Film Use to Promote Understanding in Change and Diffusion of Innovation

The paper explores cinematic films as a pedagogical tool to promote critical thinking and student discussions in a doctoral-level learning, design, and technology seminar course at a major U.S. research university. These discussions focused on systemic change and systemic thinking concepts. The authors offer evidence from the literature that supports films’ power as a visual metaphor and neurocognitive stimulator to promote development of new perspectives in graduate students on case studies through articulation, reflection, and explanation of their thought processes on change and diffusion of innovation. There are theoretical, political, social, and technological issues that create tensions during any systemic change effort. The goal of using film in this seminar is to equip students with the requisite skills, theoretical frameworks, and interpersonal experiences needed to address these issues within organizations and communities. The change expected from systemic thinking is for students to think more deeply about the interconnectedness of systems and the importance of bottom-up change efforts that consider the perspective of all stakeholders.     

Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.     

Advances in anti-viral immune defence: revealing the importance of the IFN JAK/STAT pathway

Interferon-alpha (IFN-α) is a potent anti-viral cytokine, critical to the host immune response against viruses. IFN-α is first produced upon viral detection by pathogen recognition receptors. Following its expression, IFN-α embarks upon a complex downstream signalling cascade called the JAK/STAT pathway. This signalling pathway results in the expression of hundreds of effector genes known as interferon stimulated genes (ISGs). These genes are the basis for an elaborate effector mechanism and ultimately, the clearance of viral infection. ISGs mark an elegant mechanism of anti-viral host defence that warrants renewed research focus in our global efforts to treat existing and emerging viruses. By understanding the mechanistic role of individual ISGs we anticipate the discovery of a new “treasure trove” of anti-viral mediators that may pave the way for more effective, targeted and less toxic anti-viral therapies. Therefore, with the aim of highlighting the value of the innate type 1 IFN response in our battle against viral infection, this review outlines both historic and recent advances in understanding the IFN-α JAK/STAT pathway, with a focus on new research discoveries relating to specific ISGs and their potential role in curing existing and future emergent viral infections.     

问答社区问句中多字词表达提取

基于互动问答社区问句中多字词表达和问句理解的关系,提出针对互动问答社区问句进行多字词表达抽取,并基于互动问答社区问句中多字词表达的特点,提出适用于互动问答社区的多字词表达提取方法.该方法在利用互信息和停用词表的方法从问句中抽取候选多字词表达的基础上,将候选多字词表达分为正确串、残缺串、冗余串和错误串4类,借助搜索引擎对查询串的优化和候选多字词表达在互联网上的检索结果,设计候选多字词表达校正方法,实现对多字词表达的提取.以新浪爱问知识人问题库中的问句进行实验,结果表明,多字词表达抽取的准确率、召回率和F值分别达到84%,52%和0.64,验证了该方法的有效性.     

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine amino-transferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP enzyme inhibitors against CVD is briefly discussed.     

影响螺纹副轴向力分布均匀性的关键因素分析

通过对螺纹连接结构承载分布问题的理论分析与数值模拟,探索影响螺纹副轴向力分布均匀性的关键因素.首先对螺纹副轴向承载分布进行理论分析,提出依据螺纹副截面上单位长度荷载F与螺纹牙相对变形u的关系曲线确定轴向力分布的解析方法.理论分析表明,当F-u关系曲线呈屈服形状时,螺纹副轴向承载力分布更加均匀.其次,对施必牢螺纹副进行分析,发现其F-u关系曲线呈现出屈服特征;从牙型设计、材料塑性和螺纹错动三方面进行分析,阐明施必牢螺纹副承载分布均匀性好的力学机制;最后,详细分析了螺纹副径向尺寸系数、摩擦因数和材料特性等因素对螺纹上轴向力分布的影响规律.     

一种速度偏差故障的分析与处理

通过对一起速度偏差故障排查处理过程的分析,阐述了问题的形成原因,并且展示了对这类问题的处理过程和处理思想,最后提出了相应的解决办法及注意事项,而且在对这起速度偏差故障的分析中,指明了西门子SIMADYN D-TDC控制系统的基本设计思想和系统结构;尤其是说明了在弱磁升速阶段系统在保持电枢电压不变的基础上,通过电势运算器计算电动势反馈量、引入电动势反馈信号,形成电动势控制环进行弱磁升速控制的原理。这对处理同类电气故障具有很大的借鉴意义。     

Regulation of the H<Superscript>+</Superscript>-ATP synthase by IF1: a role in mitohormesis

The mitochondrial H⁺-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H⁺-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H⁺-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H⁺-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H⁺-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases.     

Aptamer and its applications in neurodegenerative diseases

Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, transmissible spongiform encephalopathy, Huntington’s disease and multiple sclerosis.