全文获取类型
收费全文 | 436篇 |
免费 | 32篇 |
专业分类
468篇 |
出版年
2024年 | 2篇 |
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 20篇 |
2020年 | 11篇 |
2019年 | 11篇 |
2018年 | 15篇 |
2017年 | 8篇 |
2016年 | 26篇 |
2015年 | 25篇 |
2014年 | 26篇 |
2013年 | 43篇 |
2012年 | 41篇 |
2011年 | 39篇 |
2010年 | 18篇 |
2009年 | 17篇 |
2008年 | 29篇 |
2007年 | 32篇 |
2006年 | 18篇 |
2005年 | 22篇 |
2004年 | 21篇 |
2003年 | 15篇 |
2002年 | 12篇 |
2000年 | 1篇 |
1998年 | 1篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 2篇 |
排序方式: 共有468条查询结果,搜索用时 15 毫秒
1.
Michael Remesic Giorgia Macedonio Adriano Mollica Frank Porreca Victor Hruby Yeon Sun Lee 《Bioorganic & medicinal chemistry》2018,26(12):3664-3667
In an effort to improve biphalin’s potency and efficacy at the µ-(MOR) and δ-opioid receptors (DOR), a series of cyclic biphalin analogues 1–5 with a cystamine or piperazine linker at the C-terminus were designed and synthesized by solution phase synthesis using Boc-chemistry. Interestingly, all of the analogues showed balanced opioid agonist activities at all opioid receptor subtypes due to enhanced κ-opioid receptor (KOR) activity. Our results indicate that C-terminal flexible linkers play an important role in KOR activity compared to that of the other cyclic biphalin analogues with a hydrazine linker. Among them, analogue 5 is a potent (Ki?=?0.27, 0.46, and 0.87?nM; EC50?=?3.47, 1.45, and 13.5?nM at MOR, DOR, and KOR, respectively) opioid agonist with high efficacy. Based on the high potency and efficacy at the three opioid receptor subtypes, the ligand is expected to have a potential synergistic effect on relieving pain and further studies including in vivo tests are worthwhile. 相似文献
2.
Antonio Rescigno Francesca Sollai Brunella Pisu Augusto Rinaldi Enrico Sanjust 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):207-218
The active site of tyrosinase is described with a view to depicting its interactions with substrates and inhibitors. Occurrence and mechanism(s) of tyrosinase-mediated browning of agrofood products are reviewed, with regard to both enzymic and chemical reactions, and their control, modulation, and inhibition. Technical and applicational implications are discussed. 相似文献
3.
4.
5.
Theanne Schiros Gregor Kladnik Deborah Prezzi Andrea Ferretti Giorgia Olivieri Albano Cossaro Luca Floreano Alberto Verdini Christine Schenck Marshall Cox Alon A. Gorodetsky Kyle Plunkett Dean Delongchamp Colin Nuckolls Alberto Morgante Dean Cvetko Ioannis Kymissis 《Liver Transplantation》2013,3(7):894-902
While the demonstrated power conversion efficiency of organic photovoltaics (OPVs) now exceeds 10%, new design rules are required to tailor interfaces at the molecular level for optimal exciton dissociation and charge transport in higher efficiency devices. We show that molecular shape‐complementarity between donors and acceptors can drive performance in OPV devices. Using core hole clock (CHC) X‐ray spectroscopy and density functional theory (DFT), we compare the electronic coupling, assembly, and charge transfer rates at the interface between C60 acceptors and flat‐ or contorted‐hexabenzocorone (HBC) donors. The HBC donors have similar optoelectronic properties but differ in molecular contortion and shape matching to the fullerene acceptors. We show that shape‐complementarity drives self‐assembly of an intermixed morphology with a donor/acceptor (D/A) ball‐and‐socket interface, which enables faster electron transfer from HBC to C60. The supramolecular assembly and faster electron transfer rates in the shape complementary heterojunction lead to a larger active volume and enhanced exciton dissociation rate. This work provides fundamental mechanistic insights on the improved efficiency of organic photovoltaic devices that incorporate these concave/convex D/A materials. 相似文献
6.
Daniela Calzia Laura Ottaggio Alessandro Cora Giorgia Chiappori Paola Cuccarolo Enrico Cappelli Alberto Izzotti Sara Tavella Paolo Degan 《Journal of cellular physiology》2020,235(4):3508-3518
Muscle loss is a major problem for many in lifetime. Muscle and bone degeneration has also been observed in individuals exposed to microgravity and in unloading conditions. C2C12 myoblst cells are able to form myotubes, and myofibers and these cells have been employed for muscle regeneration purposes and in myogenic regeneration and transplantation studies. We exposed C2C12 cells in an random position machine to simulate microgravity and study the energy and the biochemical challenges associated with this treatment. Simulated microgravity exposed C2C12 cells maintain positive proliferation indices and delay the differentiation process for several days. On the other hand this treatment significantly alters many of the biochemical and the metabolic characteristics of the cell cultures including calcium homeostasis. Recent data have shown that these perturbations are due to the inhibition of the ryanodine receptors on the membranes of intracellular calcium stores. We were able to reverse this perturbations treating cells with thapsigargin which prevents the segregation of intracellular calcium ions in the mitochondria and in the sarco/endoplasmic reticula. Calcium homeostasis appear a key target of microgravity exposure. In conclusion, in this study we reported some of the effects induced by the exposure of C2C12 cell cultures to simulated microgravity. The promising information obtained is of fundamental importance in the hope to employ this protocol in the field of regenerative medicine 相似文献
7.
Samanta Pino Raffaele Saladino Giorgia Botta Giovanna Costanzo 《Journal of biomolecular structure & dynamics》2013,31(1):6-7
Our laboratories analyze the synthetic reactions leading from formamide, NH2COH to prebiotically relevant compounds in the presence of catalysts. We have described the formation of all the biological nucleic bases of carboxylic acids of two aminoacids, and of condensing agents in the presence of catalysts of terrestrial origin (Saladino et al., 2012) and of one meteorite. Heat-dependent synthetic reactions from NH2COH lead to the synthesis of acyclonucleosides, not (yet?) to that of nucleosides [hurdle # 1]. Nucleosides are phosphorylated in the presence of NH2COH and a phosphate source yielding cyclic nucleotides as well. (Costanzo et al., 2007). 3′,5′-cyclic GMP nonenzymatically polymerizes up to at least 25mers, as shown by PAGE, MALDI ToF, 31P-NMR, specific RNAse and inhibitors analyses (Costanzo et al., 2012).The reaction is stimulated by 1,8-diazabicycloundec-7-ene and dimethylformamide. 3′,5′-cUMP does not polymerize spontaneously [hurdle # 2], 3′,5′-cAMP polymerizes very poorly [hurdle # 3]. We will discuss data on the polymerization of 3′,5′-cCMP and on a ribozyme activity exerted by oligomers neosynthesized from cyclic nucleotides. This approach finds its larger perspective in the evolutionary scenario depicted by Trifonov (2009). 相似文献
8.
Haiyan Chen Giorgia Valle Sandra Furlan Alma Nani Sandor Gyorke Michael Fill Pompeo Volpe 《The Journal of general physiology》2013,142(2):127-136
Release of Ca2+ from the sarcoplasmic reticulum (SR) drives contractile function of cardiac myocytes. Luminal Ca2+ regulation of SR Ca2+ release is fundamental not only in physiology but also in physiopathology because abnormal luminal Ca2+ regulation is known to lead to arrhythmias, catecholaminergic polymorphic ventricular tachycardia (CPVT), and/or sudden cardiac arrest, as inferred from animal model studies. Luminal Ca2+ regulates ryanodine receptor (RyR)2-mediated SR Ca2+ release through mechanisms localized inside the SR; one of these involves luminal Ca2+ interacting with calsequestrin (CASQ), triadin, and/or junctin to regulate RyR2 function.CASQ2-RyR2 regulation was examined at the single RyR2 channel level. Single RyR2s were incorporated into planar lipid bilayers by the fusion of native SR vesicles isolated from either wild-type (WT), CASQ2 knockout (KO), or R33Q-CASQ2 knock-in (KI) mice. KO and KI mice have CPVT-like phenotypes. We show that CASQ2(WT) action on RyR2 function (either activation or inhibition) was strongly influenced by the presence of cytosolic MgATP. Function of the reconstituted CASQ2(WT)–RyR2 complex was unaffected by changes in luminal free [Ca2+] (from 0.1 to 1 mM). The inhibition exerted by CASQ2(WT) association with the RyR2 determined a reduction in cytosolic Ca2+ activation sensitivity. RyR2s from KO mice were significantly more sensitive to cytosolic Ca2+ activation and had significantly longer mean open times than RyR2s from WT mice. Sensitivity of RyR2s from KI mice was in between that of RyR2 channels from KO and WT mice. Enhanced cytosolic RyR2 Ca2+ sensitivity and longer RyR2 open times likely explain the CPVT-like phenotype of both KO and KI mice. 相似文献
9.
Tiziana Bozzini Giorgia Botta Michela Delfino Silvano Onofri Raffaele Saladino Donatella Amatore Rossella Sgarbanti Lucia Nencioni Anna Teresa Palamara 《Bioorganic & medicinal chemistry》2013,21(24):7699-7708
Catechol derivatives with lipophilic properties have been selectively synthesized by tyrosinase in high yield avoiding long and tedious protection/deprotection steps usually required in traditional procedures. The synthesis was effective also with immobilized tyrosinase able to perform for more runs. The novel catechols were evaluated against influenza A virus, that continue to represent a severe threat worldwide. A significant antiviral activity was observed in derivatives characterized by antioxidant activity and long carbon alkyl side-chains, suggesting the possibility of a new inhibition mechanism based on both redox and lipophilic properties. 相似文献
10.
Giacomo De Luca Silvia Laura Bosello Francesca Augusta Gabrielli Giorgia Berardi Federico Parisi Manuela Rucco Giovanni Canestrari Francesco Loperfido Leonarda Galiuto Filippo Crea Gianfranco Ferraccioli 《PloS one》2016,11(4)
BackgroundArrhythmias are frequent in Systemic Sclerosis (SSc) and portend a bad prognosis, accounting alone for 6% of total deaths. Many of these patients die suddenly, thus prevention and intensified risk-stratification represent unmet medical needs. The major goal of this study was the definition of ECG indexes of poor prognosis.MethodsWe performed a prospective cohort study to define the role of 24h-ECG-Holter as an additional risk-stratification technique in the identification of SSc-patients at high risk of life-threatening arrhythmias and sudden cardiac death (SCD). One-hundred SSc-patients with symptoms and/or signs suggestive of cardiac involvement underwent 24h-ECG-Holter. The primary end-point was a composite of SCD or need for implantable cardioverter defibrillator (ICD).ResultsFifty-six patients (56%) had 24h-ECG-Holter abnormalities and 24(24%) presented frequent ventricular ectopic beats (VEBs). The number of VEBs correlated with high-sensitive cardiac troponin T (hs-cTnT) levels and inversely correlated with left-ventricular ejection fraction (LV-EF) on echocardiography. During a mean follow-up of 23.1±16.0 months, 5 patients died suddenly and two required ICD-implantation. The 7 patients who met the composite end-point had a higher number of VEBs, higher levels of hs-cTnT and NT-proBNP and lower LV-EF (p = 0.001 for all correlations). All these 7 patients had frequent VEBs, while LV-EF was not reduced in all and its range was wide. At ROC curve, VEBs>1190/24h showed 100% of sensitivity and 83% of specificity to predict the primary end-point (AUROC = 0.92,p<0.0001). Patients with VEBS>1190/24h had lower LV-EF and higher hs-cTnT levels and, at multivariate analysis, the presence of increased hs-cTnT and of right bundle branch block on ECG emerged as independent predictors of VEBs>1190/24h. None of demographic or disease-related characteristics emerged as predictors of poor outcome.ConclusionsVEBS>1190/24h identify patients at high risk of life-threatening arrhythmic complications. Thus, 24h-ECG-Holter should be considered a useful additional risk-stratification test to select SSc-patients at high-risk of SCD, in whom an ICD-implantation could represent a potential life-saving intervention. 相似文献