hERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome

Potassium channels encoded by hERG (human ether-à-go-go-related gene) underlie the cardiac rapid delayed rectifier K⁺ current (I_Kr) and hERG mutations underpin clinically important repolarization disorders. Virtually all electrophysiological investigations of hERG mutations have studied exclusively the hERG1a isoform; however, recent evidence indicates that native I_Kr channels may be comprised of hERG1a together with the hERG1b variant, which has a shorter N-terminus. Here, for the first time, electrophysiological effects were studied of a gain-of-function hERG mutation (N588K; responsible for the ‘SQT1’ variant of the short QT syndrome) on current (I_hERG1a/1b) carried by co-expressed hERG1a/1b channels. There were no significant effects of N588K on I_hERG1a/1b activation or deactivation, but N588K I_hERG1a/1b showed little inactivation up to highly positive voltages (?+80 mV), a more marked effect than seen for hERG1a expressed alone. I_hERG1a/1b under action potential voltage-clamp, and the effects on this of the N588K mutation, also showed differences from those previously reported for hERG1a. The amplified attenuation of I_hERG inactivation for the N588K mutation reported here indicates that the study of co-expressed hERG1a/1b channels should be considered when investigating clinically relevant hERG channel mutations, even if these reside outside of the N-terminus region.     

The Poetics of Purpose

Hackles have been raised in biosemiotic circles by T. L. Short’s assertion that semiosis, as defined by Peirce, entails “acting for purposes” and therefore is not found below the level of the organism (2007a:174–177). This paper examines Short’s teleology and theory of purposeful behavior and offers a remedy to the disagreement. Remediation becomes possible when the issue is reframed in the terms of the complexity sciences, which allows intentionality to be understood as the interplay between local and global aspects of a system within a system. What is called “acting for purposes” is not itself a type of behavior so much as a relationship between a dynamic system that “exists for a purpose” and its microprocesses that “serve purposes.” The “intentional object” of philosophy is recast here as the holistic self-organized dynamics of a system, which exists for the purpose of self-maintenance, and that constrains the parts’ behaviors, which serve the purpose of forming the system. (A “system” can be any emergent, e.g. an abiotic form, an adapted species, a self, a conditioned response, thought, or a set of ideas.) The self-organized whole, which is represented to the parts in their own constrained behaviors, assumes the guiding function so long attributed to the mysterious “intentional object.” If emergent self-causation is not disallowed, creative originality, as well as directionality, becomes part of the definition of purposeful behavior. Thus, key tools used here, required for understanding emergence, come from poetics rather than semoitics. In the microprocesses of self-organization, I find what I call “accidental” indices and icons — which are poetic in the sense that they involve mere metonymic contiguity and metaphoric similarity — and which are preferentially selected under constrained conditions allowing radically new connections to habituate into an “intentional” self-organized system that, not coincidentally, has some of the emergent characteristics of a conventional symbolic system.

shRNA Expression Plasmids Generated by a Novel Method Efficiently Induce Gene-Specific Knockdown in a Silkworm Cell Line

RNAi knockdown by using shRNA expression plasmids is widely used to determine the function of individual genes in mammals. Here we developed a simple method to create an IR DNA in a U6 small nuclear RNA promoter-based parent vector using a single-stranded IR DNA with short hairpin structure and Bst DNA polymerase. Furthermore, we demonstrated that the shRNA expression plasmids constructed by our method effectively induced target-specific RNAi in the silkworm cell line. We also found that sequence preference in the silkworm cell line was much lower than in mammalian cells and shRNA-induced RNAi was influenced by the length of the stem region.     

Protein S-Thiolation by Glutathionylspermidine (Gsp): THE ROLE OF ESCHERICHIA COLI Gsp SYNTHETASE/AMIDASE IN REDOX REGULATION*

Certain bacteria synthesize glutathionylspermidine (Gsp), from GSH and spermidine. Escherichia coli Gsp synthetase/amidase (GspSA) catalyzes both the synthesis and hydrolysis of Gsp. Prior to the work reported herein, the physiological role(s) of Gsp or how the two opposing GspSA activities are regulated had not been elucidated. We report that Gsp-modified proteins from E. coli contain mixed disulfides of Gsp and protein thiols, representing a new type of post-translational modification formerly undocumented. The level of these proteins is increased by oxidative stress. We attribute the accumulation of such proteins to the selective inactivation of GspSA amidase activity. X-ray crystallography and a chemical modification study indicated that the catalytic cysteine thiol of the GspSA amidase domain is transiently inactivated by H₂O₂ oxidation to sulfenic acid, which is stabilized by a very short hydrogen bond with a water molecule. We propose a set of reactions that explains how the levels of Gsp and Gsp S-thiolated proteins are modulated in response to oxidative stress. The hypersensitivities of GspSA and GspSA/glutaredoxin null mutants to H₂O₂ support the idea that GspSA and glutaredoxin act synergistically to regulate the redox environment of E. coli.     

甘蓝型油菜无花瓣矮秆新种质APL03的选育

以正常四瓣双低甘蓝型油菜品系ZH004为母本、无花瓣种质APL01为父本杂交,对无花瓣及矮秆等性状进行多代定向选择,育成APL03新种质。该种质群体无花瓣株率迭100％,单株无花瓣度〉90％,植株高度130—140cm,单株有效角果数〉400个,种子含油率高达43％-47％,兼有抗倒伏、抗耐菌核病等特性,成为培育适于全程机械化作业栽培油菜新品种的基础材料。     

电针治疗老年性痴呆对其认知电位影响的临床研究

目的：本研究旨在临床观察针刺治疗对老年性痴呆（AD）患者P300认知电位的影响。方法与结果：马P300引入针刺治疗AD的研究领域,发现AD患者其认知电位P300的N2,P3潜伏期较正常组明显延长、波幅明显降低。针刺有明显兴奋AD患者认知电位P300的作用。结论：P300可作为AD的诊断与疗效评定指标,针刺疗法可以影响AD患者认知电位P300。     

Characterization of the short neuropeptide F receptor from Drosophila melanogaster

A seven transmembrane G-protein coupled receptor has been cloned from Drosophila melanogaster. This receptor shows structural similarities to vertebrate Neuropeptide Y(2) receptors and is activated by endogenous Drosophila peptides, recently designated as short neuropeptide Fs (sNPFs). sNPFs have so far been found in neuroendocrine tissues of four other insect species and of the horseshoe crab. In locusts, they accelerate ovarian maturation, and in mosquitoes, they inhibit host-seeking behavior. Expression analysis by RT-PCR shows that the sNPF receptor (Drm-sNPF-R) is present in several tissues (brain, gut, Malpighian tubules and fat body) from Drosophila larvae as well as in ovaries of adult females. All 4 Drosophila sNPFs clearly elicited a calcium response in receptor expressing mammalian Chinese hamster ovary cells. The response is dose-dependent and appeared to be very specific. The short NPF receptor was not activated by any of the other tested arthropod peptides, not even by FMRFamide-related peptides (also ending in RFamide), indicating that the Arg residue at position 4 from the amidated C-terminus appears to be crucial for the response elicited by the sNPFs.     

多巴胺D1和D2受体拮抗剂对针刺镇痛的增强

在兔K~+透入测痛模型上,应用高选择性的D_1或D_2受体拮抗剂、观察其对针刺镇痛的影响。结果表明,iv.D_2受体拮抗剂氟哌啶醇和氯氮平加强针刺镇痛,且与剂量有关。icv.D_2受体拮抗剂domperidone和舒必利及D_1受体拮抗剂SCH23390,亦能加强针刺镇痛。本文对D_1和D_2受体拮抗剂在针刺镇痛中的作用进行了讨论。     

开窍醒神补虚通络针刺治疗对脑卒中后偏瘫患者血液流变学和Notch信号通路的影响

摘要 目的：探讨开窍醒神补虚通络针刺治疗对脑卒中后偏瘫患者血液流变学和Notch信号通路的影响。方法：选取东莞市中医院2020年12月至2022年7月期间收治的110例脑卒中后偏瘫患者,按照随机数字表法分为观察组（55例,脑卒中常规康复治疗结合开窍醒神补虚通络针刺治疗）和对照组（55例,脑卒中常规康复治疗）。对比两组各项量表评分[日常生活能力量表（ADL）、美国国立卫生研究院卒中量表（NIHSS）、Fugl-Meyer量表（FMA）]、平衡功能[前后倾斜角（F-BIA）、左右倾斜角（L-RIA）、Berg平衡量表（BBS）]、血液流变学和Notch信号通路相关指标。结果：与对照组相比,观察组干预4周后ADL、FMA评分更高,NIHSS评分更低（P<0.05）。与对照组相比,观察组干预4周后BBS、F-BIA、L-RIA更高（P<0.05）。与对照组相比,观察组干预4周后全血高切黏度、纤维蛋白原、血浆黏度、全血低切黏度更低（P<0.05）。与对照组相比,观察组干预4周后Notch1信使核糖核酸（mRNA）、Notch2 mRNA、Jagged1 mRNA、Jagged2 mRNA更低（P<0.05）。结论：开窍醒神补虚通络针刺治疗可有效改善脑卒中后偏瘫患者的日常活动能力、神经功能、运动功能和平衡功能,改善血液流变学和Notch信号通路。