全文获取类型
收费全文 | 21059篇 |
免费 | 1783篇 |
国内免费 | 61篇 |
专业分类
22903篇 |
出版年
2022年 | 154篇 |
2021年 | 248篇 |
2020年 | 147篇 |
2019年 | 204篇 |
2018年 | 254篇 |
2017年 | 211篇 |
2016年 | 349篇 |
2015年 | 636篇 |
2014年 | 692篇 |
2013年 | 1055篇 |
2012年 | 1170篇 |
2011年 | 1193篇 |
2010年 | 726篇 |
2009年 | 691篇 |
2008年 | 1084篇 |
2007年 | 1124篇 |
2006年 | 1029篇 |
2005年 | 1035篇 |
2004年 | 960篇 |
2003年 | 944篇 |
2002年 | 924篇 |
2001年 | 233篇 |
2000年 | 191篇 |
1999年 | 269篇 |
1998年 | 269篇 |
1997年 | 202篇 |
1996年 | 213篇 |
1995年 | 187篇 |
1994年 | 200篇 |
1993年 | 171篇 |
1992年 | 183篇 |
1991年 | 171篇 |
1990年 | 151篇 |
1989年 | 162篇 |
1988年 | 176篇 |
1987年 | 165篇 |
1986年 | 152篇 |
1985年 | 189篇 |
1984年 | 203篇 |
1983年 | 191篇 |
1982年 | 210篇 |
1981年 | 241篇 |
1980年 | 210篇 |
1979年 | 165篇 |
1978年 | 196篇 |
1977年 | 173篇 |
1976年 | 141篇 |
1975年 | 147篇 |
1974年 | 165篇 |
1973年 | 164篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Shenoy GN Chatterjee P Kaw S Mukherjee S Rathore DK Bal V Rath S George A 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(2):521-528
Successful recall Ab responses require recruitment of quiescent memory B cells to secondary lymphoid organs. However, the cellular dynamics of memory cells responding to local antigenic challenge at lymphoid sites distal from the initial Ag encounter are not well understood. We show in this study that memory B cells generated following s.c. immunization in one footpad generate secondary responses to soluble Ag given i.p. but not to Ag given s.c. in the contralateral footpad unless LPS is coadministered. Memory B cells do not express CD62L, and CD62L(-ve) cells cannot enter lymph nodes unless LPS-mediated inflammation is induced there. Functional TLR4 is required on the B cells, as well as on non-B cells, in the lymph node to achieve full recruitment. Furthermore, splenectomized mice fail to respond to such inflammatory s.c. challenge in contralateral footpads, unlike lymphadenectomized mice lacking the original draining lymph nodes. Splenectomized mice also fail to respond to i.p. challenge with soluble Ag. Together, these data indicate that, unlike the central memory pool of T cells, which circulates through resting lymph nodes, the majority of long-lived memory B cells are spleen resident and require inflammatory signals for mounting recall responses at distal challenge sites. 相似文献
992.
Knight R Jansson J Field D Fierer N Desai N Fuhrman JA Hugenholtz P van der Lelie D Meyer F Stevens R Bailey MJ Gordon JI Kowalchuk GA Gilbert JA 《Nature biotechnology》2012,30(6):513-520
Metagenomics holds enormous promise for discovering novel enzymes and organisms that are biomarkers or drivers of processes relevant to disease, industry and the environment. In the past two years, we have seen a paradigm shift in metagenomics to the application of cross-sectional and longitudinal studies enabled by advances in DNA sequencing and high-performance computing. These technologies now make it possible to broadly assess microbial diversity and function, allowing systematic investigation of the largely unexplored frontier of microbial life. To achieve this aim, the global scientific community must collaborate and agree upon common objectives and data standards to enable comparative research across the Earth's microbiome. Improvements in comparability of data will facilitate the study of biotechnologically relevant processes, such as bioprospecting for new glycoside hydrolases or identifying novel energy sources. 相似文献
993.
Accurate identification of the local fracture zone is an important step towards the failure assessment of trabecular bone. In previous in-vitro studies, local fracture zones were visually identified in micro-CT images by experienced observers. This is a time-consuming and observer-dependent approach and it prevents any large-scale analysis of local trabecular fracture regions. The scope of this study is the application and validation of a new registration scheme for the automatic identification of trabecular bone fracture zones. Six human trabecular specimens were extracted from different anatomical sites. Five specimens were mechanically tested and scanned using micro-CT. For each specimen pre- and post-failure micro-CT datasets were obtained. The sixth specimen was scanned twice without any mechanical compression and was used to test the accuracy of the proposed scheme. The registration scheme was applied to the acquired datasets for the automatic identification of the fracture zone. The proposed scheme comprises of a three-dimensional (3D) automatic registration method to define the differences between the two datasets, and the application of a criterion for defining slices of the pre-failure dataset as "broken" or "unbroken". Identifications of the fracture zones were qualitatively validated against visual identification of observers. Furthermore, "full 3D" fracture zone identification, based on the presented scheme, was proposed. The proposed scheme proved to be more accurate and significantly faster than the currently used visual process. 相似文献
994.
Whole-genome QTL analysis for MAGIC 总被引:2,自引:0,他引:2
Arūnas P. Verbyla Andrew W. George Colin R. Cavanagh Klara L. Verbyla 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2014,127(8):1753-1770
Key message
An efficient whole genome method of QTL analysis is presented for Multi-parent advanced generation integrated crosses.Abstract
Multi-parent advanced generation inter-cross (MAGIC) populations have been developed for mice and several plant species and are useful for the genetic dissection of complex traits. The analysis of quantitative trait loci (QTL) in these populations presents some additional challenges compared with traditional mapping approaches. In particular, pedigree and marker information need to be integrated and founder genetic data needs to be incorporated into the analysis. Here, we present a method for QTL analysis that utilizes the probability of inheriting founder alleles across the whole genome simultaneously, either for intervals or markers. The probabilities can be found using three-point or Hidden Markov Model (HMM) methods. This whole-genome approach is evaluated in a simulation study and it is shown to be a powerful method of analysis. The HMM probabilities lead to low rates of false positives and low bias of estimated QTL effect sizes. An implementation of the approach is available as an R package. In addition, we illustrate the approach using a bread wheat MAGIC population. 相似文献995.
996.
997.
Emilia Krypotou Vasiliki Kosti Sotiris Amillis Vassilios Myrianthopoulos Emmanuel Mikros George Diallinas 《The Journal of biological chemistry》2012,287(44):36792-36803
The recent elucidation of crystal structures of a bacterial member of the NCS1 family, the Mhp1 benzyl-hydantoin permease from Microbacterium liquefaciens, allowed us to construct and validate a three-dimensional model of the Aspergillus nidulans purine-cytosine/H+ FcyB symporter. The model consists of 12 transmembrane α-helical, segments (TMSs) and cytoplasmic N- and C-tails. A distinct core of 10 TMSs is made of two intertwined inverted repeats (TMS1–5 and TMS6–10) that are followed by two additional TMSs. TMS1, TMS3, TMS6, and TMS8 form an open cavity that is predicted to host the substrate binding site. Based on primary sequence alignment, three-dimensional topology, and substrate docking, we identified five residues as potentially essential for substrate binding in FcyB; Ser-85 (TMS1), Trp-159, Asn-163 (TMS3), Trp-259 (TMS6), and Asn-354 (TMS8). To validate the role of these and other putatively critical residues, we performed a systematic functional analysis of relevant mutants. We show that the proposed substrate binding residues, plus Asn-350, Asn-351, and Pro-353 are irreplaceable for FcyB function. Among these residues, Ser-85, Asn-163, Asn-350, Asn-351, and Asn-354 are critical for determining the substrate binding affinity and/or the specificity of FcyB. Our results suggest that Ser-85, Asn-163, and Asn-354 directly interact with substrates, Trp-159 and Trp-259 stabilize binding through π-π stacking interactions, and Pro-353 affects the local architecture of substrate binding site, whereas Asn-350 and Asn-351 probably affect substrate binding indirectly. Our work is the first systematic approach to address structure-function-specificity relationships in a eukaryotic member of NCS1 family by combining genetic and computational approaches. 相似文献
998.
Christine A. Armstrong George D. Jones Rhona Anderson Pooja Iyer Deepan Narayanan Jatinderpal Sandhu Rajinder Singh Christopher J. Talbot Cristina Tufarelli 《Epigenetics》2012,7(8):892-902
The ability of ionizing radiation to initiate genomic instability has been harnessed in the clinic where the localized delivery of controlled doses of radiation is used to induce cell death in tumor cells. Though very effective as a therapy, tumor relapse can occur in vivo and its appearance has been attributed to the radio-resistance of cells with stem cell-like features. The molecular mechanisms underlying these phenomena are unclear but there is evidence suggesting an inverse correlation between radiation-induced genomic instability and global hypomethylation. To further investigate the relationship between DNA hypomethylation, radiosensitivity and genomic stability in stem-like cells we have studied mouse embryonic stem cells containing differing levels of DNA methylation due to the presence or absence of DNA methyltransferases. Unexpectedly, we found that global levels of methylation do not determine radiosensitivity. In particular, radiation-induced delayed genomic instability was observed at the Hprt gene locus only in wild-type cells. Furthermore, absence of Dnmt1 resulted in a 10-fold increase in de novo Hprt mutation rate, which was unaltered by radiation. Our data indicate that functional DNMTs are required for radiation-induced genomic instability, and that individual DNMTs play distinct roles in genome stability. We propose that DNMTS may contribute to the acquirement of radio-resistance in stem-like cells. 相似文献
999.
Barbara H. Janssen Nicoline B. M. Voet Christine I. Nabuurs Hermien E. Kan Jacky W. J. de Rooy Alexander C. Geurts George W. Padberg Baziel G. M. van Engelen Arend Heerschap 《PloS one》2014,9(1)
Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34–76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D 31P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05), FSHD severity score (p<0.0001), inversely with muscle strength (p<0.0001), and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle’s length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001). Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05) and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001), which correlated with initial edema (p<0.01), if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive phase with distal fat infiltration and altered energy metabolite levels. Fat replacement then relatively rapidly spreads over the whole muscle. 相似文献
1000.
Rajamanickam Anuradha Parakkal Jovvian George Luke E. Hanna Vedachalam Chandrasekaran P. Paul Kumaran Thomas B. Nutman Subash Babu 《PLoS neglected tropical diseases》2014,8(1)