全文获取类型
收费全文 | 1169篇 |
免费 | 124篇 |
出版年
2022年 | 12篇 |
2021年 | 24篇 |
2020年 | 20篇 |
2019年 | 16篇 |
2018年 | 23篇 |
2017年 | 18篇 |
2016年 | 22篇 |
2015年 | 39篇 |
2014年 | 47篇 |
2013年 | 50篇 |
2012年 | 71篇 |
2011年 | 73篇 |
2010年 | 40篇 |
2009年 | 34篇 |
2008年 | 44篇 |
2007年 | 48篇 |
2006年 | 54篇 |
2005年 | 38篇 |
2004年 | 45篇 |
2003年 | 36篇 |
2002年 | 34篇 |
2001年 | 26篇 |
2000年 | 22篇 |
1999年 | 22篇 |
1998年 | 12篇 |
1997年 | 16篇 |
1996年 | 10篇 |
1995年 | 13篇 |
1994年 | 8篇 |
1993年 | 9篇 |
1992年 | 18篇 |
1991年 | 26篇 |
1990年 | 20篇 |
1989年 | 19篇 |
1988年 | 10篇 |
1987年 | 16篇 |
1986年 | 19篇 |
1985年 | 17篇 |
1984年 | 12篇 |
1983年 | 7篇 |
1982年 | 12篇 |
1981年 | 9篇 |
1980年 | 12篇 |
1979年 | 13篇 |
1978年 | 22篇 |
1977年 | 19篇 |
1976年 | 15篇 |
1975年 | 13篇 |
1974年 | 8篇 |
1973年 | 16篇 |
排序方式: 共有1293条查询结果,搜索用时 15 毫秒
991.
992.
Jordan M. Ramsey Emanuel Schwarz Paul C. Guest Nico J. M. van Beveren F. Markus Leweke Matthias Rothermundt Bernhard Bogerts Johann Steiner Sabine Bahn 《PloS one》2013,8(11)
Background
In schizophrenia, sex specific dimorphisms related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by sex-related differences in the underlying molecular pathways.Methodology/Principal Findings
Here, we have carried out multiplex immunoassay profiling of sera from 4 independent cohorts of first episode antipsychotic naive schizophrenia patients (n = 133) and controls (n = 133) to identify such sex-specific illness processes in the periphery. The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In female patients, the inflammation-related analytes alpha-1-antitrypsin, B lymphocyte chemoattractant BLC and interleukin-15 showed negative associations with positive and negative syndrome scale (PANSS) scores. In male patients, the hormones prolactin and testosterone were negatively associated with PANSS ratings. In addition, we investigated molecular changes in a subset of 33 patients before and after 6 weeks of treatment with antipsychotics and found that treatment induced sex-specific changes in the levels of testosterone, serum glutamic oxaloacetic transaminase, follicle stimulating hormone, interleukin-13 and macrophage-derived chemokine. Finally, we evaluated overlapping and distinct biomarkers in the sex-specific molecular signatures in schizophrenia, major depressive disorder and bipolar disorder.Conclusions/Significance
We propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients. 相似文献993.
Beata Jurecka-Lubieniecka Rafal Ploski Dorota Kula Aleksandra Krol Tomasz Bednarczuk Zofia Kolosza Andrzej Tukiendorf Sylwia Szpak-Ulczok Anita Stanjek-Cichoracka Joanna Polanska Barbara Jarzab 《PloS one》2013,8(3)
Background
Graves'' disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. The aim of the study was to examine the association between genetic variants in genes encoding proteins involved in immune response and the age at diagnosis of GD.Methods
735 GD patients and 1216 healthy controls from Poland were included into the study. Eight genetic variants in the HLA-DRB1, TNF, CTLA4, CD40, NFKb, PTPN22, IL4 and IL10 genes were genotyped. Patients were stratified by the age at diagnosis of GD and the association with genotype was analysed.Results
Polymorphism in the HLA-DRB1, TNF and CTLA4 genes were associated with GD. The carriers of the HLA DRB1*03 allele were more frequent in patients with age at GD diagnosis ≤30 years than in patients with older age at GD diagnosis.Conclusions
HLADRB1*03 allele is associated with young age at diagnosis of Graves'' disease in polish population. 相似文献994.
Sandra Page Aybike Birerdinc Michael Estep Maria Stepanova Arian Afendy Emanuel Petricoin Zobair Younossi Vikas Chandhoke Ancha Baranova 《PloS one》2013,8(2)
The discovery of biomarkers is often performed using high-throughput proteomics-based platforms and is limited to the molecules recognized by a given set of purified and validated antigens or antibodies. Knowledge-based, or systems biology, approaches that involve the analysis of integrated data, predominantly molecular pathways and networks may infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled. In this study we attempted to use a knowledge-based approach to predict biomarkers reflecting the changes in underlying protein phosphorylation events using Nonalcoholic Fatty Liver Disease (NAFLD) as a model. Two soluble biomarkers, CCL-2 and FasL, were inferred in silico as relevant to NAFLD pathogenesis. Predictive performance of these biomarkers was studied using serum samples collected from patients with histologically proven NAFLD. Serum levels of both molecules, in combination with clinical and demographic data, were predictive of hepatic fibrosis in a cohort of NAFLD patients. Our study suggests that (1) NASH-specific disruption of the kinase-driven signaling cascades in visceral adipose tissue lead to detectable changes in the levels of soluble molecules released into the bloodstream, and (2) biomarkers discovered in silico could contribute to predictive models for non-malignant chronic diseases. 相似文献
995.
996.
Rosa Sanchez-Alvarez Ubaldo E. Martinez-Outschoorn Zhao Lin Rebecca Lamb James Hulit Anthony Howell Federica Sotgia Emanuel Rubin Michael P. Lisanti 《Cell cycle (Georgetown, Tex.)》2013,12(2):289-301
Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with “stemness,” more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This “two-compartment” metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert “low-risk” breast cancer patients to “high-risk” status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results also show that antioxidants [such as N-acetyl cysteine (NAC)] can effectively reverse or prevent ethanol-induced oxidative stress in cancer-associated fibroblasts, suggesting a novel strategy for cancer prevention. We also show that caveolin-1 and MCT4 protein expression can be effectively used as new biomarkers to monitor oxidative stress induced by ethanol. 相似文献
997.
Eiji Kodama-Namba Lorenz A. Fenk Andrew J. Bretscher Einav Gross K. Emanuel Busch Mario de Bono 《PLoS genetics》2013,9(12)
Different interoceptive systems must be integrated to ensure that multiple homeostatic insults evoke appropriate behavioral and physiological responses. Little is known about how this is achieved. Using C. elegans, we dissect cross-modulation between systems that monitor temperature, O2 and CO2. CO2 is less aversive to animals acclimated to 15°C than those grown at 22°C. This difference requires the AFD neurons, which respond to both temperature and CO2 changes. CO2 evokes distinct AFD Ca2+ responses in animals acclimated at 15°C or 22°C. Mutants defective in synaptic transmission can reprogram AFD CO2 responses according to temperature experience, suggesting reprogramming occurs cell autonomously. AFD is exquisitely sensitive to CO2. Surprisingly, gradients of 0.01% CO2/second evoke very different Ca2+ responses from gradients of 0.04% CO2/second. Ambient O2 provides further contextual modulation of CO2 avoidance. At 21% O2 tonic signalling from the O2-sensing neuron URX inhibits CO2 avoidance. This inhibition can be graded according to O2 levels. In a natural wild isolate, a switch from 21% to 19% O2 is sufficient to convert CO2 from a neutral to an aversive cue. This sharp tuning is conferred partly by the neuroglobin GLB-5. The modulatory effects of O2 on CO2 avoidance involve the RIA interneurons, which are post-synaptic to URX and exhibit CO2-evoked Ca2+ responses. Ambient O2 and acclimation temperature act combinatorially to modulate CO2 responsiveness. Our work highlights the integrated architecture of homeostatic responses in C. elegans. 相似文献
998.
Mowbray CE Bell AS Clarke NP Collins M Jones RM Lane CA Liu WL Newman SD Paradowski M Schenck EJ Selby MD Swain NA Williams DH 《Bioorganic & medicinal chemistry letters》2011,21(21):6596-6602
We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate 13 (PF-3893787). The pre-clinical profile of 13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and others in future drug discovery projects. 相似文献
999.
Roberts TJ Abbott EM Azizi E 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1570):1488-1495
Muscles power movement, yet the conceptual link between muscle performance and locomotor performance is poorly developed. Frog jumping provides an ideal system to probe the relationship between muscle capacity and locomotor performance, because a jump is a single discrete event and mechanical power output is a critical determinant of jump distance. We tested the hypothesis that interspecific variation in jump performance could be explained by variability in available muscle power. We used force plate ergometry to measure power produced during jumping in Cuban tree frogs (Osteopilus septentrionalis), leopard frogs (Rana pipiens) and cane toads (Bufo marinus). We also measured peak isotonic power output in isolated plantaris muscles for each species. As expected, jump performance varied widely. Osteopilus septentrionalis developed peak power outputs of 1047.0 ± 119.7 W kg(-1) hindlimb muscle mass, about five times that of B. marinus (198.5 ± 54.5 W kg(-1)). Values for R. pipiens were intermediate (543.9 ± 96.2 W kg(-1)). These differences in jump power were not matched by differences in available muscle power, which were 312.7 ± 28.9, 321.8 ± 48.5 and 262.8 ± 23.2 W kg(-1) muscle mass for O. septentrionalis, R. pipiens and B. marinus, respectively. The lack of correlation between available muscle power and jump power suggests that non-muscular mechanisms (e.g. elastic energy storage) can obscure the link between muscle mechanical performance and locomotor performance. 相似文献
1000.
In this work, we analyzed the karyotypes of five Hypostomus species. Hypostomus cf. heraldoi, from the Mogi-Gua?u River, had 2n = 72 chromosomes, with a nucleolar organizer region (NOR) in one chromosomal pair. Hypostomus regani, from the Mogi-Gua?u River had 2n = 72 chromosomes with NORs in two chromosomal pairs. Hypostomus sp., from the Mogi-Gua?u River basin, had 2n = 68 chromosomes, with NORs in two chromosomal pairs. Hypostomus aff. agna, from Cavalo Stream, had 2n = 74 chromosomes with NORs in two chromosomal pairs. Hypostomus cf. topavae, from Carrapato Stream, had 2n = 80 chromosomes, with NORs in two chromosomal pairs. Hypostomus species showed marked diversity in the karyotypic formula, which suggested the occurrence of several Robertsonian rearrangements and pericentric inversions during the evolutionary history of this genus. This hypothesis was supported by the occurrence of a large number of uniarmed chromosomes and multiple NORs in a terminal position in most species and may be a derived condition in the Loricariidae. 相似文献