全文获取类型
收费全文 | 2807篇 |
免费 | 233篇 |
专业分类
3040篇 |
出版年
2023年 | 14篇 |
2022年 | 33篇 |
2021年 | 63篇 |
2020年 | 38篇 |
2019年 | 49篇 |
2018年 | 55篇 |
2017年 | 50篇 |
2016年 | 79篇 |
2015年 | 120篇 |
2014年 | 136篇 |
2013年 | 185篇 |
2012年 | 199篇 |
2011年 | 221篇 |
2010年 | 126篇 |
2009年 | 126篇 |
2008年 | 170篇 |
2007年 | 177篇 |
2006年 | 174篇 |
2005年 | 147篇 |
2004年 | 148篇 |
2003年 | 126篇 |
2002年 | 129篇 |
2001年 | 26篇 |
2000年 | 14篇 |
1999年 | 31篇 |
1998年 | 41篇 |
1997年 | 26篇 |
1996年 | 27篇 |
1995年 | 28篇 |
1994年 | 33篇 |
1993年 | 22篇 |
1992年 | 18篇 |
1991年 | 28篇 |
1990年 | 20篇 |
1989年 | 13篇 |
1988年 | 11篇 |
1987年 | 12篇 |
1986年 | 10篇 |
1985年 | 14篇 |
1984年 | 13篇 |
1983年 | 11篇 |
1982年 | 12篇 |
1981年 | 8篇 |
1980年 | 6篇 |
1979年 | 9篇 |
1978年 | 4篇 |
1977年 | 7篇 |
1974年 | 3篇 |
1973年 | 3篇 |
1971年 | 3篇 |
排序方式: 共有3040条查询结果,搜索用时 15 毫秒
991.
Muhammad?Sajid Hussain Agatino Battaglia Sandra Szczepanski Emrah Kaygusuz Mohammad?Reza Toliat Shin-ichi Sakakibara Janine Altmüller Holger Thiele Gudrun Nürnberg Shahida Moosa G?khan Yigit Filippo Beleggia Sigrid Tinschert Jill Clayton-Smith Pradeep Vasudevan Jill?E. Urquhart Dian Donnai Alan Fryer Ferda Percin Francesco Brancati Angus Dobbie Robert ?migiel Gabriele Gillessen-Kaesbach Bernd Wollnik Angelika?Anna Noegel William?G. Newman Peter Nürnberg 《American journal of human genetics》2014,95(5):622-632
Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs∗6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome. 相似文献
992.
Mardi S. Byerly Pia S. Petersen Santosh Ramamurthy Marcus M. Seldin Xia Lei Elayne Provost Zhikui Wei Gabriele V. Ronnett G. William Wong 《The Journal of biological chemistry》2014,289(7):4055-4069
CTRP4 is a unique member of the C1q family, possessing two tandem globular C1q domains. Its physiological function is poorly defined. Here, we show that CTRP4 is an evolutionarily conserved, ∼34-kDa secretory protein expressed in the brain. In human, mouse, and zebrafish brain, CTRP4 expression begins early in development and is widespread in the central nervous system. Neurons, but not astrocytes, express and secrete CTRP4, and secreted proteins form higher-order oligomeric complexes. CTRP4 is also produced by peripheral tissues and circulates in blood. Its serum levels are increased in leptin-deficient obese (ob/ob) mice. Functional studies suggest that CTRP4 acts centrally to modulate energy metabolism. Refeeding following an overnight fast induced the expression of CTRP4 in the hypothalamus. Central administration of recombinant protein suppressed food intake and altered the whole-body energy balance in both chow-fed and high-fat diet-fed mice. Suppression of food intake by CTRP4 is correlated with a decreased expression of orexigenic neuropeptide (Npy and Agrp) genes in the hypothalamus. These results establish CTRP4 as a novel nutrient-responsive central regulator of food intake and energy balance. 相似文献
993.
Gabriele Uhl Katrin Kunz Oliver Vöcking Elisabeth Lipke 《Biological journal of the Linnean Society. Linnean Society of London》2014,113(2):345-354
Males can increase their reproductive success by mechanically hindering females to mate with subsequent males. Research on mating plugs so far has focused on the fitness consequences and demonstrated that plug size can strongly determine its efficacy. Here, we explore: (1) the site of plug production in the erigonine spider Oedothorax retusus; and (2) whether males are limited in the production of plug material when mating with three females in succession. Micro‐computed tomography, histological and ultrastructural sections demonstrate that the plug material is produced in a massive gland inside the sperm transfer organs of the male, the pedipalps. The glandular lumen is connected with the tube‐like spermophore almost at its blind end. Probably, a reservoir of plug material is built up at the end of the spermophore and released after sperm transfer onto the female genital opening. Since not all males applied a large plug during their first mating, there was no significant decline in plug size over the course of the three successive matings. However, the size of the first plug significantly affected the size of the following plug. We discuss these findings in the light of plug limitation and mate choice. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 113 , 345–354. 相似文献
994.
Monika Heilmann Anne Wellner Gabriele Gadermaier Anne Ilchmann Peter Briza Maren Krause Ryoji Nagai Sven Burgdorf Stephan Scheurer Stefan Vieths Thomas Henle Masako Toda 《The Journal of biological chemistry》2014,289(11):7919-7928
The Maillard reaction (also referred to as “glycation”) takes place between reducing sugars and compounds with free amino groups during thermal processing of foods. In the final stage of the complex reaction cascade, the so-called advanced glycation end products (AGEs) are formed, including proteins with various glycation structures. It has been suggested that some AGEs could have immunostimulatory effects. Here, we aimed to identify specific glycation structure(s) that could influence the T-cell immunogenicity and potential allergenicity of food allergens, using ovalbumin (OVA, an egg white allergen) as a model allergen. OVA was specifically modified with representative glycation structures: Nϵ-carboxymethyl lysine (CM-OVA), Nϵ-carboxyethyl lysine (CE-OVA), pyrraline (Pyr-OVA), or methylglyoxal-derived arginine derivatives (MGO-OVA). As well as AGE-OVA, a crude glycation product in thermal incubation of OVA with glucose, only Pyr-OVA, and not other modified OVAs, was efficiently taken up by bone marrow-derived murine dendritic cells (BMDCs). The uptake of Pyr-OVA was reduced in scavenger receptor class A (SR-A)-deficient BMDCs, but not in cells treated with inhibitors of scavenger receptor class B, galectin-3, or blocking antibodies against CD36, suggesting that pyrraline binds to SR-A. Compared with other modified OVAs, Pyr-OVA induced higher activation of OVA-specific CD4+ T-cells in co-culture with BMDCs. Furthermore, compared with native OVA, AGE-OVA and Pyr-OVA induced higher IgE production in mice. Pyrraline could induce better allergen uptake by DCs via association with SR-A and subsequently enhance CD4+ T-cell activation and IgE production. Our findings help us to understand how Maillard reaction enhances the potential allergenicity of food allergens. 相似文献
995.
Gabriele Andrea Lugli Christian Milani Francesca Turroni Sabrina Duranti Chiara Ferrario Alice Viappiani Leonardo Mancabelli Marta Mangifesta Bernard Taminiau Véronique Delcenserie Douwe van Sinderen Marco Ventura 《Applied and environmental microbiology》2014,80(20):6383-6394
The Bifidobacterium genus currently encompasses 48 recognized taxa, which have been isolated from different ecosystems. However, the current phylogeny of bifidobacteria is hampered by the relative paucity of genotypic data. Here, we reassessed the taxonomy of this bacterial genus using genome-based approaches, which demonstrated that the previous taxonomic view of bifidobacteria contained several inconsistencies. In particular, high levels of genetic relatedness were shown to exist between particular Bifidobacterium taxa which would not justify their status as separate species. The results presented are here based on average nucleotide identity analysis involving the genome sequences for each type strain of the 48 bifidobacterial taxa, as well as phylogenetic comparative analysis of the predicted core genome of the Bifidobacterium genus. The results of this study demonstrate that the availability of complete genome sequences allows the reconstruction of a more robust bifidobacterial phylogeny than that obtained from a single gene-based sequence comparison, thus discouraging the assignment of a new or separate bifidobacterial taxon without such a genome-based validation. 相似文献
996.
997.
Heidi de Wit Susanne Schöning Trine L Toft‐Bertelsen Juliane Lauks Iwona Ziomkiewicz Annita N Weiss Alexander Schulz Gabriele Fischer von Mollard Matthijs Verhage Jakob B Sørensen 《The EMBO journal》2014,33(15):1681-1697
The SNARE protein vti1a is proposed to drive fusion of intracellular organelles, but recent data also implicated vti1a in exocytosis. Here we show that vti1a is absent from mature secretory vesicles in adrenal chromaffin cells, but localizes to a compartment near the trans‐Golgi network, partially overlapping with syntaxin‐6. Exocytosis is impaired in vti1a null cells, partly due to fewer Ca2+‐channels at the plasma membrane, partly due to fewer vesicles of reduced size and synaptobrevin‐2 content. In contrast, release kinetics and Ca2+‐sensitivity remain unchanged, indicating that the final fusion reaction leading to transmitter release is unperturbed. Additional deletion of the closest related SNARE, vti1b, does not exacerbate the vti1a phenotype, and vti1b null cells show no secretion defects, indicating that vti1b does not participate in exocytosis. Long‐term re‐expression of vti1a (days) was necessary for restoration of secretory capacity, whereas strong short‐term expression (hours) was ineffective, consistent with vti1a involvement in an upstream step related to vesicle generation, rather than in fusion. We conclude that vti1a functions in vesicle generation and Ca2+‐channel trafficking, but is dispensable for transmitter release. 相似文献
998.
Bianca Altvater Sareetha Kailayangiri Nadine Theimann Martina Ahlmann Nicole Farwick Christiane Chen Sibylle Pscherer Ilka Neumann Gabriele Mrachatz Anna Hansmeier Jendrik Hardes Georg Gosheger Heribert Juergens Claudia Rossig 《Cancer immunology, immunotherapy : CII》2014,63(10):1047-1060
Disseminated or relapsed Ewing sarcoma (EwS) has remained fatal in the majority of patients. A promising approach to preventing relapse after conventional therapy is to establish tumor antigen-specific immune control. Efficient and specific T cell memory against the tumor depends on the expansion of rare T cells with native specificity against target antigens overexpressed by the tumor. Candidate antigens in EwS include six-transmembrane epithelial antigen of the prostate-1 (STEAP1), and the human cancer/testis antigens X-antigen family member 1 (XAGE1) and preferentially expressed antigen in melanoma (PRAME). Here, we screened normal donors and EwS patients for the presence of circulating T cells reactive with overlapping peptide libraries of these antigens by IFN-γ Elispot analysis. The majority of 22 healthy donors lacked detectable memory T cell responses against STEAP1, XAGE1 and PRAME. Moreover, ex vivo detection of T cells specific for these antigens in both blood and bone marrow were limited to a minority of EwS patients and required nonspecific T cell prestimulation. Cytotoxic T cells specific for the tumor-associated antigens were efficiently and reliably generated by in vitro priming using professional antigen-presenting cells and optimized cytokine stimulation; however, these T cells failed to interact with native antigen processed by target cells and with EwS cells expressing the antigen. We conclude that EwS-associated antigens fail to induce efficient T cell receptor (TCR)-mediated antitumor immune responses even under optimized conditions. Strategies based on TCR engineering could provide a more effective means to manipulating T cell immunity toward targeted elimination of tumor cells. 相似文献
999.
Ryan A. Saunders Martin A. Collins Emma Foster Rachel Shreeve Gabriele Stowasser Peter Ward Geraint A. Tarling 《Polar Biology》2014,37(6):789-807
The Scotia Sea is one of the most productive regions of the Southern Ocean, but its surface waters are experiencing a rapid increase in temperature, which may be changing the behaviour and distribution of many myctophids and their prey species. Electrona antarctica and Electrona carlsbergi are two of the most abundant myctophids in the region, but their ecology is poorly understood and their response to ongoing environmental change is difficult to determine. This study investigated spatial and temporal patterns in their abundance, population structure and diets using mid-water trawl nets deployed across the Scotia Sea during spring, summer and autumn. E. antarctica was the most numerically abundant species (0.09–0.21 ind. 1,000 m?3), with greatest concentrations occurring in the sea-ice sectors. E. carlsbergi occurred in more northern regions, comprising densities of 0.02–0.11 ind. 1,000 m?3. There was evidence of seasonal variation in depth distribution, size-related sexual dimorphism and size-specific vertical stratification for both species. Latitudinal trends in sex ratio and female body size were apparent for E. antarctica. Its diet varied between regions, seasons and size classes, but overall, Euphausia superba, Metridia spp. and Themisto gaudichaudii were the dominant prey items. E. carlsbergi appeared not to recruit in the Scotia Sea. Its diet was dominated by copepods, particularly Rhincalanus gigas and Metridia spp., but regional, seasonal and ontogenetic variations were evident. This study contributes to our understanding of how mid-water food webs are structured in the Southern Ocean and their sensitivity to ongoing environmental change. 相似文献
1000.
Henrik Sperber Alan Beem Sandra Shannon Ross Jones Pratyusha Banik Yu Chen Sherman Ku Gabriele Varani Shuyuan Yao Hannele Ruohola-Baker 《RNA (New York, N.Y.)》2014,20(5):621-631
microRNAs (miRNAs) are crucial for cellular development and homeostasis. In order to better understand regulation of miRNA biosynthesis, we studied cleavage of primary miRNAs by Drosha. While Drosha knockdown triggers an expected decrease of many mature miRNAs in human embryonic stem cells (hESC), a subset of miRNAs are not reduced. Statistical analysis of miRNA secondary structure and fold change of expression in response to Drosha knockdown showed that absence of mismatches in the central region of the hairpin, 5 and 9–12 nt from the Drosha cutting site conferred decreased sensitivity to Drosha knockdown. This suggests that, when limiting, Drosha processes miRNAs without mismatches more efficiently than mismatched miRNAs. This is important because Drosha expression changes over cellular development and the fold change of expression for miRNAs with mismatches in the central region correlates with Drosha levels. To examine the biochemical relationship directly, we overexpressed structural variants of miRNA-145, miRNA-137, miRNA-9, and miRNA-200b in HeLa cells with and without Drosha knockdown; for these miRNAs, elimination of mismatches in the central region increased, and addition of mismatches decreased their expression in an in vitro assay and in cells with low Drosha expression. Change in Drosha expression can be a biologically relevant mechanism by which eukaryotic cells control miRNA profiles. This phenomenon may explain the impact of point mutations outside the seed region of certain miRNAs. 相似文献