Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal Phenotype In Vivo

Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ). A good correlation between PI4KIIIβ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIβ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIβ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIβ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIβ is deleterious.     

高原地区慢性肺心病缓解期无严重低氧血症患者运动时氧疗作用的研究

目的探讨高原地区慢性肺心病缓解期不伴严重低氧血症患者运动时去氧饱和及评价氧疗对呼吸困难和从事运动能力的短期效果.方法 42例动脉氧分压(PaO2)≥50 mm Hg的患者测定肺功能、血气、呼吸肌功能后进行6 min步行试验(WT),每个患者在同一天完成3种WT.首先在呼吸空气条件下进行基础WT(BWT),然后随机吸压缩空气WT(CAWT),间隔1 h后进行吸氧WT(O2WT);或先O2WT,间隔1 h后再进行CAWT.每种试验结束后即刻测定动脉氧饱和度(SaO2)、呼吸肌功能.试验前、后用Borg评分标准评估呼吸困难指数.依据BWT时SaO2下降≥5%和＜5%将患者分为去氧饱和(DS)和无去氧饱和(NDS)两组.结果 BWT时DS者占69.0%,NDS者占31.0%.两组基础一秒钟用力呼气容积(FEV1)占预计值百分比(FEV1占预计值%)、动脉血二氧化碳(PaCO2)差异无显著性(P＞0.05),DS组PaO2、最大吸气压(PImax)、最大呼气压(PEmax)及最大跨膈压(Pdimax)显著低于NDS组(P＜0.05或＜0.01).DS组O2WT时,运动后SaO2、步行距离、PImax、PEmax及Pdimax均显著高于BWT、CAWT(P＜0.01),SaO2下降幅度、运动后Borg指数显著低于BWT、CAWT(P均＜0.01).NDS组除O2WT、运动后Borg指数和SaO2下降幅度与BWT、CAWT差异显著(P＜0.01)外,余各项指标差异均无显著性(P＞0.05).BWT时步行距离、运动后Borg指数与FEV1预计值%、SaO2、PImax、PEmax、Pdimax均呈显著正相关(P＜0.01或＜0.05),与PaCO2无相关(P＞0.05).结论多数高原慢性肺心病缓解期患者在运动时有明显去氧饱和,低氧血症越严重、呼吸肌功能越低,去氧饱和越明显.DS患者吸氧能避免去氧饱和、改善呼吸困难程度和提高运动能力.     

Bicoherence analysis of quadriceps electromyogram during isometric knee extension

Bicoherence analysis is applied to electromyogram (EMG) data for the vastus lateralis quadriceps muscle of 18 adult male subjects for isometric knee extension exercise. Bicoherence spectra display ridge-like features that are indicative of deterministic chaotic behaviour and similar to those reported for normal electrocardiogram and electroencephalogram bicoherence spectra. No other obvious features are visually identified within bicoherence spectra in response to the stimulus of isometric tension. Histograms that show the occurrence of constituent EMG frequencies associated with the strongest bicoherence display subtle fluctuations. Validation tests that include the analysis of white noise data show these fluctuations to most likely be a consequence of the normal time evolution of a deterministic chaotic process. The finding suggests that second-order phase coupling is not pronounced between any particular bands of constituent EMG frequencies for the vastus lateralis EMG generation process during the specified isometric task. Previous studies into bicoherence analysis of EMG data are not apparent in the literature for comparison. Since nonlinear processes are known, through mechanomyogram bicoherence analysis, to be significant within active muscle fibre twitch summation patterns, the finding does not exclude the potential for bicoherence analysis to complement standard EMG frequency analysis techniques in the area of sports rehabilitation and medicine. Further investigation is required to establish whether this potential exists. An introduction to bicoherence analysis theory is also presented.     

贵阳、遵义地区慢性肺原性心脏病调查——附3945例临床分析

调查了1978年5月至1985年4月贵阳、遵义地区3945例肺心病。发现该病住院患病率逐年提高,住院率占同期各类器质性心脏病的首位。年龄以61岁以上多见;原发病多为慢支炎并肺气肿;肺心病急发诱因以呼吸道感染最多见。住院病死率逐年降低,平均为9.98%,死因以呼吸衰竭占首位。本文就本病的一些实验室检查进行了统计分析。     

Antibacterial and anticandidal screening of Tunisian Citrullus colocynthis Schrad. from Medenine

Ethnopharmacological relevance

Resistance to current antibacterial drugs and the rise of opportunistic fungal infections are growing global concerns. Traditional medicine is a potential source of new antibacterials and antifungals. Citrullus colocynthis Schrad. (Cucurbitaceae) endemic in Southern Tunisia, is used in folk medicine against dermatological, gynaecological and pulmonary infections.

Aim of study

To assess in vitro antibacterial and anticandidal activity of aqueous and diluted acetone extracts of Citrullus colocynthis Schrad. MIC and MBC/MFC were determined for plant organs at different maturation stages.

Materials and methods

Citrullus colocynthis Schrad. was harvested and its identification was verified. Aqueous and diluted acetone extracts (from the plant's roots, stems, leaves and three maturation stages of its fruit and seeds) were screened for activity against Gram-negative and Gram-positive bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis)—and various Candida spp. (Candida glabrata, Candida albicans, Candida parapsilosis and Candida kreusei).

Results

All extracts showed activity against all strains. The highest MICs and MBCs/MFCs were obtained from the fruit aqueous extracts (MIC 0.10 mg/ml against Candida albicans and Candida glabrata, 0.20 mg/ml against Escherichia coli and Pseudomonas aeruginosa), lowest activity from the root extracts.

Conclusions

Citrullus colocynthis Schrad. shows antibacterial and anticandidal properties. The folk medicinal use as a broad-spectrum antimicrobial agent is validated.     

Preparation and evaluation of a new class of gene transfer reagents: poly(-alkylaminosiloxanes).

We report the evaluation of poly(-alkylaminosiloxane) as a novel class of polycationic DNA carriers. Controlled hydrolysis of mono- and di-aminoalkylmethyldimethoxysilane provided a wide range of defined oligomeric mixtures. Basic hydrolysis conditions yielded mixtures composed mainly of cyclic and long linear oligomers, while under acidic conditions mainly short-linear oligomers were derived. They all efficiently interacted with plasmid DNA as revealed by electron microscopy and DNA retardation assays. However, only diamine-based oligomers prepared under basic conditions were able to mediate substantial levels of DNA transfection in human HeLa cells. SiDA1b, prepared by basic hydrolysis of 3-(2-aminoethylamino)propyl-methyl-dimethoxysilane, was found to be at least as efficient as the frequently used cationic transfection agents DOTAP and polyethylenimine (PEI). The transfection activity was sensitive to bafilomycin A1, suggesting a mechanism that depends on proton capture during the acidification process associated with endocytosis.