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151.
Jun Wang Tobias Sinnberg Heike Niessner Rebecca Dölker Birgit Sauer Wolfgang E. Kempf Friedegund Meier Nick Leslie Birgit Schittek 《Pigment cell & melanoma research》2015,28(5):572-589
Inhibition of the mitogen‐activated protein kinase (MAPK) pathway is a major advance in the treatment of metastatic melanoma. However, its therapeutic success is limited by the rapid emergence of drug resistance. The insulin‐like growth factor‐1 receptor (IGF‐1R) is overexpressed in melanomas developing resistance toward the BRAFV600 inhibitor vemurafenib. Here, we show that hyperactivation of BRAF enhances IGF‐1R expression. In addition, the phosphatase activity of PTEN as well as heterocellular contact to stromal cells increases IGF‐1R expression in melanoma cells and enhances resistance to vemurafenib. Interestingly, PTEN‐negative melanoma cells escape IGF‐1R blockade by decreased expression of the receptor, implicating that only in melanoma patients with PTEN‐positive tumors treatment with IGF‐1R inhibitors would be a suitable strategy to combat therapy resistance. Our data emphasize the crosstalk and therapeutic relevance of microenvironmental and tumor cell‐autonomous mechanisms in regulating IGF‐1R expression and by this sensitivity toward targeted therapies. 相似文献
152.
153.
Jorge Esparza-Gordillo Anja Matanovic Ingo Marenholz Anja Bauerfeind Klaus Rohde Katja Nemat Min-Ae Lee-Kirsch Magnus Nordenskj?ld Marten C. G. Winge Thomas Keil Renate Krüger Susanne Lau Kirsten Beyer Birgit Kalb Bodo Niggemann Norbert Hübner Heather J. Cordell Maria Bradley Young-Ae Lee 《PLoS genetics》2015,11(3)
Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome''s influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10−36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10−8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring’s susceptibility to a common human disease. 相似文献
154.
Rita-Eva Varga Mukhran Khundadze Markus Damme Sandor Nietzsche Birgit Hoffmann Tobias Stauber Nicole Koch J. Christopher Hennings Patricia Franzka Antje K. Huebner Michael M. Kessels Christoph Biskup Thomas J. Jentsch Britta Qualmann Thomas Braulke Ingo Kurth Christian Beetz Christian A. Hübner 《PLoS genetics》2015,11(8)
Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice. 相似文献
155.
Illegal drugs exacerbate global social challenges such as substance addiction, mental health issues and violent crime. Police and customs officials often rely on specially-trained sniffer dogs, which act as sensitive biological detectors to find concealed illegal drugs. However, the dog “alert” is no longer sufficient evidence to allow a search without a warrant or additional probable cause because cannabis has been legalized in two US states and is decriminalized in many others. Retraining dogs to recognize a narrower spectrum of drugs is difficult and training new dogs is time consuming, yet there are no analytical devices with the portability and sensitivity necessary to detect substance-specific chemical signatures. This means there is currently no substitute for sniffer dogs. Here we describe an insect screening procedure showing that the western honeybee (Apis mellifera) can sense volatiles associated with pure samples of heroin and cocaine. We developed a portable electroantennographic device for the on-site measurement of volatile perception by these insects, and found a positive correlation between honeybee antennal responses and the concentration of specific drugs in test samples. Furthermore, we tested the ability of honeybees to learn the scent of heroin and trained them to show a reliable behavioral response in the presence of a highly-diluted scent of pure heroin. Trained honeybees could therefore be used to complement or replace the role of sniffer dogs as part of an automated drug detection system. Insects are highly sensitive to volatile compounds and provide an untapped resource for the development of biosensors. Automated conditioning as presented in this study could be developed as a platform for the practical detection of illicit drugs using insect-based sensors. 相似文献
156.
Rocio Acuna-Hidalgo Denny Schanze Ariana Kariminejad Ann Nordgren Mohamad Hasan Kariminejad Peter Conner Giedre Grigelioniene Daniel Nilsson Magnus Nordenskjöld Anna Wedell Christoph Freyer Anna Wredenberg Dagmar Wieczorek Gabriele Gillessen-Kaesbach Hülya Kayserili Nursel Elcioglu Siavash Ghaderi-Sohi Payman Goodarzi Hamidreza Setayesh Maartje van de Vorst Marloes Steehouwer Rolph Pfundt Birgit Krabichler Cynthia Curry Malcolm G. MacKenzie Kym M. Boycott Christian Gilissen Andreas R. Janecke Alexander Hoischen Martin Zenker 《American journal of human genetics》2014
157.
Eva C. Schulte Maria Kousi Perciliz L. Tan Erik Tilch Franziska Knauf Peter Lichtner Claudia Trenkwalder Birgit Högl Birgit Frauscher Klaus Berger Ingo Fietze Magdolna Hornyak Wolfgang H. Oertel Cornelius G. Bachmann Alexander Zimprich Annette Peters Christian Gieger Thomas Meitinger Bertram Müller-Myhsok Nicholas Katsanis Juliane Winkelmann 《American journal of human genetics》2014
158.
Marten Michaelis Oliver Gralla Thomas Behrends Marcus Scharpf Tobias Endermann Eddy Rijntjes Nicole Pietschmann Birgit Hollenbach Lutz Schomburg 《Biochemical and biophysical research communications》2014
Hepatically-derived selenoprotein P (SePP) transports selenium (Se) via blood to other tissues including the testes. Male Sepp-knockout mice are infertile. SePP-mediated Se transport to Sertoli cells is needed for supporting biosynthesis of the selenoenzyme glutathione peroxidase-4 (GPX4) in spermatozoa. GPX4 becomes a structural component of sperm midpiece during sperm maturation, and its expression correlates to semen quality. We tested whether SePP is also present in seminal plasma, potentially correlating to fertility parameters. Semen quality was assessed by sperm density, morphology and motility. SePP was measured by an immunoluminometric assay, and trace elements were determined by X-ray fluorescence spectroscopy. SePP levels were considerably lower in seminal plasma as compared to serum (0.4 ± 0.1 mg/l vs. 3.5 ± 1.0 mg/l); Se concentrations showed a similar but less pronounced difference (48.9 ± 20.7 μg/l vs. 106.7 ± 17.3 μg/l). Se and Zn correlated positively in seminal fluid but not in serum. Seminal plasma SePP concentrations were independent of serum SePP concentrations, but correlated positively to sperm density and fraction of vital sperm. SePP concentrations in seminal plasma of vasectomized men were similar to controls indicating that accessory sex glands are a testes-independent source of SePP. This notion was corroborated by histochemical analyses localizing SePP in epithelial cells of seminal vesicles. We conclude that SePP is not only involved in Se transport to testes supporting GPX4 biosynthesis but it also becomes secreted into seminal plasma, likely important to protect sperm during storage, genital tract passage and final journey. 相似文献
159.
160.
Birgit Hoff Jens Kamerewerd Claudia Sigl Ivo Zadra Ulrich Kück 《Applied microbiology and biotechnology》2010,85(4):1081-1094
In Penicillium chrysogenum, the industrial producer of the β-lactam antibiotic penicillin, generating gene replacements for functional analyses is very
inefficient. Here, we constructed a recipient strain that allows efficient disruption of any target gene via homologous recombination.
Following isolation of the Pcku70 (syn. hdfA) gene encoding a conserved eukaryotic DNA-binding protein involved in non-homologous end joining (NHEJ), a Pcku70 knockout strain was constructed using a novel nourseothricin-resistance cassette as selectable marker. In detailed physiological
tests, strain ΔPcku70 showed no significant reduction in vegetative growth due to increased sensitivity to different mutagenic
substances. Importantly, deletion of the Pcku70 gene had no effect on penicillin biosynthesis. However, strain ΔPcku70 exhibits higher sensitivity to osmotic stress than
the parent strain. This correlated well with comparative data from microarray analyses: Genes related to the stress response
are significantly up-regulated in the Pcku70 deletion mutant. To demonstrate the applicability of strain ΔPcku70, three genes related to β-lactam antibiotic biosynthesis
were efficiently disrupted, indicating that this strain shows a low frequency of NHEJ, thus promoting efficient homologous
recombination. Furthermore, we discuss strategies to reactivate Pcku70 in strains successfully used for gene disruptions. 相似文献