Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model

Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.     

New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y₆₈₂ mutation in the ₆₈₂YENPTY₆₈₇ domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the ₆₈₂YENPTY₆₈₇ peptide, its mutated form, ₆₈₂GENPTY₆₈₇ or its phosphorylated form, ₆₈₂pYENPTY₆₈₇. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y₆₈₂ in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.     

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer’s Disease

The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.     

Ile-1781-Leu and Asp-2078-Gly Mutations in ACCase Gene,Endow Cross-resistance to APP,CHD, and PPZ in Phalaris minor from Mexico

Herbicides that inhibit acetyl coenzyme A carboxylase (ACCase) are commonly used in Mexico to control weedy grasses such as little seed canarygrass (Phalaris minor). These herbicides are classified into three major families (ariloxyphenoxypropionates (APP), cyclohexanodiones (CHD), and, recently, phenylpyrazolines (PPZ)). In this work, the resistance to ACCase (APP, CHD, and PPZ) inhibiting herbicides was studied in a biotype of Phalaris minor (P. minor) from Mexico, by carrying out bioassays at the whole-plant level and investigating the mechanism behind this resistance. Dose-response and ACCase in vitro activity assays showed cross-resistance to all ACCase herbicides used. There was no difference in the absorption, translocation, and metabolism of the ¹⁴C-diclofop-methyl between the R and S biotypes. The PCR generated CT domain fragments of ACCase from the R biotype and an S reference were sequenced and compared. The Ile-1781-Leu and Asp-2078-Gly point mutations were identified. These mutations could explain the loss of affinity for ACCase by the ACCase-inhibing herbicides. This is the first report showing that this substitution confers resistance to APP, CHD, and PPZ herbicides in P. minor from Mexico. The mutations have been described previously only in a few cases; however, this is the first study reporting on a pattern of cross-resistance with these mutations in P. minor. The findings could be useful for better management of resistant biotypes carrying similar mutations.     

基于STM32的餐桌隔间装置控制系统的设计

为了解决中小型餐厅餐桌有空余位置而顾客不想拼桌并离开的问题,设计出一种基于手机APP和下位机STM32的餐桌隔间装置。该装置可实现将餐桌划分成四个至多个独立空间供单独客人使用,结合上下位机的工作模式,能实现餐桌分隔和不分隔的功能。系统包含液晶显示屏,方便顾客点选菜品,提高餐厅服务人员的工作效率。从控制系统的实现方法角度介绍该系统。实验表明,新设计具有良好的稳定性和可靠性,有效地提高了中小型餐厅餐桌座位的利用率。     

智能网联汽车APP中控制模块的视觉设计与应用

目的研究智能网联汽车手机APP中控制模块的视觉设计与应用,强化视觉设计过程的合理性,为智能汽车HMI设计实践工作提供启示与借鉴。方法首先从用户体验的角度分析APP控制模块存在的视觉设计问题,主要是视觉结构单一、视觉层级混乱、视觉特征缺失,再从行为逻辑的角度思考视觉设计方法,"由面及点"地提出控制模块的视觉设计思路,并结合设计应用案例论证其可行性。结果从合理视觉布局、明确视觉层级和提炼视觉语言的角度提出APP控制模块的视觉设计思路。结论智能网联汽车APP控制模块的视觉设计应该重视行为逻辑的影响。从任务角度思考视觉布局、从行为逻辑的角度思考视觉层级、从行为特征的角度思考视觉语言,提高视觉设计工作的合理性,减少与交互设计工作脱节的现象,强化控制求助的高效性和安全性。     

基于STC89C52RC与STM8S005技术的智能书桌

本设计采用STC89C52RC与STM8S005为核心控制的可升降智能书桌,由数码管显示模块,超声波模块,按键模块,红外测距模块,接近式感应,手机充电,蓝牙连接播放音乐,推杆和语音录放装置以及app控制台灯组成.本设计采用人性化的方式,可以上升的高度范围为50 cm到110 cm,实现人体的站立和坐下,书桌实时对人体的姿态作出反应,实时测量高度,同时设计APP实现外加音乐播放,led照明和七彩灯变化等功能.     

基于ADDIE模型的职校教学APP系统设计与开发

随着移动互联网的高速发展,国家大力推进职校教育信息化,基于信息技术的新型教育手段成为发展方向。笔者基于ADDIE模型对职校教学模式进行问卷调查与数据分析,根据需求分析提出职校教学APP系统的功能模块与后台系统设计方案,对系统开发平台与封装APP系统方案提出建议,为职校构建“互联网+教育”打造支撑服务平台,促进信息技术与课程教学的深度融合。     

基于情境感知的户外运动类应用设计策略研究

目的 探索情境感知相关理论在户外运动类APP中的应用,以期改善目前市场上户外运动类应用中安全保障性不强、同质化严重、个性化与专属性不强等问题,从而全方位优化用户体验及提升用户户外运动的安全感,并为今后户外运动类应用的设计开发提供参考依据。方法 首先对户外运动及其应用的实践和理论现状进行分析,其次在梳理情境感知理论的基础上,分析户外运动类应用中的用户、环境、社交和设备4类情境信息及情境感知介入户外运动类应用的技术支撑。通过桌面调研、问卷调查和用户访谈3种方法洞察出用户需求,最后总结出基于上述4类情境信息的针对性设计策略。结论 情境感知理论的运用有助于在设计应用时深度理解和挖掘用户需求,在更大程度上保障用户安全的同时向用户提供更具智能化、个性化、情感化的服务。     

以广西壮族铜鼓文化传播为主题的APP产品架构设计

目的在"非遗"传承创新的语境下,研究以广西壮族铜鼓文化传播为主题的APP产品设计。方法为了更好地完成"非遗"类APP的产品设计,需要依据主题内容确定交互目标和用户体验,依照核心功能进行产品的架构,继而进行最后的视觉界面设计。结论将传统艺术语言与信息技术、数字艺术、虚拟现实技术、移动终端平台相结合,是保护、传承、传播民族文化的创新方式。在"非遗"类APP的设计上,应不断提升APP的用户交互和用户体验,传达民族文化的内涵。