Oxytocin Signaling as a Target to Block Social Defeat-Induced Increases in Drug Abuse Reward

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain.     

Adenosine Receptor Agonist HE-NECA Enhances Antithrombotic Activities of Cangrelor and Prasugrel in vivo by Decreasing of Fibrinogen Density in Thrombus

Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y₁₂ could serve as components of dual anti-platelet therapy. We have found that a selective A_2A agonist 2-hexynyl-5’-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y₁₂ inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood–brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood–brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood–brain barrier. We conclude that chronic administration of the A_2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146.     

大型软包锂离子电池的热物性实验研究

针对大型软包锂离子电池热物性参数的测定问题,提出适用于该型电池的热参数表征方法. 基于准稳态导热原理,建立电池的传热理论模型. 开展实验研究电池的比定压热容和导热系数与温度的依变关系,分析热损对测试结果的影响,对测试方法的有效性进行验证. 结果表明,电池比定压热容随着温度的升高而线性增大,导热系数受温度的影响较小. 在900 s内可以测得电池热参数在10~60 °C下的变化状况,实验验证结果显示测算精度高于92.3%,具有测算周期短、准确度高和测试灵活等优势.     

A blueprint for capturing grid value in a decentralized electricity sector

This study addresses the question of how the electricity grid can best be priced, in the context of disruptive technologies, increasing decentralisation of the power sector and new business models. The emergence of business models can affect the design of tariffs, but at the same time, tariff design can trigger new business models as they can nudge adoption towards certain technologies. Network tariffs have traditionally been established using a cost accounting method. Due to its cost structure, network tariffs are second best constructs, as marginal cost pricing does not lead to cost recovery. Second best solutions, in all probability, will overcompensate some inputs which in turn will be overused (the Averch-Johnson effect). New distributed energy technologies that perform better in these overcompensated inputs will therefore see a higher penetration in the market. Penetration of some technologies over others in a previously monolithic vertically integrated power sector will open up new customer needs and therefore business opportunities. Each resulting business opportunity would make use of the grid differently from which it was originally conceived, and at one extreme, they can bypass it altogether. We provide a framework of analysis that leads to the pricing of the services provided by the electricity grid for each new business opportunity.     

AKT Inhibitors: The Road Ahead to Computational Modeling-Guided Discovery

AKT, is a serine/threonine protein kinase comprising three isoforms—namely: AKT1, AKT2 and AKT3, whose inhibitors have been recognized as promising therapeutic targets for various human disorders, especially cancer. In this work, we report a systematic evaluation of multi-target Quantitative Structure-Activity Relationship (mt-QSAR) models to probe AKT’ inhibitory activity, based on different feature selection algorithms and machine learning tools. The best predictive linear and non-linear mt-QSAR models were found by the genetic algorithm-based linear discriminant analysis (GA-LDA) and gradient boosting (Xgboost) techniques, respectively, using a dataset containing 5523 inhibitors of the AKT isoforms assayed under various experimental conditions. The linear model highlighted the key structural attributes responsible for higher inhibitory activity whereas the non-linear model displayed an overall accuracy higher than 90%. Both these predictive models, generated through internal and external validation methods, were then used for screening the Asinex kinase inhibitor library to identify the most potential virtual hits as pan-AKT inhibitors. The virtual hits identified were then filtered by stepwise analyses based on reverse pharmacophore-mapping based prediction. Finally, results of molecular dynamics simulations were used to estimate the theoretical binding affinity of the selected virtual hits towards the three isoforms of enzyme AKT. Our computational findings thus provide important guidelines to facilitate the discovery of novel AKT inhibitors.     

Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.     

Focal Ischemic Injury to the Early Neonatal Rat Brain Models Cognitive and Motor Deficits with Associated Histopathological Outcomes Relevant to Human Neonatal Brain Injury

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.     

Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models

Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling.     

Preparation of High Strength and Toughness Aramid Fiber by Introducing Flexible Asymmetric Monomer to Construct Misplaced-Nunchaku Structure

High performance fibers with high strength and toughness have great potential in composites, but contradiction between tensile strength and elongation at break makes the preparation to become a current challenge. Herein, an asymmetric structure of more flexible diamine, 3,4′-diaminodiphenyl ether (3,4′-ODA), is introduced into heterocyclic aramid (PBIA) fibers to replace rigid symmetric p-phenylenediamine (PDA). By studying the properties of copolymer (mPEBA) fibers with different ratios of diamine, it is found that the mPEBA fiber reached the optimal mechanical properties with the 30% content of 3,4′-ODA. Compared with homopolymerized heterocyclic aramid fibers, the tensile strength and elongation at break of mPEBA fiber are improved by 26.2% and 38.7%, respectively. Results of X-ray diffraction show that the introduction of 3,4′-ODA structure can increase stretchability of mPEBA fibers, improving the orientation degree during hot-drawing. Molecular dynamics simulations confirm that 3,4′-ODA structure undergoes a conformation transformation to form a straightened chain during hot-drawing, while symmetrical 4,4′-diaminodiphenyl ether (4,4′-ODA) cannot form the same conformation. The misplaced-nunchaku structure is formed based on the special meta-para position of 3,4′-ODA, achieving the synergy of high strength and high toughness.     

面向配电网电压暂降治理的线路改造优化模型

线路改造是在电网侧进行电压暂降治理的主要方式之一。为了经济、合理地确定线路的改造位置和治理方式,建立了面向配电网电压暂降治理的线路改造优化模型。针对断路器重合闸和熔断器配合保护的配电网,考虑故障位置、故障类型等因素,讨论分析了10种典型的保护动作配合方式,评估了配电网电压暂降持续时间。结合传统电压暂降幅值的计算方法,计算线路改造治理方案的成本及效果。考虑用户电压暂降耐受能力,建立了用户生产中断次数评估模型。定义了电压暂降总支出,以总支出最小为目标,计及技术约束、经济约束、治理范围约束和风险域约束,建立了面向配电网电压暂降治理的线路改造优化模型,并基于人工蜂群算法进行模型求解。以IEEE 33节点系统为算例,考虑治理投资成本充足和不足2种场景,通过仿真验证了所提方法的正确性和实用性。