abderrahim H Alarcón-Riquelme ME 《Nature genetics》2008,40(2):211-216
86.
We present a system for combining the different types of predictions given by a wide category of mechanical trading rules through statistical learning methods (boosting, and several model averaging methods like Bayesian or simple averaging methods). Statistical learning methods supply better out‐of‐sample results than most of the single moving average rules in the NYSE Composite Index from January 1993 to December 2002. Moreover, using a filter to reduce trading frequency, the filtered boosting model produces a technical strategy which, although it is not able to overcome the returns of the buy‐and‐hold (B&H) strategy during rising periods, it does overcome the B&H during falling periods and is able to absorb a considerable part of falls in the market. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
87.
Many notions regarding the function, structure and regulation of cholera toxin expression have remained essentially unaltered
in the last 15 years. At the same time, recent findings have generated additional perspectives. For example, the cholera toxin
genes are now known to be carried by a non-lytic bacteriophage, a previously unsuspected condition. Understanding of how the
expression of cholera toxin genes is controlled by the bacterium at the molecular level has advanced significantly and relationships
with cell-density-associated (quorum-sensing) responses have recently been discovered. Regarding the cell intoxication process,
the mode of entry and intracellular transport of cholera toxin are becoming clearer. In the immunological field, the strong
oral immunogenicity of the non-toxic B subunit of cholera toxin (CTB) has been exploited in the development of a now widely
licensed oral cholera vaccine. Additionally, CTB has been shown to induce tolerance against co-administered (linked) foreign
antigens in some autoimmune and allergic diseases.
Received 25 October 2007; accepted 12 December 2007 相似文献
88.
Twigger SN Pruitt KD Fernández-Suárez XM Karolchik D Worley KC Maglott DR Brown G Weinstock G Gibbs RA Kent J Birney E Jacob HJ 《Nature genetics》2008,40(5):523-527
It has been four years since the original publication of the draft sequence of the rat genome. Five groups are now working together to assemble, annotate and release an updated version of the rat genome. As the prevailing model for physiology, complex disease and pharmacological studies, there is an acute need for the rat's genomic resources to keep pace with the rat's prominence in the laboratory. In this commentary, we describe the current status of the rat genome sequence and the plans for its impending 'upgrade'. We then cover the key online resources providing access to the rat genome, including the new SNP views at Ensembl, the RefSeq and Genes databases at the US National Center for Biotechnology Information, Genome Browser at the University of California Santa Cruz and the disease portals for cardiovascular disease and obesity at the Rat Genome Database. 相似文献
89.
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis 总被引:21,自引:0,他引:21
Palmer CN Irvine AD Terron-Kwiatkowski A Zhao Y Liao H Lee SP Goudie DR Sandilands A Campbell LE Smith FJ O'Regan GM Watson RM Cecil JE Bale SJ Compton JG DiGiovanna JJ Fleckman P Lewis-Jones S Arseculeratne G Sergeant A Munro CS El Houate B McElreavey K Halkjaer LB Bisgaard H Mukhopadhyay S McLean WH 《Nature genetics》2006,38(4):441-446
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease. 相似文献
90.
Kertész A Váradi G Tóth GK Fajka-Boja R Monostori E Sármay G 《Cellular and molecular life sciences : CMLS》2006,63(22):2682-2693
Phosphopeptides interacting with src homology 2 (SH2) domains can activate essential signaling enzymes in vitro. When delivered to cells, they may disrupt protein-protein interactions, thereby influencing intracellular signaling. We
showed earlier that phosphopeptides corresponding to the inhibitory motif of Fcγ receptor IIb and a motif of the Grb2-associated
binder 1 adaptor protein activate SH2-containing tyrosine phosphatase 2 in vitro. To study the ex vivo effects of these peptides, we have now compared different methods for peptide delivery: (i) permeabilization of the target
cells and (ii) the use of cell-permeable vectors, which are potentially able to transport biologically active compounds into
B cells. We found octanoyl-Arg8 to be an optimal carrier for the delivery of phosphopeptides to the cells. With this strategy, the function of cell-permeable
SHP-2-binding phosphopeptides was analyzed. These peptides modulated the protein phosphorylation in B cells in a dose- and
time-dependent manner.
Received 27 July 2006; received after revision 4 September 2006; accepted 18 September 2006 相似文献