全文获取类型
收费全文 | 44007篇 |
免费 | 147篇 |
国内免费 | 289篇 |
专业分类
系统科学 | 538篇 |
丛书文集 | 1032篇 |
教育与普及 | 143篇 |
理论与方法论 | 243篇 |
现状及发展 | 17817篇 |
研究方法 | 1649篇 |
综合类 | 22182篇 |
自然研究 | 839篇 |
出版年
2013年 | 443篇 |
2012年 | 794篇 |
2011年 | 1657篇 |
2010年 | 504篇 |
2009年 | 454篇 |
2008年 | 955篇 |
2007年 | 1035篇 |
2006年 | 1079篇 |
2005年 | 1026篇 |
2004年 | 814篇 |
2003年 | 766篇 |
2002年 | 780篇 |
2001年 | 1244篇 |
2000年 | 1212篇 |
1999年 | 825篇 |
1992年 | 734篇 |
1991年 | 610篇 |
1990年 | 629篇 |
1989年 | 612篇 |
1988年 | 615篇 |
1987年 | 615篇 |
1986年 | 592篇 |
1985年 | 726篇 |
1984年 | 624篇 |
1983年 | 504篇 |
1982年 | 456篇 |
1981年 | 444篇 |
1980年 | 569篇 |
1979年 | 1237篇 |
1978年 | 1059篇 |
1977年 | 1070篇 |
1976年 | 759篇 |
1975年 | 857篇 |
1974年 | 1223篇 |
1973年 | 1062篇 |
1972年 | 1062篇 |
1971年 | 1311篇 |
1970年 | 1646篇 |
1969年 | 1291篇 |
1968年 | 1232篇 |
1967年 | 1301篇 |
1966年 | 1116篇 |
1965年 | 822篇 |
1959年 | 487篇 |
1958年 | 708篇 |
1957年 | 567篇 |
1956年 | 475篇 |
1955年 | 440篇 |
1954年 | 468篇 |
1948年 | 246篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
831.
832.
833.
Pan Q Qiao F Gao C Norman B Optican L Zelenka PS 《Cellular and molecular life sciences : CMLS》2011,68(20):3425-3436
The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In
normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent
ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work
has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75).
Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability
of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation,
is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75
or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent
cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life
is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src
and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75)
is a physiologically significant mechanism of regulating intracellular Src activity. 相似文献
834.
Ververis K Rodd AL Tang MM El-Osta A Karagiannis TC 《Cellular and molecular life sciences : CMLS》2011,68(24):4101-4114
Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid
(Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that
histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies
such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies,
involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified
that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in
cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase
inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes.
Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors
tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained
nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight
the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination
therapies for cancer. 相似文献
835.
The maintenance of mucosal barrier equilibrium in the intestine requires a delicate and dynamic balance between enterocyte
loss by apoptosis and the generation of new cells by proliferation from stem cell precursors at the base of the intestinal
crypts. When the balance shifts towards either excessive or insufficient apoptosis, a broad range of gastrointestinal diseases
can manifest. Recent work from a variety of laboratories has provided evidence in support of a role for receptors of the innate
immune system, including Toll-like receptors 2, 4, and 9 as well as the intracellular pathogen recognition receptor NOD2/CARD15,
in the initiation of enterocyte apoptosis. The subsequent induction of enterocyte apoptosis in response to the activation
of these innate immune receptors plays a key role in the development of various intestinal diseases, including necrotizing
enterocolitis, Crohn’s disease, ulcerative colitis, and intestinal cancer. This review will detail the regulatory pathways
that govern enterocyte apoptosis, and will explore the role of the innate immune system in the induction of enterocyte apoptosis
in gastrointestinal disease. 相似文献
836.
Lubka-Pathak M Shah AA Gallozzi M Müller M Zimmermann U Löwenheim H Pfister M Knipper M Blin N Schimmang T 《Cellular and molecular life sciences : CMLS》2011,68(16):2739-2749
Introduction
Tff3 peptide exerts important functions in cytoprotection and restitution of the gastrointestinal (GI) tract epithelia. Moreover, its presence in the rodent inner ear and involvement in the hearing process was demonstrated recently. However, its role in the auditory system still remains elusive. Our previous results showed a deterioration of hearing with age in Tff3-deficient animals.Results
Present detailed analysis of auditory brain stem response (ABR) measurements and immunohistochemical study of selected functional proteins indicated a normal function and phenotype of the cochlea in Tff3 mutants. However, a microarray-based screening of tissue derived from the auditory central nervous system revealed an alteration of securin (Pttg1) and serpina3n expression between wild-type and Tff3 knock-out animals. This was confirmed by qRT-PCR, immunostaining and western blots.Conclusions
We found highly down-regulated Pttg1 and up-regulated serpina3n expression as a consequence of genetically deleting Tff3 in mice, indicating a potential role of these factors during the development of presbyacusis. 相似文献837.
Biological cells harbor a variety of molecular machines that carry out mechanical work at the nanoscale. One of these nanomachines
is the bacterial motor protein SecA which translocates secretory proteins through the protein-conducting membrane channel
SecYEG. SecA converts chemically stored energy in the form of ATP into a mechanical force to drive polypeptide transport through
SecYEG and across the cytoplasmic membrane. In order to accommodate a translocating polypeptide chain and to release transmembrane
segments of membrane proteins into the lipid bilayer, SecYEG needs to open its central channel and the lateral gate. Recent
crystal structures provide a detailed insight into the rearrangements required for channel opening. Here, we review our current
understanding of the mode of operation of the SecA motor protein in concert with the dynamic SecYEG channel. We conclude with
a new model for SecA-mediated protein translocation that unifies previous conflicting data. 相似文献
838.
Yvonne G. J. van Helden Roger W. L. Godschalk Hans J. M. Swarts Peter C. H. Hollman Frederik J. van Schooten Jaap Keijer 《Cellular and molecular life sciences : CMLS》2011,68(3):489-504
Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray
gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1
−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1
−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1
−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1
−/− mice, which had, unlike wild-type (Bcmo1
+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence
lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after
BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice. 相似文献
839.
The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity
in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed
several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and
protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses
to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production,
cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been
associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient’s susceptibility
to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders. 相似文献
840.
Jeffrey J. Yeo 《西北部美国博物学家》2011,65(1)
Nineteen exclosures on sagebrush steppe and shadscale rangelands, varying in age from 18 to 38 years, were sampled for plant species richness, plant composition, indicators of soil erosion, ground cover, vegetative cover, and herb-low shrub layer screening cover. Features within the exclosures were compared with adjacent sites of the same size that were open to grazing by livestock and wildlife. Species richness typically was slightly greater inside exclosures than in adjacent grazed sites (median = 2 more species inside exclosures), but the difference was not significant ( P = 0.16). Similarity of plant community composition between exclosures and adjacent grazed sites ranged from 45% to 82%. Evidences of soil movement, soil pedestals, and soil flow patterns were all more pronounced outside exclosures than inside ( P ≤ 0.02), even though many sites were on flat to mild slopes (median slope = 12%). Meta-analysis of the 19 exclosure sites indicated that grazing exclusion resulted in less bare ground cover compared with adjacent grazed sites ( P ≤ 0.05). The effect of grazing exclusion on visible soil surface cryptogams was significant ( P ≤ 0.05), with generally greater cover inside exclosures. Cryptogam cover differences between grazed sites and exclosures tended to increase with the number of years of grazing exclusion ( r = 0.64, P = 0.046). Pseudoroegneria spicata , a principal livestock forage, averaged greater basal cover inside exclosures than outside on 4 of 10 sites where it occurred, although no exclosure sites had greater P. spicata cover on grazed sites. Meta-analysis of the 10 sites indicated that grazing exclusion resulted in greater P. spicata cover compared with adjacent grazed areas ( P ≤ 0.05). Poa secunda , a short-growing grass that initiates growth early in the spring and is not important livestock forage, averaged greater basal cover outside exclosures on 5 of 15 sites where it occurred. Meta-analysis of the 15 sites indicated a significant treatment effect ( P ≤ 0.05), with greater Poa secunda basal cover outside exclosures. Grazing exclusion resulted in greater screening cover in the herb-low shrub layer (0-0.5 m height; P ≤ 0.05). These results indicate that despite improved livestock grazing management over the past half century, livestock grazing still can limit the potential of native plant communities in sagebrush steppe ecosystems, and that the health of semiarid ecosystems can improve with livestock exclusion in the absence of other disturbances. A few exclosure sites were similar for the measured parameters, suggesting that these sites were ecologically stable and that exclusion of livestock grazing was not sufficient to move succession toward more pristine conditions, at least within the time periods studied. Managed disturbance such as fire or mechanical brush treatments may be necessary to restore herb productivity on these ecologically stable sites. 相似文献