Antimalarial drugs impact chemical messenger secretion by blood platelets

BackgroundAdvances in antimalarial drug development are important for combating malaria. Among the currently identified antimalarial drugs, it is suggested that some interact directly with the malarial parasites while others interact indirectly with the parasites. While this approach leads to parasite elimination, little is known about how these antimalarial drugs impact immune cells that are also critical in malarial response.MethodsHerein, the effects of two common antimalarial drugs, chloroquine and quinine, on platelets were explored at both the bulk level, using high performance liquid chromatography, and the single cell level, using carbon-fiber microelectrode amperometry, to characterize any changes in chemical messenger secretion.ResultsThe data reveal that both drugs cause platelet activation and reduce the number of platelet exocytosis events as well as delay fusion pore opening and closing.ConclusionsThis work demonstrates how chloroquine and quinine quantitatively and qualitatively impact in vitro platelet function.General significanceOverall, the goal of this work is to promote understanding about how antimalarial drugs impact platelets as this may affect antimalarial drug development as well as therapeutic approaches to treat malarial infection.     

The fitness costs and benefits of trisomy of each Candida albicans chromosome

Candida albicans is a prevalent human fungal pathogen. Rapid genomic change, due to aneuploidy, is a common mechanism that facilitates survival from multiple types of stresses including the few classes of available antifungal drugs. The stress survival of aneuploids occurs despite the fitness costs attributed to most aneuploids growing under idealized lab conditions. Systematic study of the aneuploid state in C. albicans has been hindered by the lack of a comprehensive collection of aneuploid strains. Here, we describe a collection of diploid C. albicans aneuploid strains, each carrying one extra copy of each chromosome, all from the same genetic background. We tested the fitness of this collection under several physiological conditions including shifts in pH, low glucose, oxidative stress, temperature, high osmolarity, membrane stress, and cell wall stress. We found that most aneuploids, under most conditions, were less fit than their euploid parent, yet there were specific conditions under which specific aneuploid isolates provided a fitness benefit relative to the euploid parent strain. Importantly, this fitness benefit was attributable to the change in the copy number of specific chromosomes. Thus, C. albicans can tolerate aneuploidy of each chromosome and some aneuploids confer improved growth under conditions that the yeast encounters in its host niches.     

The transmission-blocking effects of antimalarial drugs revisited: fitness costs and sporontocidal effects of artesunate and sulfadoxine-pyrimethamine

Assays used to evaluate the transmission-blocking activity of antimalarial drugs are largely focused on their potential to inhibit or reduce the infectivity of gametocytes, the blood stages of the parasite that are responsible for the onward transmission to the mosquito vector. For this purpose, the drug is administered concomitantly with gametocyte-infected blood, and the results are evaluated as the percentage of reduction in the number of oocysts in the mosquito midgut. We report the results of a series of experiments that explore the transmission-blocking potential of two key antimalarial drugs, artesunate and sulfadoxine-pyrimethamine, when administered to mosquitoes already infected from a previous blood meal. For this purpose, uninfected mosquitoes and mosquitoes carrying a 6 day old Plasmodium relictum infection (early oocyst stages) were allowed to feed either on a drug-treated or an untreated host in a fully factorial experiment. This protocol allowed us to bypass the gametocyte stages and establish whether the drugs have a sporontocidal effect, i.e. whether they are able to arrest the ongoing development of oocysts and sporozoites, as would be the case when a mosquito takes a post-infection treated blood meal. In a separate experiment, we also explored whether a drug-treated blood meal impacted key life history traits of the mosquito relevant for transmission, and if this depended on their infection status. Our results showed that feeding on an artesunate- or sulfadoxine-pyrimethamine-treated hosts has no epidemiologically relevant effects on the fitness of infected or uninfected mosquitoes. In contrast, when infected mosquitoes fed on an sulfadoxine-pyrimethamine-treated host, we observed both a significant increase in the number of oocysts in the midgut, and a drastic decrease in both sporozoite prevalence (?30%) and burden (?80%) compared with the untreated controls. We discuss the potential mechanisms underlying these seemingly contradictory results and contend that, provided the results are translatable to human malaria, the potential epidemiological and evolutionary consequences of the current preventive use of sulfadoxine-pyrimethamine in malaria-endemic countries could be substantial.     

不同营养条件下甜菜夜蛾幼虫感染核型多角体病毒的敏感性及取食趋性

为探讨不同营养条件下甜菜夜蛾Spodoptera exigua对甜菜夜蛾核型多角体病毒(Spodoptera exigua multiple nucleopolyhedrovirus,SeMNPV)的敏感性及取食行为响应,本研究通过改变甜菜夜蛾人工饲料配方建立高蛋白低糖(简称高蛋白)、中蛋白中糖(简称中蛋白)、低蛋白高糖(简称低蛋白)3种营养品系,观察不同营养品系幼虫对SeMNPV的敏感性,以及染毒前后对不同营养饲料的取食趋性.结果 显示,高蛋白、中蛋白、低蛋白3种营养品系中,SeMNPV对甜菜夜蛾初孵幼虫的半数致死浓度(LC50)分别是1.76×105 PIB/mL、2.85×105 PIB/mL和2.10×104 PIB/mL.统计分析显示,中蛋白品系的LC50显著高于低蛋白品系,高蛋白品系的LC50同其余两种品系相比无显著性差异.以8×105 PIB/mL浓度的病毒饲喂甜菜夜蛾初孵幼虫,3种营养品系的半数致死时间(LT50)分别是6.07 d、6.85 d和5.20 d,中蛋白品系的存活时间显著长于低蛋白品系,高蛋白品系的LT50同其余两种品系相比无显著性差异.未染毒状态下,低龄幼虫偏向蛋白质含量较高的饲料,而高龄幼虫则偏向于高糖的饲料;染毒状态下,甜菜夜蛾各龄期幼虫都偏向于取食蛋白质含量较高的饲料.以上研究结果表明,营养条件的变化可以显著影响甜菜夜蛾幼虫对SeMNPV的敏感性,染毒后幼虫明显偏向于蛋白质含量高的饲料,推测蛋白质可能有助于提高甜菜夜蛾幼虫对SeMNPV的抵抗力.     

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects.     

The tyrosine kinase v-Src modifies cytotoxicities of anticancer drugs targeting cell division

v-Src oncogene causes cell transformation through its strong tyrosine kinase activity. We have revealed that v-Src-mediated cell transformation occurs at a low frequency and it is attributed to mitotic abnormalities-mediated chromosome instability. v-Src directly phosphorylates Tyr-15 of cyclin-dependent kinase 1 (CDK1), thereby causing mitotic slippage and reduction in Eg5 inhibitor cytotoxicity. However, it is not clear whether v-Src modifies cytotoxicities of the other anticancer drugs targeting cell division. In this study, we found that v-Src restores cancer cell viability reduced by various microtubule-targeting agents (MTAs), although v-Src does not alter cytotoxicity of DNA-damaging anticancer drugs. v-Src causes mitotic slippage of MTAs-treated cells, consequently generating proliferating tetraploid cells. We further demonstrate that v-Src also restores cell viability reduced by a polo-like kinase 1 (PLK1) inhibitor. Interestingly, treatment with Aurora kinase inhibitor strongly induces cell death when cells express v-Src. These results suggest that the v-Src modifies cytotoxicities of anticancer drugs targeting cell division. Highly activated Src-induced resistance to MTAs through mitotic slippage might have a risk to enhance the malignancy of cancer cells through the increase in chromosome instability upon chemotherapy using MTAs.     

2015年至2019年辽宁省某医院血培养病原菌分布及耐药分析

分析2015年至2019年辽宁省人民医院血培养分离菌的科室分布及耐药情况,为临床提供数据参考。利用Whonet5.6软件对2015年至2019年辽宁省人民医院血培养临床数据进行分析。血培养阳性率为12.3%,共分离病原菌1 266株,其中革兰阴性菌546株、革兰阳性菌649株、真菌71株;革兰阴性菌主要为大肠埃希菌(Escherichia coli, Eco)占19.1%(234/1 226)和肺炎克雷伯菌(Klebsiella pneumoniae, Kpn)占12.6%(155/1 226);革兰阳性菌主要为人葡萄球菌(Staphylococcushomini, Sho)占13.3%(98/1 226)和表皮葡萄球菌(Staphylococcus epidermidis)占9.7%(82/1 226)。血培养阳性率较高的科室分别为重症医学科、普外科、呼吸内科。耐甲氧西林的金黄色葡萄球菌(Staphylococcus aureus,Sau)的检出率为40%、未检出对万古霉素耐药的金黄色葡萄球菌和肠球菌(Enterococcus)。肠杆菌科对碳青霉烯类抗生素的耐药率低于25%。鲍曼不动杆菌(Acinetobacter baumannii, Aba)对碳青霉烯类抗生素的耐药率达到80%以上。临床应重视血培养标本的送检和细菌耐药监测,合理使用抗生素,早期控制血流感染,降低患者的病死率。