Intrinsically disordered proteins in crowded milieu: when chaos prevails within the cellular gumbo

Effects of macromolecular crowding on structural and functional properties of ordered proteins, their folding, interactability, and aggregation are well documented. Much less is known about how macromolecular crowding might affect structural and functional behaviour of intrinsically disordered proteins (IDPs) or intrinsically disordered protein regions (IDPRs). To fill this gap, this review represents a systematic analysis of the available literature data on the behaviour of IDPs/IDPRs in crowded environment. Although it was hypothesized that, due to the excluded-volume effects present in crowded environments, IDPs/IDPRs would invariantly fold in the presence of high concentrations of crowding agents or in the crowded cellular environment, accumulated data indicate that, based on their response to the presence of crowders, IDPs/IDPRs can be grouped into three major categories, foldable, non-foldable, and unfoldable. This is because natural cellular environment is not simply characterized by the presence of high concentration of “inert” macromolecules, but represents an active milieu, components of which are engaged in direct physical interactions and soft interactions with target proteins. Some of these interactions with cellular components can cause (local) unfolding of query proteins. In other words, since crowding can cause both folding and unfolding of an IDP or its regions, the outputs of the placing of a query protein to the crowded environment would depend on the balance between these two processes. As a result, and because of the spatio-temporal heterogeneity in structural organization of IDPs, macromolecular crowding can differently affect structures of different IDPs. Recent studies indicate that some IDPs are able to undergo liquid–liquid-phase transitions leading to the formation of various proteinaceous membrane-less organelles (PMLOs). Although interiors of such PMLOs are self-crowded, being characterized by locally increased concentrations of phase-separating IDPs, these IDPs are minimally foldable or even non-foldable at all (at least within the physiologically safe time-frame of normal PMLO existence).     

Macropinocytosis,mTORC1 and cellular growth control

The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth.     

Constructing and evaluating core inflation measures from component‐level inflation data

This paper undertakes a comprehensive examination of 10 measures of core inflation and evaluates which measure produces the best forecast of headline inflation out‐of‐sample. We use the Personal Consumption Expenditure Price Index as our measure of inflation. We use two sets of components (17 and 50) of the Personal Consumption Expenditure Price Index to construct these core inflation measures and evaluate these measures at the three time horizons (6, 12 and 24 months) most relevant for monetary policy decisions. The best measure of core inflation for both sets of components and over all time horizons uses weights based on the first principal component of the disaggregated (component‐level) prices. Interestingly, the results vary by the number of components used; when more components are used the weights based on the persistence of each component is statistically equivalent to the weights generated by the first principal component. However, those forecasts using the persistence of 50 components are statistically worse than those generated using the first principal component of 17 components. The statistical superiority of the principal component method is due to the fact that it extracts (in the first principal component) the common source of variation in the component level prices that accurately describes trend inflation over the next 6–24 months.     

Systemic Thinking and Practice Toward Facilitating Inclusive Education: Reflections on a Case of Co-Generated Knowledge and Action in South Africa

This article offers our reflections around a case of facilitating systemic thinking and practice in which the first author of the article (Tlale) interacted with research participants/participant researchers with the intention of strengthening systemic thought and action toward fostering inclusive education in the setting (a rural school in the Eastern Cape in South Africa). We reflect upon the process and also how our engagement was perceived by participants, as expressed in feedback received from them. We point to how Tlale introduced the idea of systemic thinking (to teachers, school management team, school governing body, and a district officer for the district) as tied to the possibility of acting to generate transformation toward a more inclusive educational context for the benefit of the learners at the school in question, thus acting as a systemic mediator on their behalf.     

Zr基非晶合金准静态压缩下的多重剪切带行为

利用IUTM和SEM研究了Zr-Ti-Ni-Cu块状非晶合金的准静态单轴压缩变形和断裂行为. 研究表明:该合金的室温压缩变形过程主要表现为弹性和塑性变形,塑性变形阶段没有加工硬化现象. 在准静态压缩条件下Zr基非晶合金表现出多重剪切效应,提高了塑性. 微观研究证明,剪切带的滑移分枝与相互交叉是非晶合金塑性提高的主要机制. 沿着剪切带发现了微空洞和微裂纹,剪切带的形成与自由体积的合并有关. 塑性变形过程中形成脉纹状断口形貌,受力状态的不同脉状花纹表现为不同的形式.     

基于随机森林赋权和改进ELECTRE-Ⅲ方法的科技奖励评价研究

针对科技奖励评价中各指标权重的不确定性问题,提出随机森林赋权法,利用可靠性分析计算专家评分数据的泛化误差,根据最小错误率得到各评价项目的各评价指标权重,减少主观赋权的影响;引入一致可信度、非一致可信度和净可信度信息,提出改进的ELECTRE-Ⅲ方法,将某一评价项目优于其他评价项目的程度具体量化,解决专家评分数据为次序变量的问题.实证表明:随机森林赋权法和改进后的ELECTRE-Ⅲ方法相结合,既提高了权重估计的精确度和可信度,又解决了难以给定门槛值和不能完全排序的问题,使评价结果更加科学、客观、合理.