Restricted access: spatial sequestration of damaged proteins during stress and aging

The accumulation of damaged and aggregated proteins is a hallmark of aging and increased proteotoxic stress. To limit the toxicity of damaged and aggregated proteins and to ensure that the damage is not inherited by succeeding cell generations, a system of spatial quality control operates to sequester damaged/aggregated proteins into inclusions at specific protective sites. Such spatial sequestration and asymmetric segregation of damaged proteins have emerged as key processes required for cellular rejuvenation. In this review, we summarize findings on the nature of the different quality control sites identified in yeast, on genetic determinants required for spatial quality control, and on how aggregates are recognized depending on the stress generating them. We also briefly compare the yeast system to spatial quality control in other organisms. The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging.     

Time optimal control of an additional food provided predator–prey system with applications to pest management and biological conservation

Use of additional food has been widely recognized by experimental scientists as one of the important tools for biological control such as species conservation and pest management. The quality and quantity of additional food supplied to the predators is known to play a vital role in the controllability of the system. The present study is continuation of a previous work that highlights the importance of quality and quantity of the additional food in the dynamics of a predator–prey system in the context of biological control. In this article the controllability of the predator–prey system is analyzed by considering inverse of quality of the additional food as the control variable. Control strategies are offered to steer the system from a given initial state to a required terminal state in a minimum time by formulating Mayer problem of optimal control. It is observed that an optimal strategy is a combination of bang-bang controls and could involve multiple switches. Properties of optimal paths are derived using necessary conditions for Mayer problem. In the light of the results evolved in this work it is possible to eradicate the prey from the eco-system in the minimum time by providing the predator with high quality additional food, which is relevant in the pest management. In the perspective of biological conservation this study highlights the possibilities to drive the state to an admissible interior equilibrium (irrespective of its stability nature) of the system in a minimum time.     

Quality Control of Fungal and Viral Biocontrol Agents - Assurance of Product Performance

An essential feature of the production of all microbial control agents is an effective quality control system. Well-defined product specifications with accompanying quality control procedures help to maximize product performance, ensure product safety, standardize manufacturing costs and reduce the risks of supply failure, thus building user confidence. A production system that does not have a quality control system is one whose output is uncontrolled and a lack of thorough quality feedback can result in batches of product with variable concentrations of active agent. This results in products with variable performance leading to control failures by users and serious loss of user confidence. Strict quality control procedures are not only essential for product consistency, but also for safety. Where quality control is inadequate, microbial contamination of the final product is inevitable. In most of such cases this will merely lead to a loss of efficacy due to dilution of the active ingredient by competing microorganisms, but also the potential of producing human pathogens must be ruled out. Recognition of contaminants and quantification of the degree of contamination are therefore important in determining any possible risk to human health. Many low technology production systems in use around the world have minimal or no quality control procedures. This is unacceptable and can damage the reputation of microbial control in addition to possibly posing health risks to those that produce or are exposed to the product. Two case studies from developing countries, are used to illustrate how the lack of quality control procedures can lead to the production of low viability, highly contaminated products with low or negligible concentrations of the active ingredient. However, it is also demonstrated that low technology production systems in developing countries can produce high quality products, provided appropriate quality control procedures are firmly implemented. It must be recognized that quality control procedures can be more complex and technologically demanding than the production procedures themselves, but it is largely on the effectiveness of these control procedures that the long-term acceptability of fungal and viral products depends. This paper details the quality control procedures considered necessary in the mass production of fungi and viruses for use as biocontrol agents, and attempts to suggest reasonable standards that can be achieved by all producers.     

城市生态观测:质量控制对象、体系和规范编制

城市生态系统长期观测是开展城市生态安全评价和制定人居环境健康管理政策的基础。为了确保城市生态观测数据的准确性和科学性,通过辨识城市生态观测质量控制的概念,基于"人机料法环"理论构建了城市生态观测质量控制体系,结合城市生态观测质量控制相关规范的编制与实施现状,探讨了城市生态观测质量控制规范的编制技术。结果表明：（1）城市生态观测质量控制是面向城市生态观测内容（要素、空间格局、功能、服务）,为保证生态观测全过程质量要求、提高生态观测结果的准确性而实施的质量控制活动和措施。（2）城市生态观测质量控制体系可从对象和过程这两个维度进行界定：对象维度方面,包括"人"-人员、"机"-仪器设备、"料"-数据、"法"-文件和"环"-观测过程5个方面;过程维度方面,涵盖城市生态观测全过程,包括城市生态观测前期准备工作、观测过程中以及观测后的数据录入、审核与评价等环节的质量控制措施。（3）我国已发布的生态观测相关技术标准中,发布的时间越晚,质量控制内容越完整,目前生态观测相关标准共102则,仅38则明确提出了质量控制具体要求。（4）《城市生态观测质量控制规范》编制需包含质量体系和质量控制措施两项技术内容,主要包括前引、正文和附录三个章节,对生态观测全过程质量保证和质量控制技术进行规定。     

CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control

During the course of biological aging, there is a gradual accumulation of damaged proteins and a concomitant functional decline in the protein degradation system. Protein quality control is normally ensured by the coordinated actions of molecular chaperones and the protein degradation system that collectively help to maintain protein homeostasis. The carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase/cochaperone, participates in protein quality control by targeting a broad range of chaperone substrates for proteasome degradation via the ubiquitin-proteasome system, demonstrating a broad involvement of CHIP in maintaining cytoplasmic protein quality control. In the present study, we have investigated the influence that protein quality control exerts on the aging process by using CHIP-/- mice. CHIP deficiency in mice leads to a markedly reduced life span, along with accelerated age-related pathophysiological phenotypes. These features were accompanied by indications of accelerated cellular senescence and increased indices of oxidative stress. In addition, CHIP-/- mice exhibit a deregulation of protein quality control, as indicated by elevated levels of toxic oligomer proteins and a decline in proteasome activity. Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo.     

Quality control systems for aberrant mRNAs induced by aberrant translation elongation and termination

RNA processing is an essential gene expression step and plays a crucial role to achieve diversity of gene products in eukaryotes. Various aberrant mRNAs transiently produced during RNA processing reactions are recognized and eliminated by specific quality control systems. It has been demonstrated that these mRNA quality control systems stimulate the degradation of aberrant mRNA to prevent the potentially harmful products derived from aberrant mRNAs. Recent studies on quality control systems induced by abnormal translation elongation and termination have revealed that both aberrant mRNAs and proteins are subjected to rapid degradation. In NonStop Decay (NSD) quality control system, a poly(A) tail of nonstop mRNA is translated and the synthesis of poly-lysine sequence results in translation arrest followed by co-translational degradation of aberrant nonstop protein. In No-Go Decay (NGD) quality control system, the specific amino acid sequences of the nascent polypeptide induce ribosome stalling, and the arrest products are ubiquitinated and rapidly degraded by the proteasome. In Nonfunctional rRNA Decay (NRD) quality control system, aberrant ribosomes composed of nonfunctional ribosomal RNAs are also eliminated when aberrant translation elongation complexes are formed on mRNA. I describe recent progresses on the mechanisms of quality control systems and the relationships between quality control systems. This article is part of a Special issue entitled: RNA Decay mechanisms.     

Needless Retesting of Quality-Assured, Commercially Prepared Culture Media

Current revival of interest in quality control of bacteriological culture media prompted this laboratory to develop and implement a system of quality control testing of media purchased from commercial manufacturers. During 8 months we tested more than 900 lots of 46 different media representing 350,000 units of culture media purchased from two major and one minor supplier(s). Only 17 lots were found to be unsatisfactory. This experience raised a question about the real necessity for extensive retesting by users of commercially prepared, quality-assured media. It is suggested that primary responsibility for quality control be placed on the relatively few manufacturer-vendors rather than on the multiple purchaser-users, who may not possess either the expertise or the resources for quality control programs.     

药品生产质量保证体系的建立

以《药品生产质量管理规范》(GMP)为依据,运用“过程方法”、“管理的系统方法”和“层次分析”理论,以药品生产体系的增值链系统为线索,对药品生产质量管理中的工序控制、信息传递、各子系统间的关联和衔接进行分析,以流程图的形式表示,并将系统要素人、物、信息和程序控制标明,建立起质量保证体系。涵盖了系统的全部关键质量控制点,职责清晰、不易遗漏、便于控制和发现问题。解决了药品生产质量控制及GMP实施中的难点,是药品生产企业行之有效的质量管理的手段。     

Autophagy machinery promotes the chaperone-mediated formation and compartmentalization of protein aggregates during appressorium development by the rice blast fungus

The chaperone-mediated sequestration of misfolded proteins into specialized quality control compartments represents an important strategy for maintaining protein homeostasis in response to stress. However, precisely how this process is controlled in time and subcellular space and integrated with the cell''s protein refolding and degradation pathways remains unclear. We set out to understand how aggregated proteins are managed during infection-related development by a globally devastating plant pathogenic fungus and to determine how impaired protein quality control impacts cellular differentiation and pathogenesis in this system. Here we show that in the absence of Hsp104 disaggregase activity, aggregated proteins are spatially sequestered into quality control compartments within conidia, but not within terminally differentiated infection cells, and thus spatial protein quality control is cell type–dependent. We demonstrate that impaired aggregate resolution results in a short-term developmental penalty but has no significant impact upon appressorium function. Finally, we show that, somewhat unexpectedly, the autophagy machinery is necessary for the normal formation and compartmentalization of protein aggregates. Taken together, our findings provide important new insight into spatial protein quality control during the process of terminal cellular differentiation by a globally important model eukaryote and reveal a new level of interplay between major proteostasis pathways.     

Quality control of an unreliable flexible manufacturing system with scrapping and infinite buffer capacity

Manufacturing multiple part types on a flexible manufacturing system (FMS) is increasingly becoming a rule rather than an exception. In such systems, attention has been drawn to the application of zero-defect technologies. However, in practice, this goal has remained elusive and costly. As a result, even though FMSs may be more reliable, producing fewer defective parts, system complexity and more stringent quality standards are rendering quality control in FMSs potentially useful. The goals of this article are threefold. First, we introduce a procedure for measuring and managing the in-process quality control of an FMS, which is described by an Open Queueing Network (OQN), bridging thereby a gap between queueing theory and quality control. Second, by focusing attention on the potential unreliabilities of FMSs, we provide some managerial insights regarding the role, position, and distribution of the quality control effort in an FMS. Finally, we stress the intricate relations between an FMS's operating characteristics and the manufactured quality and its control. Using numerical analyses, we draw some inferences regarding the design of such FMSs when both quality and quantity issues in the FMSs are considered. These simultaneous considerations of quantity and quality flows in an FMS have not been previously considered in the study of FMSs.     

实验用鱼遗传质量控制及标准化

在遗传学及其他生命科学研究领域, 实验用鱼已成为一类应用越来越广的实验动物, 但是尚缺少标准化的质量控制标准和监管。在我国, 实验动物实行严格的许可证制度和质量监督制度。实验用鱼遗传质量控制标准是实验用鱼质量控制的基础。为了规范实验用鱼的遗传质量, 避免实验用鱼种质退化、遗传漂移, 导致实验结果误差, 开展了本标准的研究。依据《实验动物管理条例》, 参考国内外实验用鱼遗传学相关的研究成果, 结合我国实验用鱼生产和使用的实际情况, 在全面收集、分析实验数据和广泛征询专家意见的基础上, 以实验用斑马鱼和剑尾鱼遗传质量控制为规范对象, 研究制定了实验用鱼遗传质量控制标准, 供科研工作者参考、讨论。本标准对实验用斑马鱼和剑尾鱼的遗传分类及命名原则、实验用鱼的繁殖方法、近交系和封闭群的遗传质量监测进行了规范。新标准将为实验用鱼的使用和管理提供理论支撑。     

Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD)

ER-associated degradation (ERAD) is a component of the protein quality control system, ensuring that aberrant polypeptides cannot transit through the secretory pathway. This is accomplished by a complex sequence of events in which unwanted proteins are selected in the ER and exported to the cytosol for degradation by the proteasome. Given that protein quality control can be essential for cell survival, it is not surprising that ERAD is linked to numerous disease states. Here we review the molecular mechanisms of ERAD, its role in metabolic regulation and biomedical implications, and the unanswered questions regarding this process.     

生物制品检定动态管理系统的开发和应用

掌握生物制品的检定动态是质量管理的重要内容,由于检定周期随着制品种类、批数及检定条件的变化而变化,以往靠手工方式查阅繁杂的检定记录,难以随时快速、全面了解当时的检定状况。检定动态管理软件的开发可应用计算机自动跟踪显示检定进度和检定状态,及时反映制品质量和检定条件变化,明显提高了生产和质量管理部门的工作效率。     

Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast

Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, DeltaF508, leads to nearly complete degradation via endoplasmic reticulum-associated degradation (ERAD). Elucidation of the quality control and degradation mechanisms might give rise to new therapeutic approaches to cure this disease. In the yeast Saccharomyces cerevisiae, a variety of components of the protein quality control and degradation system have been identified. Nearly all of these components share homology with mammalian counterparts. We therefore used yeast mutants defective in the ERAD system to identify new components that are involved in human CFTR quality control and degradation. We show the role of the lectin Htm1p in the degradation process of CFTR. Complementation of the HTM1 deficiency in yeast cells by the mammalian orthologue EDEM underlines the necessity of this lectin for CFTR degradation and highlights the similarity of quality control and ERAD in yeast and mammals. Furthermore, degradation of CFTR requires the ubiquitin protein ligases Der3p/Hrd1p and Doa10p as well as the cytosolic trimeric Cdc48p-Ufd1p-Npl4p complex. These proteins also were found to be necessary for ERAD of a mutated yeast "relative" of CFTR, Pdr5(*)p.     

检验全流程数字化管理及质量控制体系的构建

通过对检验工作各环节流程、质控情况的分析,制定了新的检验业务管理及质量控制流程,并利用数字化技术对流程各环节进行系统实现。检验全流程数字化管理及质量控制体系的构建,有效提高了检验工作的效率与质量安全,进一步促进了医院医疗质量管理水平的提高。     

Drop-on-Demand System for Manufacturing of Melt-based Solid Oral Dosage: Effect of Critical Process Parameters on Product Quality

The features of a drop-on-demand-based system developed for the manufacture of melt-based pharmaceuticals have been previously reported. In this paper, a supervisory control system, which is designed to ensure reproducible production of high quality of melt-based solid oral dosages, is presented. This control system enables the production of individual dosage forms with the desired critical quality attributes: amount of active ingredient and drug morphology by monitoring and controlling critical process parameters, such as drop size and product and process temperatures. The effects of these process parameters on the final product quality are investigated, and the properties of the produced dosage forms characterized using various techniques, such as Raman spectroscopy, optical microscopy, and dissolution testing. A crystallization temperature control strategy, including controlled temperature cycles, is presented to tailor the crystallization behavior of drug deposits and to achieve consistent drug morphology. This control strategy can be used to achieve the desired bioavailability of the drug by mitigating variations in the dissolution profiles. The supervisor control strategy enables the application of the drop-on-demand system to the production of individualized dosage required for personalized drug regimens.     

Role of calnexin in the glycan-independent quality control of proteolipid protein

The endoplasmic (ER) quality control apparatus ensures that misfolded or unassembled proteins are not deployed within the cell, but are retained in the ER and degraded. A glycoprotein-specific system involving the ER lectins calnexin and calreticulin is well documented, but very little is known about mechanisms that may operate for non-glycosylated proteins. We have used a folding mutant of a non- glycosylated membrane protein, proteolipid protein (PLP), to examine the quality control of this class of polypeptide. We find that calnexin associates with newly synthesized PLP molecules, binding stably to misfolded PLP. Calnexin also binds stably to an isolated transmembrane domain of PLP, suggesting that this chaperone is able to monitor the folding and assembly of domains within the ER membrane. Notably, this glycan-independent interaction with calnexin significantly retards the degradation of misfolded PLP. We propose that calnexin contributes to the quality control of non-glycosylated polytopic membrane proteins by binding to misfolded or unassembled transmembrane domains, and discuss our findings in relation to the role of calnexin in the degradation of misfolded proteins.     

Biological control through provision of additional food to predators: a theoretical study

In this paper we analyze a variation of a standard predator-prey model with type II functional response which represents predator-prey dynamics in the presence of some additional food to the predator. The aim is to study the consequences of providing additional food on the system dynamics. We conclude that handling times for the available foods play a key role in determining the eventual state of the ecosystem. It is interesting to observe that by varying the quality and quantity of additional food we can not only control and limit the prey, but also limit and eradicate the predators. In the context of biological pest control, the results caution the manager on the choice of quality and quantity of the additional food used for this purpose. An arbitrary choice may have opposite effects leading to increase in pest concentration and eradication of the predator. This study offers insight into the possible management strategies that involve manipulation of quality and supply level of additional food to predators, for the benefit of biological control. The theoretical conclusions agree with results of some practical biological control experiments.     

Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins

Cellular toxicity introduced by protein misfolding threatens cell fitness and viability. Failure to eliminate these polypeptides is associated with numerous aggregation diseases. Several protein quality control mechanisms degrade non-native proteins by the ubiquitin-proteasome system. Here, we use quantitative mass spectrometry to demonstrate that heat-shock triggers a large increase in the level of ubiquitylation associated with misfolding of cytosolic proteins. We discover that the Hul5 HECT ubiquitin ligase participates in this heat-shock stress response. Hul5 is required to maintain cell fitness after heat-shock and to degrade short-lived misfolded proteins. In addition, localization of Hul5 in the cytoplasm is important for its quality control function. We identify potential Hul5 substrates in heat-shock and physiological conditions to reveal that Hul5 is required for ubiquitylation of low-solubility cytosolic proteins including the Pin3 prion-like protein. These findings indicate that Hul5 is involved in a cytosolic protein quality control pathway that targets misfolded proteins for degradation.