全文获取类型
收费全文 | 821篇 |
免费 | 59篇 |
出版年
2023年 | 6篇 |
2022年 | 9篇 |
2021年 | 43篇 |
2020年 | 23篇 |
2019年 | 27篇 |
2018年 | 43篇 |
2017年 | 40篇 |
2016年 | 33篇 |
2015年 | 70篇 |
2014年 | 73篇 |
2013年 | 82篇 |
2012年 | 77篇 |
2011年 | 88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 | 18篇 |
2003年 | 9篇 |
2002年 | 12篇 |
2001年 | 2篇 |
2000年 | 3篇 |
1999年 | 1篇 |
1998年 | 3篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1990年 | 1篇 |
1988年 | 1篇 |
1986年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1965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880条查询结果,搜索用时 171 毫秒
111.
Frankiewicz Lukasz P. Pulka Karolina Lipkowski Andrzej W. Misicka Aleksandra 《International journal of peptide research and therapeutics》2002,9(2-3):77-81
Summary This article presents kinetic studies of cross interaction of β-amyloid peptide and prion protein fragments. Syntheses of
three peptides (β25-35, β22-35 and PrP 109–126) were performed. Those peptides were used for aggregation studies in PBS and
TRIS buffers using HPLC with DAD detector. Comparison of aggregation of peptides alone and in combination with other fragments
was investigated. In all cases aggregation was faster in PBS than in TRIS solution. Obtained results suggest that β-amyloid
peptide and prion protein may interact to form macromolecular complexes with different ability for aggregation. 相似文献
112.
Daniel E. Adkins Renan P. Souza Karolina ?berg Shaunna L. Clark Joseph L. McClay Patrick F. Sullivan Edwin J. C. G. van den Oord 《PloS one》2013,8(2)
Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient’s unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (n = 765) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (n = 1892). Next, we performed multiple regression analyses to estimate the predictive power of these ancestral dimensions. For 136/89 treatment-outcome combinations tested in CATIE/STAR*D, results indicated 1.67/1.84 times higher median test statistics than expected under the null hypothesis assuming no predictive power (p<0.01, both samples). Thus, ancestry showed robust and pervasive correlations with drug efficacy and side effects in both CATIE and STAR*D. Comparison of the marginal predictive power of MDS ancestral dimensions and self-reported race indicated significant improvements to model fit with the inclusion of MDS dimensions, but mixed evidence for self-reported race. Knowledge of each patient’s unique mosaic of ancestral backgrounds provides a potent immediate starting point for developing algorithms identifying the most effective and safe medication for a wide variety of drug-treatment response combinations. As relatively few new psychiatric drugs are currently under development, such personalized medicine offers a promising approach toward optimizing pharmacotherapy for psychiatric conditions. 相似文献
113.
Magdalena Czeredys ?ukasz Samluk Katarzyna Michalec Karolina Tu?odziecka Krzysztof Skowronek Katarzyna A. Na??cz 《PloS one》2013,8(12)
OCTN2 - the Organic Cation Transporter Novel family member 2 (SLC22A5) is known to be a xenobiotic/drug transporter. It transports as well carnitine - a compound necessary for oxidation of fatty acids and mutations of its gene cause primary carnitine deficiency. Octn2 regulation by protein kinase C (PKC) was studied in rat astrocytes - cells in which β-oxidation takes place in the brain. Activation of PKC with phorbol ester stimulated L-carnitine transport and increased cell surface presence of the transporter, although no PKC-specific phosphorylation of Octn2 could be detected. PKC activation resulted in an augmented Octn2 presence in cholesterol/sphingolipid-rich microdomains of plasma membrane (rafts) and increased co-precipitation of Octn2 with raft-proteins, caveolin-1 and flotillin-1. Deletion of potential caveolin-1 binding motifs pointed to amino acids 14–22 and 447–454 as the caveolin-1 binding sites within Octn2 sequence. A direct interaction of Octn2 with caveolin-1 in astrocytes upon PKC activation was detected by proximity ligation assay, while such an interaction was excluded in case of flotillin-1. Functioning of a multi-protein complex regulated by PKC has been postulated in rOctn2 trafficking to the cell surface, a process which could be important both under physiological conditions, when carnitine facilitates fatty acids catabolism and controls free Coenzyme A pool as well as in pathology, when transport of several drugs can induce secondary carnitine deficiency. 相似文献
114.
115.
116.
Federica Bozzano Chiara Dentone Carola Perrone Antonio Di Biagio Daniela Fenoglio Alessia Parodi Malgorzata Mikulska Bianca Bruzzone Daniele Roberto Giacobbe Antonio Vena Lucia Taramasso Laura Nicolini Nicol Patroniti Paolo Pelosi Angelo Gratarola Raffaele De Palma Gilberto Filaci Matteo Bassetti Andrea De Maria 《PLoS pathogens》2021,17(4)
The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19.Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells.Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches. 相似文献
117.
Ben J. Bowles Karolina Dziemidowicz Felipe L. Lopez Mine Orlu Catherine Tuleu Andrew J. Edwards Terry B. Ernest 《AAPS PharmSciTech》2018,19(6):2598-2609
Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr’s index ? 20), excellent tabletability (tensile strength >?3.0 MPa at 0.85 solid fraction), very low friability (<?1% after 15 min), rapid disintegration times (27–49 s) and produced dispersions of ideal fineness (<?250 μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients. 相似文献
118.
Cucumber metal tolerance protein 7 (CsMTP7) is involved in the accumulation of Fe in mitochondria under Fe excess 下载免费PDF全文
119.
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
120.
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