Institut du Cerveau et de la Moelle epiniere - ICM Brain ＆ Spine Institute, Paris

The Institut du Cerveau et de la Moelle epiniere - ICM （Brain ＆ Spine Institute） - is an international brain and spinal cord research center whose innovative concept and structure make ita unique institute of its kind. The ICM brings patients, medics and researchers together with the aim of rapidly develop treatments for disorders of the nervous system and enable patients to benefit from them as quickly as possible. Scientists from different backgrounds and countries come together at the Institute to perform leading-edge research in this area.

Predicting liposome formulations by the integrated machine learning and molecular modeling approaches

Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability.Due to the complex formulation components and preparation process,formulation screening mostly relies on trial-and-error process with low efficiency.Here liposome formulation prediction models have been built by machine learning(ML)approaches.The important parameters of liposomes,including size,polydispersity index(PDI),zeta potential and encapsulation,are predicted individually by optimal ML algorithm,while the formulation features are also ranked to provide important guidance for formulation design.The analysis of key parameter reveals that drug molecules with logS[-3,-6],molecular complexity[500,1000]and XLogP3(≥2)are priority for preparing liposome with higher encapsulation.In addition,naproxen(NAP)and palmatine HCl(PAL)represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability.The consistency between predicted and experimental value verifies the satisfied accuracy of ML models.As the drug properties are critical for liposome particles,the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations.The modeling structure reveals that NAP molecules could distribute into lipid layer,while most PAL molecules aggregate in the inner aqueous phase of liposome.The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations.In summary,the general prediction models are built to predict liposome formulations,and the impacts of key factors are analyzed by combing ML with molecular modeling.The availability and rationality of these intelligent prediction systems have been proved in this study,which could be applied for liposome formulation development in the future.

Progress in oncolytic viruses modified with nanomaterials for intravenous application

In oncolytic virus(OV)therapy,a critical component of tumor immunotherapy,viruses selectively infect,replicate within,and eventually destroy tumor cells.Simultaneously,this therapy activates immune responses and mobilizes immune cells,thereby eliminating residual or distant cancer cells.However,because of OVs’high immunogenicity and immune clearance during circulation,their clinical applications are currently limited to intratumoral injections,and their use is severely restricted.In recent years,numerous studies have used nanomaterials to modify OVs to decrease virulence and increase safety for intravenous injection.The most commonly used nanomaterials for modifying OVs are liposomes,polymers,and albumin,because of their biosafety,practicability,and effectiveness.The aim of this review is to summarize progress in the use of these nanomaterials in preclinical experiments to modify OVs and to discuss the challenges encountered from basic research to clinical application.

NTSS-6评分在糖尿病周围神经病变中的诊断价值

目的探讨NTSS-6评分在糖尿病周围神经病变中的诊断价值。方法 283例2型糖尿病患者,依据神经肌电图检查是否异常分为DPN组和NDPN组。用ROC曲线评价NTSS-6评分在DPN中的诊断价值,并比较单独用神经肌电图以及联合NTSS-6评分后DPN的检出率的变化。结果①在收集的病例中DPN发生率为53.4%,其中合并DPN组有更长的病程、较高的血糖、HbA1c、BMI、WHR、TG、hsCRP及NTSS-6评分,较低的INS和DBP;②下肢腓总神经感觉神经传导速度与WHR、病程、FBS、HbA1c呈负相关。Logistic回归分析显示,病程、WHR、HbA1c为糖尿病周围神经病变的独立危险因素;③ROC曲线示NTSS-6评分的最佳切割点为3.995分(灵敏度=0.848,特异度=0.561),其曲线下面积为0.703;④联合神经肌电图和NTSS-6评分DPN的检出率高于单独使用神经肌电图的检出率。结论①病程、WHR、HbA1c为糖尿病周围神经病变的独立危险因素;②NTSS-6评分可作为早期筛查糖尿病周围神经病变的方法之一;③神经肌电图检查联合NTSS-6评分可提高DPN检出率。

正交频分复用技术(3)

前两讲已经对正交频分复用(OFDM)的基本原理和OFDM的相关信号处理技术进行了介绍。本讲我们将介绍OFDM中的多址接入方式,包括时分多址、码分多址和频分多址,并简要探讨各种多址方式的特点;然后以数字音频广播、非对称数字用户线以及IEEE 802.11a无线局域网系统为例,介绍OFDM技术在实际通信系统中的应用。

不敏感PBX炸药的多尺度结构与感度

不敏感炸药是指对热刺激、机械刺激和冲击波等感度较低的一类炸药,包括不敏感单质炸药和混合炸药,是提高弹药安全性的关键材料。用于装填武器弹药的炸药通常是以单质炸药为主成分(填料)、以聚合物为连续相或以熔铸型含能化合物(如三硝基甲苯、二硝基苯甲醚等)或热熔型石蜡为载体的混合炸药。其中,聚合物粘结炸药(polymer bonded explosive,PBX)是当前发展不敏感混合炸药的主流产品,广泛应用于现代武器弹药。不敏感PBX的感度特性与其多尺度结构密切关联,主要包括单质炸药分子的结构与稳定性、炸药分子的堆积方式与晶体结构及晶体品质、混合炸药的组成结构等与感度的关系3个层面的多尺度问题。通过不敏感含能分子的设计与合成、晶体结构的设计调控与高品质晶体降感技术、基于力热耗散的高效协同降感技术及PBX构效关系,发展不敏感炸药多尺度系统设计与结构调控及制备,是获得高能不敏感PBX的主要途径。加强超分子单质炸药和共晶炸药的设计研发,及发展第三代单质炸药高品质晶体降感技术等研究,是发展高能不敏感炸药的重要方向。

基于机器视觉的煤中杂物智能分选系统研究

为解决煤炭分选过程中杂物对生产的影响及由此产生的各种问题,设计了基于深度学习和机器视觉的集煤中杂物智能识别、定位和分拣于一体的杂物智能分选系统。该系统建立了基于语义分割的像素级杂物识别模型,计算成本比标准卷积网络模型降低8~9倍;构建了复杂环境条件下的机械手精准抓取策略,能够避开干扰物,实现硬质物料、轻质物料抓取点的精确选择。在涡北选煤厂的应用测试表明,该系统杂物检测准确率为96.647%,机械手分拣成功率为94.759%,系统分拣率为91.640%,能够高效除去煤中杂物,提高了杂物分选过程的智能化水平。

星载微波散射计两种体制的比较

星载微波散射计可以提供全球、全天候、高精度、高分辨率和短周期的海面风场数据。根据雷达天线足印的形状,雷达散射计主要包括扇形波束体制与笔形波束体制两种形式。概述了两种体制微波散射计在设计结构及后期数据处理算法中的优缺点,并对两种不同体制散射计的系统仿真数据进行比较。分析结果表明:对于小型卫星平台,Ku波段的旋转扫描扇形波束散射计比笔形波束圆锥扫描散射计具有更优的风场反演性能。

靶向抑制肠道菌β-葡萄糖醛酸苷酶在肿瘤预防和治疗中的应用

肠道菌β-葡萄糖醛酸苷酶(BGUSs)是肠道菌群产生的一类重要水解酶,其通过水解内源性和外源性葡萄糖醛酸苷影响肿瘤发生发展以及化疗药物的疗效(药效/毒性)。近年来,越来越多的研究尝试通过抑制肠道BGUSs降低患癌风险和减轻化疗药物引起的毒副作用。但由于BGUSs具有基因和结构的多样性、生理病理功能的复杂性以及对特定抑制剂响应的差异性,表征介导特定疾病或药物不良反应的BGUSs并发展有效的选择性抑制剂面临巨大的挑战。本文概述了BGUSs的结构和功能的最新进展,汇总了近年来在BGUSs介导的致癌物和肿瘤化疗药物代谢方面的发现、BGUSs抑制剂的研发及其预防肿瘤和缓解化疗药物不良反应的临床前研究结果,并讨论了将抑制BGUSs作为肿瘤预防和药物治疗新策略的前景。

Neoadjuvant therapy for gastroesophageal adenocarcinoma

Gastric and esophageal adenocarcinomas are one of the main causes of cancer-related death worldwide. While the incidence of gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction adenocarcinoma is rising rapidly in Western countries. Considering that surgical resection is currently the major curative treatment, and that the 5-year survival rate highly depends on the p TNM stage at diagnosis, gastroesophageal adenocarcinoma management is very challenging for oncologists. Several treatment strategies are being evaluated, and among them systemic chemotherapy, to decrease recurrences and improve overall survival. The MAGIC and FNCLCCFFCD trials showed a survival benefit of perioperative chemotherapy in patients with operable gastric and lower esophageal cancer, and these results had an impact on the European clinical practice. New strategies, including induction chemotherapy followed by preoperative chemoradiotherapy, targeted therapies in combination with perioperative chemotherapy and the new cytotoxic regimens, are currently assessed to improve current standards and help developing patienttailored therapeutic interventions.

Predicting oral disintegrating tablet formulations by neural network techniques

Oral disintegrating tablets(ODTs) are a novel dosage form that can be dissolved on thetongue within 3 min or less especially for geriatric and pediatric patients. Current ODT for-mulation studies usually rely on the personal experience of pharmaceutical experts andtrial-and-error in the laboratory, which is inefficient and time-consuming. The aim of cur-rent research was to establish the prediction model of ODT formulations with direct com-pression process by artificial neural network(ANN) and deep neural network(DNN) tech-niques. 145 formulation data were extracted from Web of Science. All datasets were dividedinto three parts: training set(105 data), validation set(20) and testing set(20). ANN andDNN were compared for the prediction of the disintegrating time. The accuracy of the ANNmodel have reached 85.60%, 80.00% and 75.00% on the training set, validation set and testingset respectively, whereas that of the DNN model were 85.60%, 85.00% and 80.00%, respec-tively. Compared with the ANN, DNN showed the better prediction for ODT formulations.It is the first time that deep neural network with the improved dataset selection algorithmis applied to formulation prediction on small data. The proposed predictive approach couldevaluate the critical parameters about quality control of formulation, and guide researchand process development. The implementation of this prediction model could effectivelyreduce drug product development timeline and material usage, and proactively facilitatethe development of a robust drug product.

流式细胞仪测定三种鸢尾科植物基因组的大小

目的:研究传统药用植物射干和鸢尾的基因组大小,为射干属和鸢尾属药用植物种质资源、品种鉴定和基因组研究提供参考。方法:本研究采用OTTO两步法制备细胞核悬液,使用碘化丙啶(PI)染色,以番茄作为内标植物,用流式细胞仪分别测定鸢尾、射干和巴西鸢尾新鲜叶片核悬液的荧光吸收强度,估算它们的基因组大小。结果:射干的基因组大小约为(5 296.27±177.06)Mbp,鸢尾基因组大小约为(4 494.07±76.57)Mbp,巴西鸢尾的基因组大小约为(4 074.91±170.70)Mbp。结论:3种鸢尾科药用植物的基因组较为复杂,射干和鸢尾、巴西鸢尾基因组间差异较大,鸢尾和巴西鸢尾的基因组差异较小。

Effective photocatalytic conversion of formic acid using iron,copper and sulphate doped TiO_(2)

In this paper,the combined addition of copper or iron and sulphate ions onto TiO_(2) prepared by a simple sol-gel method is studied for formic acid photocatalytic conversion.A wide structural and morphological characterization of the different photocatalysts was performed by X-ray diffraction(XRD),N_(2)-physisorption for BET surface area measurements,scanning and transmission electronic microscopies(SEM and TEM),UV-Vis diffuse spectroscopy(DRS)and X-ray photoelectron spectroscopy(XPS),in order to correlate the physico-chemical properties of the materials to their photocatalytic efficiencies for formic acid oxidation.Results have shown important differences among the catalysts depending on the metal added.Sulphated TiO_(2)/Cu(1%Cu)was the best photocatalyst obtaining about 100% formic acid conversion in only 5 min.The appropriate physico-chemical features of this photocatalyst,given by the addition of combined copper and sulphate ions,explain its excellence in photocatalytic reaction.

Investigation of molecular aggregation mechanism of glipizide/cyclodextrin complexation by combined experimental and molecular modeling approaches

Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.

Integrated computer-aided formulation design:A case study of andrographolide/cyclodextrin ternary formulation

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.

Rifampicin quinone pretreatment improves neuronal survival by modulating microglia inflammation induced by α-synuclein

The World Health Organization has predicted that neurodegenerative diseases affecting the motor function will become the second most prevalent cause of death in the next 20 years.New therapies can result from three main sources:synthetic compounds,natural products,and existing drugs.Parkinson’s disease(PD)is a common neurodegenerative disease affecting 1–3%of the adult population over 50 years of age worldwide.It is initially characterized by the death of dopaminergic neurons in the substantia nigra pars compact and later by the widespread loss of nondopaminergic neurons,including those in the cortex.

Restorating marine coastal ecosystem health as a new goad for integrated catchment management in Tolo Harbour,Hong Kong,China

The paper demonstrates why it is necessary to take the restoration of marine coastal ecosystem health as a new goal for integrated catchment management, in coastal area of the Tolo Harbour. The present goal of integrated catchment management (ICM) in the Tolo Harbour is to meet with Water Quality Objectives. The performance of an ICM plan, Tolo Harbour Action Plan (THAP), is evaluated by using marine coastal ecosystem health indicators including stress indicators and responses indicators. Since the implementation of THAP in 1988, some significant reduction in pollution loading has been observed - reduction of 83 % of BOD load and 82 % of TN between 1988 and 1999. There has been an improvement in the health state of Tolo Harbour marine coastal ecosystem as evidenced in the trends of the physical, chemical and biological indicators, although some reverse fluctuations in some periods exist. However, this can only be considered as the first sign of the ecosystem health restoration, since ecosystem health

Community Based Flood Risk Management: Local Knowledge and Actor’s Involvement Approach from Lower Karnali River Basin of Nepal

Connecting to the disaster risk reduction (DRR) studies, community-based initiatives are found to be more effective in both developed and developing countries, with a specific focus on the empowerment of local communities to build resilience. Building on social capital theory, the paper investigates on local knowledge (LK) practices experienced by the actors in an emerging economy using the community-based flood risk management (CB-FRM) approach. The qualitative research method was used by collecting data from focused group discussions, and interviews with the key informants including actors from local governments and non-government organizations. Additionally, informal discussions, field visits, and desk studies were undertaken to support the findings. The findings reveal that the local communities carry out various local knowledge experiences to respond during disaster management phases. They own a creative set of approaches based on the LK and that empowers them to live in the flood-prone areas, accepting the paradigm shift from fighting with floods to living with that. The local actor’s involvement is recognized as an essential component for CB-FRM activities. Yet, their program’s implementation is more oriented towards humanitarian assistance in emergency responses. Even, they often overlook the role of LK. Additionally, the results show a high level of presence of local communities during the preparedness and recovery phases, while NGOs and local governments have a medium role in preparedness and low in recovery phase. The lack of local ownership has also emerged as the major challenge. The research provides valuable insights for integrated CB-FRM policies by adopting to LK practices.

Making Cultural Integration Work——Lessons form the Successful Air France KLM Combination

The reccnt Alcatel Lucent failure is an example of how many mergers run into considerable implementing difficulties in the months following their launch. Despite promising perspectives,no coherent whole seems to come out of the merger,just as anticipated synergies have a hard time materializing.