全文获取类型
收费全文 | 815篇 |
免费 | 59篇 |
专业分类
874篇 |
出版年
2023年 | 8篇 |
2022年 | 23篇 |
2021年 | 42篇 |
2020年 | 23篇 |
2019年 | 27篇 |
2018年 | 43篇 |
2017年 | 40篇 |
2016年 | 33篇 |
2015年 | 67篇 |
2014年 | 71篇 |
2013年 | 81篇 |
2012年 | 75篇 |
2011年 | 86篇 |
2010年 | 52篇 |
2009年 | 24篇 |
2008年 | 34篇 |
2007年 | 34篇 |
2006年 | 36篇 |
2005年 | 22篇 |
2004年 | 17篇 |
2003年 | 9篇 |
2002年 | 12篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1964年 | 1篇 |
1941年 | 1篇 |
1939年 | 1篇 |
1905年 | 1篇 |
排序方式: 共有874条查询结果,搜索用时 0 毫秒
1.
Jonas G. Barlind Linda K. Buckett Sharon G. Crosby Öjvind Davidsson Hans Emtenäs Anne Ertan Ulrik Jurva Malin Lemurell Pablo Morentin Gutierrez Karolina Nilsson Gavin O’Mahony Annika U. Petersson Alma Redzic Fredrik Wågberg Zhong-Qing Yuan 《Bioorganic & medicinal chemistry letters》2013,23(9):2721-2726
[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration. 相似文献
2.
Balzs Trk David G. Nagy Mariann Kiss Karolina Janacsek Dezs Nmeth Gerg Orbn 《PLoS computational biology》2022,18(6)
Internal models capture the regularities of the environment and are central to understanding how humans adapt to environmental statistics. In general, the correct internal model is unknown to observers, instead they rely on an approximate model that is continually adapted throughout learning. However, experimenters assume an ideal observer model, which captures stimulus structure but ignores the diverging hypotheses that humans form during learning. We combine non-parametric Bayesian methods and probabilistic programming to infer rich and dynamic individualised internal models from response times. We demonstrate that the approach is capable of characterizing the discrepancy between the internal model maintained by individuals and the ideal observer model and to track the evolution of the contribution of the ideal observer model to the internal model throughout training. In particular, in an implicit visuomotor sequence learning task the identified discrepancy revealed an inductive bias that was consistent across individuals but varied in strength and persistence. 相似文献
3.
Marcin Olszak William Truman Karolina Stefanowicz Elwira Sliwinska Masaki Ito Piotr Walerowski Stephen Rolfe Robert Malinowski 《The Plant journal : for cell and molecular biology》2019,97(4):715-729
Plasmodiophora brassicae is a soil‐borne biotroph whose life cycle involves reprogramming host developmental processes leading to the formation of galls on its underground parts. Formation of such structures involves modification of the host cell cycle leading initially to hyperplasia, increasing the number of cells to be invaded, followed by overgrowth of cells colonised by the pathogen. Here we show that P. brassicae infection stimulates formation of the E2Fa/RBR1 complex and upregulation of MYB3R1, MYB3R4 and A‐ and B‐type cyclin expression. These factors were previously described as important regulators of the G2?M cell cycle checkpoint. As a consequence of this manipulation, a large population of host hypocotyl cells are delayed in cell cycle exit and maintained in the proliferative state. We also report that, during further maturation of galls, enlargement of host cells invaded by the pathogen involves endoreduplication leading to increased ploidy levels. This study characterises two aspects of the cell cycle reprogramming efforts of P. brassicae: systemic, related to the disturbance of host hypocotyl developmental programs by preventing cell cycle exit; and local, related to the stimulation of cell enlargement via increased endocycle activity. 相似文献
4.
5.
6.
Marianna Małek Bożena Bogusz Paulina Mrowiec Mariusz Szuta Maciej Opach Iwona Skiba-Kurek Paweł Nowak Karolina Klesiewicz Alicja Budak Elżbieta Karczewska 《Revista iberoamericana de micología》2018,35(3):140-146
Background
Fungal rhinosinusitis has become an increasingly recognized disease, being Aspergillus species responsible for most of the cases. Its diagnosis is quite difficult because of the non-specific symptoms and low sensitivity of the current diagnostic methods.Aims
An Aspergillus-specific nested polymerase chain reaction (PCR) assay using biopsy specimens taken from the maxillary sinuses was performed in order to assess its usefulness. Conventional diagnostic methods (histology and culture) were also carried out.Methods
A case–control study was performed in the Institute of Stomatology, Jagiellonian University in Kraków, between 2011 and 2014. The case group consisted of 21 patients with suspected rhinosinusal mycetoma while the control group included 46 patients with no suspicion of fungal rhinosinusitis. The two-step PCR assay amplified an Aspergillus specific portion of the 18S rRNA gene. Interval estimation of sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated to assess the diagnostic test performance. The agreement between the PCR and the other tests was evaluated using the Kappa coefficient (k).Results
Ninety percent of the samples obtained from patients diagnosed with mycetoma yielded positive PCR results. The PCR showed almost perfect concordance with histology (k = 0.88). Sensitivity, specificity, PPV and NPV estimates were 90%; 95% CI: (55.5–99.7%), 98.3%; 95% CI: (90.9–100%), 90%; 95% CI: (55.5–99.7%) and 98.3%; 95% CI: (90.9–100%), respectively. One clinical sample showed growth of Aspergillus fumigatus and positive PCR despite the negative histological examination.Conclusions
Nested PCR assay is a promising diagnostic tool to evaluate the presence of Aspergillus in the tissue of maxillary sinus from patients with suspicion of sinus aspergillosis. 相似文献7.
Biotransformation of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide,a novel potent 5‐HT7 receptor antagonist with antidepressant‐like and anxiolytic properties: In vitro and in silico approach 下载免费PDF全文
Karolina Słoczyńska Katarzyna Wójcik‐Pszczoła Vittorio Canale Paweł Żmudzki Paweł Zajdel Elżbieta Pękala 《Journal of biochemical and molecular toxicology》2018,32(5)
The aim of the study was to investigate the metabolism of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide (PZ‐1150), a novel 5‐HT7 receptor antagonist with antidepressant‐like and anxiolytic properties, by the following three ways: in vitro with microsomes; in vitro employing Cunninghamella echinulata, and in silico using MetaSite. Biotransformation of PZ‐1150 with microsomes resulted in five metabolites, while transformation with C. echinulata afforded two metabolites. In both models, the predominant metabolite occurred due to hydroxylation of benzene ring. In silico data coincide with in vitro experiments, as three MetaSite metabolites matched compounds identified in microsomal samples. In human liver microsomes PZ‐1150 exhibited in vitro half‐life of 64 min, with microsomal intrinsic clearance of 54.1 μL/min/mg and intrinsic clearance of 48.7 mL/min/kg. Therefore, PZ‐1150 is predicted to be a high‐clearance agent. The study demonstrated the applicability of using microsomal model coupled with microbial model to elucidate the metabolic pathways of compounds and comparison with in silico metabolite predictions. 相似文献
8.
Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology. 相似文献
9.
Does operational sex ratio influence relative strength of purging selection in males versus females?
Agata Plesnar‐Bielak Karolina Sychta Tomasz S. Gaczorek Joanna K. Palka Monika A. Prus Zofia M. Prokop 《Journal of evolutionary biology》2020,33(1):80-88
According to theory, sexual selection in males may efficiently purge mutation load of sexual populations, reducing or fully compensating ‘the cost of males’. For this to occur, mutations not only need to be deleterious to both sexes, they also must affect males more than females. A frequently overlooked problem is that relative strength of selection on males versus females may vary between environments, with social conditions being particularly likely to affect selection in males and females differently. Here, we induced mutations in red flour beetles (Tribolium castaneum) and tested their effect in both sexes under three different operational sex ratios (1:2, 1:1 and 2:1). Induced mutations decreased fitness of both males and females, but their effect was not stronger in males. Surprisingly, operational sex ratio did not affect selection against deleterious mutations nor its relative strength in the sexes. Thus, our results show no support for the role of sexual selection in the evolutionary maintenance of sex. 相似文献