全文获取类型
收费全文 | 708篇 |
免费 | 63篇 |
国内免费 | 3篇 |
出版年
2024年 | 1篇 |
2023年 | 4篇 |
2022年 | 14篇 |
2021年 | 35篇 |
2020年 | 19篇 |
2019年 | 16篇 |
2018年 | 30篇 |
2017年 | 26篇 |
2016年 | 42篇 |
2015年 | 54篇 |
2014年 | 56篇 |
2013年 | 53篇 |
2012年 | 68篇 |
2011年 | 62篇 |
2010年 | 36篇 |
2009年 | 29篇 |
2008年 | 45篇 |
2007年 | 33篇 |
2006年 | 29篇 |
2005年 | 14篇 |
2004年 | 16篇 |
2003年 | 23篇 |
2002年 | 17篇 |
2001年 | 4篇 |
1999年 | 3篇 |
1998年 | 1篇 |
1997年 | 6篇 |
1996年 | 1篇 |
1995年 | 10篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1988年 | 1篇 |
1984年 | 1篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1973年 | 2篇 |
1966年 | 1篇 |
1932年 | 1篇 |
1910年 | 1篇 |
排序方式: 共有774条查询结果,搜索用时 15 毫秒
101.
Benedikt Rauscher Florian Heigwer Luisa Henkel Thomas Hielscher Oksana Voloshanenko Michael Boutros 《Molecular systems biology》2018,14(2)
Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype‐dependent vulnerabilities, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework to integrate CRISPR/Cas9 screens originating from different libraries building on approaches pioneered for genetic network discovery in model organisms. We applied this method to integrate and analyze data from 85 CRISPR/Cas9 screens in human cancer cells combining functional data with information on genetic variants to explore more than 2.1 million gene‐background relationships. In addition to known dependencies, we identified new genotype‐specific vulnerabilities of cancer cells. Experimental validation of predicted vulnerabilities identified GANAB and PRKCSH as new positive regulators of Wnt/β‐catenin signaling. By clustering genes with similar genetic interaction profiles, we drew the largest genetic network in cancer cells to date. Our scalable approach highlights how diverse genetic screens can be integrated to systematically build informative maps of genetic interactions in cancer, which can grow dynamically as more data are included. 相似文献
102.
Benedikt Weber Manuel Hora Pamina Kazman Christoph Göbl Carlo Camilloni Bernd Reif Johannes Buchner 《Journal of molecular biology》2018,430(24):4925-4940
The antibody light chain (LC) consists of two domains and is essential for antigen binding in mature immunoglobulins. The two domains are connected by a highly conserved linker that comprises the structurally important Arg108 residue. In antibody light chain (AL) amyloidosis, a severe protein amyloid disease, the LC and its N-terminal variable domain (VL) convert to fibrils deposited in the tissues causing organ failure. Understanding the factors shaping the architecture of the LC is important for basic science, biotechnology and for deciphering the principles that lead to fibril formation. In this study, we examined the structure and properties of LC variants with a mutated or extended linker. We show that under destabilizing conditions, the linker modulates the amyloidogenicity of the LC. The fibril formation propensity of LC linker variants and their susceptibility to proteolysis directly correlate implying an interplay between the two LC domains. Using NMR and residual dipolar coupling-based simulations, we found that the linker residue Arg108 is a key factor regulating the relative orientation of the VL and CL domains, keeping them in a bent and dense, but still flexible conformation. Thus, inter-domain contacts and the relative orientation of VL and CL to each other are of major importance for maintaining the structural integrity of the full-length LC. 相似文献
103.
Ulrike Schoetz Diana Klein Julia Hess Seyd Shnayien Steffen Spoerl Michael Orth Samet Mutlu Roman Hennel Anja Sieber Ute Ganswindt Benedikt Luka Andreas R. Thomsen Kristian Unger Verena Jendrossek Horst Zitzelsberger Nils Blüthgen Claus Belka Steffen Unkel Bertram Klinger Kirsten Lauber 《Cell death & disease》2021,12(12)
Resistance against radio(chemo)therapy-induced cell death is a major determinant of oncological treatment failure and remains a perpetual clinical challenge. The underlying mechanisms are manifold and demand for comprehensive, cancer entity- and subtype-specific examination. In the present study, resistance against radiotherapy was systematically assessed in a panel of human head-and-neck squamous cell carcinoma (HNSCC) cell lines and xenotransplants derived thereof with the overarching aim to extract master regulators and potential candidates for mechanism-based pharmacological targeting. Clonogenic survival data were integrated with molecular and functional data on DNA damage repair and different cell fate decisions. A positive correlation between radioresistance and early induction of HNSCC cell senescence accompanied by NF-κB-dependent production of distinct senescence-associated cytokines, particularly ligands of the CXCR2 chemokine receptor, was identified. Time-lapse microscopy and medium transfer experiments disclosed the non-cell autonomous, paracrine nature of these mechanisms, and pharmacological interference with senescence-associated cytokine production by the NF-κB inhibitor metformin significantly improved radiotherapeutic performance in vitro and in vivo. With regard to clinical relevance, retrospective analyses of TCGA HNSCC data and an in-house HNSCC cohort revealed that elevated expression of CXCR2 and/or its ligands are associated with impaired treatment outcome. Collectively, our study identifies radiation-induced tumor cell senescence and the NF-κB-dependent production of distinct senescence-associated cytokines as critical drivers of radioresistance in HNSCC whose therapeutic targeting in the context of multi-modality treatment approaches should be further examined and may be of particular interest for the subgroup of patients with elevated expression of the CXCR2/ligand axis.Subject terms: Radiotherapy, Head and neck cancer, Senescence, Tumour heterogeneity 相似文献
104.
105.
Laëtitia Trapp-Fragnet Julia Schermuly Marina Kohn Luca D. Bertzbach Florian Pfaff Caroline Denesvre Benedikt B. Kaufer Sonja Hrtle 《PLoS pathogens》2021,17(10)
Marek’s disease virus (MDV) is an alphaherpesvirus that causes immunosuppression and deadly lymphoma in chickens. Lymphoid organs play a central role in MDV infection in animals. B-cells in the bursa of Fabricius facilitate high levels of MDV replication and contribute to dissemination at early stages of infection. Several studies investigated host responses in bursal tissue of MDV-infected chickens; however, the cellular responses specifically in bursal B-cells has never been investigated. We took advantage of our recently established in vitro infection system to decipher the cellular responses of bursal B-cells to infection with a very virulent MDV strain. Here, we demonstrate that MDV infection extends the survival of bursal B-cells in culture. Microarray analyses revealed that most cytokine/cytokine-receptor-, cell cycle- and apoptosis-associated genes are significantly down-regulated in these cells. Further functional assays validated these strong effects of MDV infections on cell cycle progression and thus, B-cell proliferation. In addition, we confirmed that MDV infections protect B-cells from apoptosis and trigger an accumulation of the autophagy marker Lc3-II. Taken together, our data indicate that MDV-infected bursal B-cells show hallmarks of a senescence-like phenotype, leading to a prolonged B-cell survival. This study provides an in-depth analysis of bursal B-cell responses to MDV infection and important insights into how the virus extends the survival of these cells. 相似文献
106.
107.
108.
Ayotokunbo O. Egbontan Clement G. Afolabi Iyabode A. Kehinde Ololade A. Enikuomehin Chibundu N. Ezekiel Michael Sulyok Benedikt Warth Rudolf Krska 《Mycotoxin Research》2017,33(1):59-64
A preliminary survey involving limited sample size was conducted to determine the spectrum of moulds and mycotoxins in wheat grains from flour mills and local markets in Nigeria. Fourteen wheat samples were analyzed for moulds using standard mycological methods and for toxic fungal metabolites using a liquid chromatography-tandem mass spectrometric method. Fusarium (range of incidence 12.5–61.7%) dominated in the wheat grains though species of Aspergillus (range of incidence 2.24–3.86%) were also recovered from the samples. The identified fungal species were Aspergillus flavus (7.7%), Aspergillus niger clade (2.6%), Fusarium avenaceum (10.9%), Fusarium culmorum (22.4%) and Fusarium graminearum (56.4%). A total of 54 microbial metabolites were detected in the samples at concentration ranging between 0.01 μg/kg for macrosporin and 2560 μg/kg for deoxynivalenol. Among the four mycotoxins addressed by regulations in the European Union (EU) found in the samples, deoxynivalenol (incidence 100%) dominated in the samples and its levels exceeded the maximum acceptable EU limit (750 μg/kg) in 36% of the samples. This report underscores the need for more robust surveys with larger sample sizes and across several agro-ecologies in the country. 相似文献
109.
The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function,brain perfusion,and glucose metabolism
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Gernot Kleinberger Matthias Brendel Eva Mracsko Benedikt Wefers Linda Groeneweg Xianyuan Xiang Carola Focke Maximilian Deußing Marc Suárez‐Calvet Fargol Mazaheri Samira Parhizkar Nadine Pettkus Wolfgang Wurst Regina Feederle Peter Bartenstein Thomas Mueggler Thomas Arzberger Irene Knuesel Axel Rominger Christian Haass 《The EMBO journal》2017,36(13):1837-1853
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD‐like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock‐in mouse model for the disease‐associated Trem2 p.T66M mutation. Consistent with a loss‐of‐function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock‐in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (μPET) demonstrates an age‐dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG‐μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss‐of‐function mutation causes brain‐wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism. 相似文献
110.
Dirk Raiser Stephanie Mildner Benedikt Ifland Mohsen Sotoudeh Peter Blöchl Simone Techert Christian Jooss 《Liver Transplantation》2017,7(12)
Understanding and controlling the relaxation process of optically excited charge carriers in solids with strong correlations is of great interest in the quest for new strategies to exploit solar energy. Usually, optically excited electrons in a solid thermalize rapidly on a femtosecond to picosecond timescale due to interactions with other electrons and phonons. New mechanisms to slow down thermalization will thus be of great significance for efficient light energy conversion, e.g., in photovoltaic devices. Ultrafast optical pump–probe experiments in the manganite Pr0.65Ca0.35MnO3, a photovoltaic, thermoelectric, and electrocatalytic material with strong polaronic correlations, reveal an ultraslow recombination dynamics on a nanosecond‐time scale. The nature of long living excitations is further elucidated by photovoltaic measurements, showing the presence of photodiffusion of excited electron–hole polaron pairs. Theoretical considerations suggest that the excited charge carriers are trapped in a hot polaron state. Escape from this state is possible via a slow dipole‐forbidden recombination process or via rare thermal fluctuations toward a conical intersection followed by a radiation‐less decay. The strong correlation between the excited polaron and the octahedral dynamics of its environment appears to be substantial for stabilizing the hot polaron. 相似文献