Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus

The yellow fever virus (YFV) is an emerging RNA virus and has caused large outbreaks in Africa and Central and South America. The virus is often transmitted through infected mosquitoes and spreads from area to area because of international travel. Being an acute viral hemorrhagic disease, yellow fever can be prevented by an effective, safe, and reliable vaccine, but not be eliminated. Currently, there is no antiviral drug available for its cure. Thus, two series of novel bis(benzofuran–1,3-imidazolidin-4-one)s and bis(benzofuran–1,3-benzimidazole)s were designed and synthesized for the development of anti-YFV lead candidates. Among 23 new bis-conjugated compounds, 4 of them inhibited YFV strain 17D (Stamaril) on Huh-7 cells in the cytopathic effect reduction assays. These conjugates exhibited the most compelling efficacy and selectivity with an EC₅₀ of <3.54 μM and SI of >15.3. The results are valuable for the development of novel antiviral drug leads against emerging diseases.     

Human Milk Oligosaccharide 2′-Fucosyllactose Modulates Local Viral Immune Defense by Supporting the Regulatory Functions of Intestinal Epithelial and Immune Cells

Human milk contains bioactive components that provide protection against viral infections in early life. In particular, intestinal epithelial cells (IEC) have key regulatory roles in the prevention of enteric viral infections. Here we established an in vitro model to study the modulation of host responses against enteric viruses mimicked by poly I:C (pIC). The effects of 2′-fucosyllactose (2′FL), abundantly present in human milk, were studied on IEC and/or innate immune cells, and the subsequent functional response of the adaptive immune cells. IEC were pre-incubated with 2′FL and stimulated with naked or Lyovec™-complexed pIC (LV-pIC). Additionally, monocyte-derived dendritic cells (moDC) alone or in co-culture with IEC were stimulated with LV-pIC. Then, conditioned-moDC were co-cultured with naïve CD4⁺ T helper (Th)-cells. IEC stimulation with naked or LV-pIC promoted pro-inflammatory IL-8, CCL20, GROα and CXCL10 cytokine secretion. However, only exposure to LV-pIC additionally induced IFNβ, IFNλ1 and CCL5 secretion. Pre-incubation with 2′FL further increased pIC induced CCL20 secretion and LV-pIC induced CXCL10 secretion. LV-pIC-exposed IEC/moDC and moDC cultures showed increased secretion of IL-8, GROα, IFNλ1 and CXCL10, and in the presence of 2′FL galectin-4 and -9 were increased. The LV-pIC-exposed moDC showed a more pronounced secretion of CCL20, CXCL10 and CCL5. The moDC from IEC/moDC cultures did not drive T-cell development in moDC/T-cell cultures, while moDC directly exposed to LV-pIC secreted Th1 driving IL-12p70 and promoted IFNγ secretion by Th-cells. Hereby, a novel intestinal model was established to study mucosal host-defense upon a viral trigger. IEC may support intestinal homeostasis, regulating local viral defense which may be modulated by 2′FL. These results provide insights regarding the protective capacity of human milk components in early life.     

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin αIIbβ3. Our analysis points to the (autocrine) ADP P2Y₁ and P2Y₁₂ receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.     

Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the ‘supernatant of (hirudin-treated) coagulated plasma’ (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin α_IIbβ₃ activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.     

Load forecasting using a multivariate meta-learning system

Although over a thousand scientific papers address the topic of load forecasting every year, only a few are dedicated to finding a general framework for load forecasting that improves the performance, without depending on the unique characteristics of a certain task such as geographical location. Meta-learning, a powerful approach for algorithm selection has so far been demonstrated only on univariate time-series forecasting. Multivariate time-series forecasting is known to have better performance in load forecasting. In this paper we propose a meta-learning system for multivariate time-series forecasting as a general framework for load forecasting model selection. We show that a meta-learning system built on 65 load forecasting tasks returns lower forecasting error than 10 well-known forecasting algorithms on 4 load forecasting tasks for a recurrent real-life simulation. We introduce new metafeatures of fickleness, traversity, granularity and highest ACF. The meta-learning framework is parallelized, component-based and easily extendable.     

Enforcing structural regularities in software using IntensiVE

The design and implementation of a software system is often governed by a variety of coding conventions, design patterns, architectural guidelines, design rules, and other so-called structural regularities. To prevent a deterioration of the system’s source code, it is important that these regularities are verified and enforced upon evolution of the system. The Intensional Views Environment (IntensiVE), presented in this article, is a tool suite for specifying relevant structural regularities in an (object-oriented) software system and verifying them against the current and later versions of the system. At the heart of the IntensiVE tool suite are (logic) program queries and the model of intensional views and relations, through which regularities are expressed. Upon verification of these regularities in the source code of the system, IntensiVE reports the code entities (i.e. classes, methods, variables, statements, etc.) that violate these constraints. We present IntensiVE and illustrate its application to the verification of an Abstract Factory design pattern in the implementation of a software system.     

Development of a Modelica Compiler Using JastAdd

This paper describes experiences from implementing key parts of a compiler for Modelica, an object-oriented language supporting declarative modeling and simulation of complex physical systems. Our implementation uses the attribute-grammar based tool JastAdd. In particular, we discuss the implementation of Modelica name analysis which is highly context-dependent, type analysis which is based on structural subtyping, and flattening which is a fundamental part of the Modelica compilation process.of so called modifications, Modelica.     

变速永磁同步发电机系统稳压控制（连载之五）直接电压控制在发电机系统中的应用

在所研究的具有强弱磁能力变速永磁同步发电机的270V直流电能系统中,应用PWM整流器,提出直接电压控制技术,设计了直流母线电压PI控制器,并结合有源阻尼技术,在Matlab/Simulink仿真及测试平台中加以实现。最后,对本系列连载所研究的各类控制算法的性能进行对比研究。     

低IQ DC/DC控制器帮助延长汽车电池运行时间

尽管开关模式电源效率很高,但是所有开关模式电源都需要一定量的功率,以在甚至没有输出负载或输出负载非常小时工作.尽管这一功率可能很低,但是在能量稀缺和多个始终保持接通电路处于体眠模式的应用中,这一功率却可能高得不可接受.为了解决这个问题,凌力尔特公司提供的LTC3857/-1双输出同步降压型控制器采用了突发模式(Burst Mode)工作,这种工作模式在DC/DC转换器轻负载时最大限度地降低了功耗     

The effect of random grain distributions on fatigue crack initiation in a notched coarse grained superalloy specimen

Coarse grained superalloys are of large interest in high temperature applications, and can be found in e.g. gas turbine components, where great care must be given with respect to high temperature fatigue. Due to the large grain size, the material behaviour at e.g. sharp notches cannot be considered homogeneous. As a consequence, the fatigue behaviour is likely to expose a large variation. In order to numerically investigate this variation, a Monte Carlo analysis has been carried out by 100 FE-simulations of notched specimens, where placements and orientations of the grains were randomised. Furthermore, each grain was modelled as a unique single-crystal, displaying both anisotropic elastic and plastic behaviour and tension/compression asymmetry. The effect of randomness was investigated by the obtained dispersion in fatigue crack initiation life. It was concluded that the fatigue life behaviour of coarse grained nickel-base superalloys may show a considerable variation, which cannot be captured by one single deterministic analysis based on data for a homogenised material. Furthermore, the dispersion is of such a magnitude that it needs to be taken into account in industrial applications where highly stressed coarse grained materials are used.