全文获取类型
收费全文 | 20329篇 |
免费 | 1892篇 |
国内免费 | 12篇 |
出版年
2023年 | 102篇 |
2022年 | 268篇 |
2021年 | 563篇 |
2020年 | 266篇 |
2019年 | 388篇 |
2018年 | 435篇 |
2017年 | 340篇 |
2016年 | 586篇 |
2015年 | 985篇 |
2014年 | 1020篇 |
2013年 | 1399篇 |
2012年 | 1597篇 |
2011年 | 1565篇 |
2010年 | 967篇 |
2009年 | 844篇 |
2008年 | 1212篇 |
2007年 | 1192篇 |
2006年 | 1073篇 |
2005年 | 1015篇 |
2004年 | 914篇 |
2003年 | 852篇 |
2002年 | 823篇 |
2001年 | 197篇 |
2000年 | 153篇 |
1999年 | 178篇 |
1998年 | 168篇 |
1997年 | 140篇 |
1996年 | 116篇 |
1995年 | 110篇 |
1994年 | 116篇 |
1993年 | 112篇 |
1992年 | 119篇 |
1991年 | 107篇 |
1990年 | 97篇 |
1989年 | 85篇 |
1988年 | 92篇 |
1987年 | 72篇 |
1986年 | 66篇 |
1985年 | 89篇 |
1984年 | 96篇 |
1983年 | 62篇 |
1982年 | 81篇 |
1981年 | 72篇 |
1980年 | 67篇 |
1979年 | 77篇 |
1978年 | 54篇 |
1977年 | 60篇 |
1976年 | 65篇 |
1975年 | 70篇 |
1973年 | 55篇 |
排序方式: 共有10000条查询结果,搜索用时 479 毫秒
911.
Evolutionary diversifications are commonly attributed to thecontinued modifications of a conserved genetic toolkit of developmentalpathways, such that complexity and convergence in organismalforms are assumed to be due to similarity in genetic mechanismsor environmental conditions. This approach, however, confoundsthe causes of organismal development with the causes of organismaldifferences and, as such, has only limited utility for addressingthe cause of evolutionary change. Molecular mechanisms thatare closely involved in both developmental response to environmentalsignals and major evolutionary innovations and diversificationsare uniquely suited to bridge this gap by connecting explicitlythe causes of within-generation variation with the causes ofdivergence of taxa. Developmental pathways of bone formationand a common role for bone morphogenetic proteins (BMPs) inboth epigenetic bone remodeling and the evolution of major adaptivediversifications provide such opportunity. We show that variationin timing of ossification can result in similar phenotypic patternsthrough epigenetically induced changes in gene expression andpropose that both genetic accommodation of environmentally induceddevelopmental pathways and flexibility in development acrossenvironments evolve through heterochronic shifts in bone maturationrelative to exposure to unpredictable environments. We suggestthat such heterochronic shifts in ossification can not onlybuffer development under fluctuating environments while maintainingepigenetic sensitivity critical for normal skeletal formation,but also enable epigenetically induced gene expression to generatespecialized morphological adaptations. We review studies ofenvironmental sensitivity of BMP pathways and their regulationof formation, remodeling, and repair of cartilage and bone toexamine the hypothesis that BMP-mediated skeletal adaptationsare facilitated by evolved reactivity of BMPs to external signals.Surprisingly, no empirical study to date has identified themolecular mechanism behind developmental plasticity in skeletaltraits. We outline a conceptual framework for future studiesthat focus on mediation of phenotypic plasticity in skeletaldevelopment by the patterns of BMP expression. 相似文献
912.
Volk A Karbasiyan M Semmler A Todt U Urbach H Klockgether T Linnebank M 《Birth defects research. Part A, Clinical and molecular teratology》2007,79(3):249-251
BACKGROUND: The symptom triad of autosomal dominant Currarino syndrome (CS; MIM #176450) consists of anorectal malformation, a sacral bone defect, and presacral masses. Mutations in the homeoboxHLXB9 gene have already been described in a subset of sacrococcygeal anomalies characterized by partial sacral agenesis. CASE: We report a 28-year-old male patient with Currarino syndrome due to a heterozygous novel frame-shift mutation c.336dupG (p.P113fsX224) in the homeoboxHLXB9 gene. CONCLUSIONS: Molecular diagnostics may be helpful in cases of Hirschsprung's disease accompanied by other symptoms suggestive for Currarino syndrome, since it can lead to major complications such as perianal sepsis, meningitis, and malignant transformation. 相似文献
913.
Protein oxidation implicated as the primary determinant of bacterial radioresistance 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《PLoS biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Daly MJ Gaidamakova EK Matrosova VY Vasilenko A Zhai M Leapman RD Lai B Ravel B Li SM Kemner KM Fredrickson JK 《PLoS biology》2007,5(4):e92
In the hierarchy of cellular targets damaged by ionizing radiation (IR), classical models of radiation toxicity place DNA at the top. Yet, many prokaryotes are killed by doses of IR that cause little DNA damage. Here we have probed the nature of Mn-facilitated IR resistance in Deinococcus radiodurans, which together with other extremely IR-resistant bacteria have high intracellular Mn/Fe concentration ratios compared to IR-sensitive bacteria. For in vitro and in vivo irradiation, we demonstrate a mechanistic link between Mn(II) ions and protection of proteins from oxidative modifications that introduce carbonyl groups. Conditions that inhibited Mn accumulation or Mn redox cycling rendered D. radiodurans radiation sensitive and highly susceptible to protein oxidation. X-ray fluorescence microprobe analysis showed that Mn is globally distributed in D. radiodurans, but Fe is sequestered in a region between dividing cells. For a group of phylogenetically diverse IR-resistant and IR-sensitive wild-type bacteria, our findings support the idea that the degree of resistance is determined by the level of oxidative protein damage caused during irradiation. We present the case that protein, rather than DNA, is the principal target of the biological action of IR in sensitive bacteria, and extreme resistance in Mn-accumulating bacteria is based on protein protection. 相似文献
914.
Rapid SNP diagnostics using asymmetric isothermal amplification and a new mismatch-suppression technology 总被引:2,自引:0,他引:2
Mitani Y Lezhava A Kawai Y Kikuchi T Oguchi-Katayama A Kogo Y Itoh M Miyagi T Takakura H Hoshi K Kato C Arakawa T Shibata K Fukui K Masui R Kuramitsu S Kiyotani K Chalk A Tsunekawa K Murakami M Kamataki T Oka T Shimada H Cizdziel PE Hayashizaki Y 《Nature methods》2007,4(3):257-262
We developed a rapid single nucleotide polymorphism (SNP) detection system named smart amplification process version 2 (SMAP 2). Because DNA amplification only occurred with a perfect primer match, amplification alone was sufficient to identify the target allele. To achieve the requisite fidelity to support this claim, we used two new and complementary approaches to suppress exponential background DNA amplification that resulted from mispriming events. SMAP 2 is isothermal and achieved SNP detection from whole human blood in 30 min when performed with a new DNA polymerase that was cloned and isolated from Alicyclobacillus acidocaldarius (Aac pol). Furthermore, to assist the scientific community in configuring SMAP 2 assays, we developed software specific for SMAP 2 primer design. With these new tools, a high-precision and rapid DNA amplification technology becomes available to aid in pharmacogenomic research and molecular-diagnostics applications. 相似文献
915.
916.
Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies 总被引:4,自引:0,他引:4
Hau P Jachimczak P Schlingensiepen R Schulmeyer F Jauch T Steinbrecher A Brawanski A Proescholdt M Schlaier J Buchroithner J Pichler J Wurm G Mehdorn M Strege R Schuierer G Villarrubia V Fellner F Jansen O Straube T Nohria V Goldbrunner M Kunst M Schmaus S Stauder G Bogdahn U Schlingensiepen KH 《Oligonucleotides》2007,17(2):201-212
Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors. 相似文献
917.
Dong A Xu X Edwards AM;Midwest Center for Structural Genomics;Structural Genomics Consortium Chang C Chruszcz M Cuff M Cymborowski M Di Leo R Egorova O Evdokimova E Filippova E Gu J Guthrie J Ignatchenko A Joachimiak A Klostermann N Kim Y Korniyenko Y Minor W Que Q Savchenko A Skarina T Tan K Yakunin A Yee A Yim V Zhang R Zheng H Akutsu M Arrowsmith C Avvakumov GV Bochkarev A Dahlgren LG Dhe-Paganon S Dimov S Dombrovski L Finerty P Flodin S Flores A Gräslund S Hammerström M Herman MD Hong BS 《Nature methods》2007,4(12):1019-1021
We tested the general applicability of in situ proteolysis to form protein crystals suitable for structure determination by adding a protease (chymotrypsin or trypsin) digestion step to crystallization trials of 55 bacterial and 14 human proteins that had proven recalcitrant to our best efforts at crystallization or structure determination. This is a work in progress; so far we determined structures of 9 bacterial proteins and the human aminoimidazole ribonucleotide synthetase (AIRS) domain. 相似文献
918.
919.
Bettendorff L Wirtzfeld B Makarchikov AF Mazzucchelli G Frédérich M Gigliobianco T Gangolf M De Pauw E Angenot L Wins P 《Nature chemical biology》2007,3(4):211-212
Several important cofactors are adenine nucleotides with a vitamin as the catalytic moiety. Here, we report the discovery of the first adenine nucleotide containing vitamin B1: adenosine thiamine triphosphate (AThTP, 1), or thiaminylated ATP. We discovered AThTP in Escherichia coli and found that it accumulates specifically in response to carbon starvation, thereby acting as a signal rather than a cofactor. We detected smaller amounts in yeast and in plant and animal tissues. 相似文献
920.
Akunevich Anastasia Aleksandrovna Khrustalev Vladislav Victorovich Khrustaleva Tatyana Aleksandrovna Poboinev Victor Vitoldovich Shalygo Nikolai Vladimirovich Stojarov Aleksander Nicolaevich Arutyunyan Alexander Migranovich Kordyukova Larisa Valentinovna Sapon Yehor Gennadyevich 《The protein journal》2022,41(2):245-259
The Protein Journal - An interplay between monomeric and dimeric forms of human epidermal growth factor (EGF) affecting its interaction with EGF receptor (EGFR) is poorly understood. While EGF... 相似文献