Modulation of acetylcholine receptor desensitization by forskolin is independent of cAMP

Biochemical and electrophysiological studies suggest that adenosine 3',5'-monophosphate (cAMP)-dependent phosphorylation of the nicotinic acetylcholine receptor channel is functionally significant because it modifies the receptor's rate of desensitization to acetylcholine. In studies that support this conclusion researchers have used forskolin to stimulate cAMP-dependent phosphorylation in intact muscle. It is now shown that although forskolin facilitated desensitization in voltage-clamped rat muscle, this effect was not correlated with the abilities of forskolin and forskolin analogs to activate adenylate cyclase or phosphorylate the receptor. Furthermore, elevation of intracellular cAMP or addition of the catalytic subunit of A-kinase failed to alter desensitization. Therefore, in intact skeletal muscle, cAMP-dependent phosphorylation does not modulate desensitization.     

Structural analysis of the mechanism of adenovirus binding to its human cellular receptor, CAR

Binding of virus particles to specific host cell surface receptors is known to be an obligatory step in infection even though the molecular basis for these interactions is not well characterized. The crystal structure of the adenovirus fiber knob domain in complex with domain I of its human cellular receptor, coxsackie and adenovirus receptor (CAR), is presented here. Surface-exposed loops on knob contact one face of CAR, forming a high-affinity complex. Topology mismatches between interacting surfaces create interfacial solvent-filled cavities and channels that may be targets for antiviral drug therapy. The structure identifies key determinants of binding specificity, which may suggest ways to modify the tropism of adenovirus-based gene therapy vectors.     

木犀草素对对乙酰氨基酚诱导肝损伤的保护作用

【目的】基于内质网应激（ERS）和氧化应激途径,探讨木犀草素（luteolin）对对乙酰氨基酚（APAP）诱导的肝损伤的保护效果及其潜在的作用机制。【方法】将48只昆明小白鼠随机分为6组,分别为正常对照组（NC）、木犀草素对照组（MD）、APAP肝损伤模型组（APAP）以及木犀草素低、中、高剂量组（ML、MM、MH）,每组8只小鼠,NC和MD组腹腔注射生理盐水,其余各组小鼠按300 mg/kg的剂量腹腔注射APAP注射液,每天2次,连续注射4 d,给药4 d后NC组和APAP组灌胃生理盐水,MD、ML、MM、MH小鼠分别按照100,25,50,100 mg/kg的剂量灌胃木犀草素药液,每天2次,连续灌胃3 d,最后一次灌胃12 h后,分别检测小鼠血液中的谷丙转氨酶（ALT）和谷草转氨酶（AST）活性以及肝脏中的氧化应激指标（超氧化物歧化酶（SOD）活性及过氧化氢（H₂O₂）、谷胱甘肽（GSH）和丙二醛（MDA）含量）,在显微镜下观察各组小鼠肝组织的病理变化,并采用探针药物法测定肝脏微粒体细胞色素P450 2E1酶(CYP2E1)活性,采用qRT-PCR检测CYP2E1 mRNA表达水平,用Western Blot检测肝组织葡萄糖调节蛋白78（GRP78）、增强子CCAAT结合蛋白同源蛋白（CHOP）、CYP2E1蛋白表达水平。【结果】与NC组相比,APAP模型组的ALT和AST活性极显著升高,MD组上述2种酶活性无显著变化。与APAP模型组相比,MM、MH组ALT和AST活性显著或极显著下降。与APAP模型组相比,ML、MM、MH组的GSH含量和SOD活性均明显增加,MDA和H₂O₂含量均明显降低。小鼠肝组织病理形态显微观察结果表明,MM、MH组可以改善APAP导致的肝索消失以及肝细胞排列散乱和细胞核溶解等病理症状。探针药物法测定结果显示,0.1,0.01和0.001 mg/mL的木犀草素可以显著降低CYP2E1活性。qRT-PCR和Western Blot结果显示,木犀草素可以显著或极显著降低CYP2E1基因及其蛋白的表达水平,极显著降低GRP78和CHOP蛋白表达水平。【结论】木犀草素具有明显的抗APAP诱导的肝损伤作用,其作用机理可能是通过抑制CYP2E1的表达、减轻氧化应激和内质网应激水平,从而减轻APAP诱导的肝损伤。     

Modulation of rod-cone coupling by light

Although electrical coupling between rods and cones in the retina has been assumed to be static, it has now been shown that rod-cone coupling can be strengthened by light. Increment threshold measurements reveal that cone input to rods increases progressively as background light becomes brighter. Current injection into cones produces larger responses in adjacent rods in the presence of background light than in darkness. Weak coupling under dark-adapted conditions facilitates synaptic transmission of small rod signals, and strong coupling under light-adapted conditions enhances transmission of large cone signals.     

Modulation of brain reward circuitry by leptin

Leptin, a hormone secreted by fat cells, suppresses food intake and promotes weight loss. To assess the action of this hormone on brain reward circuitry, changes in the rewarding effect of lateral hypothalamic stimulation were measured after leptin administration. At five stimulation sites near the fornix, the effectiveness of the rewarding electrical stimulation was enhanced by chronic food restriction and attenuated by intracerebroventricular infusion of leptin. In contrast, the rewarding effect of stimulating neighboring sites was insensitive to chronic food restriction and was enhanced by leptin in three of four cases. These opposing effects of leptin may mirror complementary changes in the rewarding effects of feeding and of competing behaviors.     

血清微小RNA在中药肝毒性临床前评价中的应用研究

通过对19种具有潜在肝脏毒性的中草药进行临床前安全性评价,在观测体重、摄食量、血清生化指标、脏器系数与肝脏组织病理学改变的同时,探讨血清微小RNA(miRNA)作为新型候选标志物在中草药肝损伤诊断中的应用价值。结果表明:与溶剂对照组相比,血清miRNA-122水平显著升高的给药组有6组,而血清谷丙转氨酶(ALT)和谷草转氨酶(AST)水平显著升高的分别为2组和3组,其中五倍子组表现为急性药源性肝损伤。在血清miRNA-122的时间相关性和剂量相关性分析中,与血清ALT和AST相比,血清miRNA-122呈现出更高的敏感性,表现为更早期和更大幅度的显著升高。说明血清miRNA-122可作为中草药肝损伤的新型候选诊断标志物,与肝脏组织病理学改变具有良好的相关性,且较传统血清生化学指标更为敏感。     

Modulation of folding pathways of exported proteins by the leader sequence

Leader peptides that function to direct export of proteins through membranes have some common features but exhibit a remarkable sequence diversity. Thus there is some question whether leader peptides exert their function through conventional stereospecific protein-protein interaction. Here it is shown that the leader peptides retarded the folding of precursor maltose-binding protein and ribose-binding protein from Escherichia coli. This kinetic effect may be crucial in allowing precursors to enter the export pathway.     

Modulation of hurricane activity in the gulf of mexico by the madden-julian oscillation

The Madden-Julian oscillation (MJO) is a large-scale episodic modulation of tropical winds and precipitation that travels eastward from Asia to America, with a characteristic repeat time of 30 to 60 days. Here it is shown that when MJO wind anomalies in the lower troposphere of the eastern Pacific are westerly, Gulf of Mexico and western Caribbean hurricane genesis is four times more likely than when the MJO winds are easterly. Accurate predictions of the MJO may lead to improved long-range forecasts of tropical cyclone activity.     

Modulation of memory processing by cholecystokinin: dependence on the vagus nerve

Allowing mice access to food immediately after an aversive training session enhances memory retention. Cholecystokinin-octapeptide (CCK-8), which is a gastrointestinal hormone released during feeding, also enhances memory retention when administered intraperitoneally. This memory-enhancing effect of CCK-8 is blocked when the vagus nerve is cut, indicating that CCK-8 may produce its effect on memory retention by activating ascending fibers in the vagus nerve. Thus, CCK-8, a peripherally acting peptide, may mediate the memory-enhancing effects of feeding.     

Modulation of the metastatic capability in B16 melanoma by cell shape

The lung colonization of B16-F1 cells grown in flat and spherical configurations was studied. Cells cultivated in vitro as spheroids on a nonadhesive substrate expressed in a reversible fashion a marked increase in their propensity to establish metastases. The altered metastatic capability was accompanied by a reversible reduction in the accessibility of cell surface proteins to external iodination and by a dramatic decrease in the synthesis of vimentin.     

Modulation of the copulatory sequence of the male rat by a schedule of reinforcement

Copulating male rats were permitted a maximum of seven intromissions in which to ejaculate. This experimental constraint of the male rat's sexual behavior produced an increase in the number of sessions in which the male ejaculated before the seventh intromrission. This species-specific behavior pattern is therefore susceptible to environmental conditioning.     

Modulation of human visual cortex by crossmodal spatial attention

A sudden touch on one hand can improve vision near that hand, revealing crossmodal links in spatial attention. It is often assumed that such links involve only multimodal neural structures, but unimodal brain areas may also be affected. We tested the effect of simultaneous visuo-tactile stimulation on the activity of the human visual cortex. Tactile stimulation enhanced activity in the visual cortex, but only when it was on the same side as a visual target. Analysis of effective connectivity between brain areas suggests that touch influences unimodal visual cortex via back-projections from multimodal parietal areas. This provides a neural explanation for crossmodal links in spatial attention.     

Modulation of oscillatory neuronal synchronization by selective visual attention

In crowded visual scenes, attention is needed to select relevant stimuli. To study the underlying mechanisms, we recorded neurons in cortical area V4 while macaque monkeys attended to behaviorally relevant stimuli and ignored distracters. Neurons activated by the attended stimulus showed increased gamma-frequency (35 to 90 hertz) synchronization but reduced low-frequency (<17 hertz) synchronization compared with neurons at nearby V4 sites activated by distracters. Because postsynaptic integration times are short, these localized changes in synchronization may serve to amplify behaviorally relevant signals in the cortex.     

Functional analysis of CAR, the target sequence for the Rev protein of HIV-1

Expression of high levels of the structural proteins of the human immunodeficiency virus type 1 (HIV-1) requires the presence of the protein encoded by the rev open reading frame (Rev) and its associated target sequence CAR (cis anti-repression sequence) which is present in the env region of viral RNA. Extensive mutagenesis demonstrated that CAR has a complex secondary structure consisting of a central stem and five stem/loops. Disruption of any of these structures severely impaired the Rev response, but many of the stem/loops contain material that was unnecessary for Rev regulation and must be retained in these structures to avoid disturbing adjacent structures critical for CAR function. Probably no more than two of the described structural components are involved in sequence-specific recognition by regulatory proteins.     

基于CAR模型国内A股市场反应不足的实证分析

主要关注的主体异象为反应不足,在已有的HS模型基础上,对我国IPO改革背景下的证券市场投资策略进行了实证研究.实证过程中主要采用了市场调整模型计算累计超额收益率,并根据样本条件划分适当的形成期和检验期.在此基础上,以经典的“赢者组合”和“输者组合”方法对实证数据进行分析,最终发现A股市场中存在反应不足的金融异象.     

南方贮木场原木库存量CAR模型的研究

本文主要论述利用多变量ＣＡＲ模型预报南方贮木场原木库存量动态变化，并用微机模拟．结果表明：该方法模型预报精度高，且应用方便．     

猪组成型雄烷受体激动剂高通量药物筛选模型的建立

构建猪组成型雄烷受体(pgCAR)激动剂体外高通量筛选模型。利用RT-PCR技术从猪肝脏总RNA中扩增出pgCAR基因序列,将测序后正确的pgCAR片段连接到pcDNA 3.1 vector上构建表达载体pcDNA 3.1-CAR;将合成的5个拷贝NR1(Nuclear receptor sites)插入PGL3-TK-promoter构成报告质粒(NR1)5-TK-luc,与PRL-TK报告质粒构成双荧光报告系统。用PEI转染技术将表达载体与报告质粒共转染HepG 2细胞株中,通过检测荧光素酶基因表达状况评价具有生物活性配体化合物对pgCAR激动活性。阳性药苯妥英钠明显提高荧光素酶的表达,最大上调倍增数可达约2.53倍,并且在一定浓度下阳性药与相对荧光酶的活性表达有较好量效关系。