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Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： GERHARD HAMILTON MARIE-therese EGGERSTORFER SANDRA STICKLER Institute of Pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

Levant Drought Occurrence, Lebanon Case

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Atmospheric and Climate Sciences 2024年第1期14卷 118-127页

作者： Ihab Jomaa Mariam Choker Nisrine El Haj Marie therese Abi Saab Matteo Funaro Simone Mereu Department of Irrigation and AgroMeteorology (DIAM) of the Lebanese Agriculture Research Institute (LARI) Tal Amara Lebanon Climate and Water Unit Lebanese Agricultural Research Institute Fanar Lebanon CMCC—Centro Euro-Mediterraneo sui Cambiamenti Climatici IAFES Division Sassari Italy

Rainfall data is probably one of the longest-recorded climatic parameters in Lebanon. On the central coast of Lebanon, the Beirut weather station started collecting rainfall data in 1876. However, the recorded data is not available at one data provider source. Published data is found in historical documents but it reaches the early 1970s and then appears a data gap till 1990. Still the data is available, but it might be found to be saved privately. This study investigated the SPI variability on annual time scale between the years 1876 and 2021. The SPI was computed using R-Stat software to compare every year between 1876 and 2021. The majority (about 70% of the years) of the years are near normal in the precipitation rate. The Standardized Precipitation Index (SPI) demonstrated a normal distribution of years. Dry and wet years constitute about 15% of the total 146 years (1876-2021). Extremely dry years might appear in two consecutive years between 50 to 60 years count. After 1991, there were no wet years it was only near normal and few dry years. The last 30 years showed a trend of increasing drought years without any occurrence of wet years. This study demonstrated the importance of keeping records of at least rainfall data and it must be recorded on a daily basis or intensity on time. It is highly important on a managerial basis and for water security reasons to understand the drought event occurrence and investigate the changes in rainfall rates. Climate change scenarios always forecast a decrease in rainfall rates which will not appear without such studies.

关键词： Climate Change Standardized Precipitation Index (SPI) Beirut Rainfall Gag-es

From Solar System to Exoplanets:What can we learn from Planetary Spectroscopy?

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Research in Astronomy and Astrophysics 2022年第12期22卷 1-14页

作者： therese Encrenaz LESIA Paris Observatory-PSL UniversitéCNRSSorbonne UniversitéUniversitéde ParisParisFrance

The purpose of this paper is to address the question:Using our knowledge of infrared planetary spectroscopy,what can we learn about the atmospheres of exoplanets?In a first part,a simplified classification of exoplanets,assuming thermochemical equilibrium,is presented,based on their masses and their equilibrium temperatures,in order to propose some possible estimations about their atmospheric *** the second part,infrared spectra of planets are discussed,in order to see what lessons can be drawn for exoplanetary *** the last part,we consider the solar system as it would appear from a star located in the ecliptic *** first appears that the solar system(except in a few specific cases)would not be seen as a multiple system,because,contrary to many exoplanetary systems,the planets are too far from the Sun and the inclinations of their orbits with respect to the ecliptic plane are too *** transit synthetic spectra of solar system planets are used to discuss the relative merits of transmission and direct emission spectroscopy for probing exoplanetary atmospheres.

关键词： planets and satellites:atmospheres planets and satellites:composition (stars:)planetary systems

Pharmacogenetic Treatments for Alcohol and Stimulants

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Pharmacogenetic Treatments for Alcohol and Stimulants

Usability perceptions and beliefs about smart thermostats by chi-square test, signal detection theory, and fuzzy detection theory in regions of Mexico

自主创新与持续增长第十一届中国科协年会

作者： Thomas R.kosten therese kosten Colin Haile Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine

Pharmacogenetics uses genetic tests to predict the effectiveness of medication treatments for individual patients with drug dependence such as alcohol and opiates. An important shared neurobiological component of the reinforcement and dependence on alcohol and opiates is alcohol’s enhancement of β- endorphin release. The physiological and subjective effects of both alcohol and opiates are associated with β-endorphin and the mu opiate system. A pharmacotherapy that has been effective for both disorders is naltrexone, which increases baseline β-endorphin release blocking further release by alcohol. Naltrexone’s action as an alcohol pharmacotherapy is facilitated by a putative functional single nucleotide polymorphism (SNP) in the opioid mu receptor gene (Al18G) which alters its receptor function. Patients with this SNP have significantly lower relapse rates to alcoholism when treated with naltrexone. This SNP is particularly common among northern Chinese suggesting an important role for naltrexone treatment of alcoholism in China. Another important genetic polymorphism related to stimulant and perhaps other types of dependence frequently occurs (about 40% of the population) in the promoter region of the gene coding for dopamine beta hydroxylase (DβH). This polymorphism leads to 10 to 100 times lower levels of the DβH enzyme, which converts dopamine to norepinephrine in neurons. Stimulant abusers with normal levels of this enzyme show significant reductions in stimulant abuse when treated with DβH inhibitors, while those with the polymorphism for low DβH levels show no treatment efficacy with these medications. Pharmacogenetics has great potential for improving treatment outcome as we identify gene variants that affect pharmacodynamic as well as the more commonly studied pharmacokinetic factors. These mutations can guide pharmacotherapeutic agent choice for optimum treatment of alcohol and stimulant abuse and reduce relapse after successful initial abstinence.

关键词： pharmacogenetic treatments alcohol stimulants

来源： cnki会议评论

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Frontiers in Energy 2019年第3期13卷 522-538页

作者： Pedro PONCE therese PEFFER Arturo MOLINA Tecnologico de Monterrey calle del puente 222 MexicoMexico CityNon-US/Non-Canadian 64849Mexico California Institute for Energy and Environment University of California BerkeleyBerkeleyCA 94720USA

It is well known that smart thermostats (STs) have become key devices in the implementation of smart homes;thus, they are considered as primary elements for the control of electrical energy consumption in households. Moreover, energy consumption is drastically affected when the end users select unsuitable STs or when they do not use the STs correctly. Furthermore, in future, Mexico will face serious electrical energy challenges that can be considerably resolved if the end users operate the STs in a correct manner. Hence, it is important to carry out an in-depth study and analysis on thermostats, by focusing on social aspects that influence the technological use and performance of the thermostats. This paper proposes the use of a signal detection theory (SDT), fuzzy detection theory (FDT), and chi-square (CS) test in order to understand the perceptions and beliefs of end users about the use of STs in Mexico. This paper extensively shows the perceptions and beliefs about the selected thermostats in Mexico. Besides, it presents an in-depth discussion on the cognitive perceptions and beliefs of end users. Moreover, it shows why the expectations of the end users about STs are not met. It also promotes the technological and social development of STs such that they are relatively more accepted in complex electrical grids such as smart grids.

关键词： thermostats perceptions beliefs signal detection theory (SDT) fuzzy signal detection theory (FSDT) chi-square (CS) test

Modeling analytics in COVID-19: prediction, prevention, control, and evaluation

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Journal of Management Analytics 2021年第3期8卷 424-442页

作者： Yang Lu therese L.Williams Department of Information Systems and Operations Management University of Central OklahomaEdmondOKUSA

The outbreak of COVID-19 has attracted attention from all around the *** and institutions have adopted ways to fight COVID-19, but itsprevalence is still strong. The SIR model has important reference value for thenovel coronavirus epidemic, offering both preventive measures and the ability topredict future trends. Based on an analysis of the classical epidemiological SIRmodel along with key parameters, this paper aims to analyze the patterns ofCOVID-19, to discuss potential anti-COVID-19 measures, and to explain whywe need to conduct appropriate measures against COVID-19. The use of theSIR model can play an important role in public health emergencies. Among theparameters of the SIR model, the contact ratio and the reproduction ratio arethe factors that have the potential to mitigate the consequences of ***-COVID-19 measures include wearing a mask, washing one’s hands,keeping social distance, and staying at home if possible.

关键词： COVID-19 epidemiological compartment model SIR model the contact ratio the reproduction ratio social distancing

Blast disruption using 3D grids/perforated plates for vehicle protection

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Defence Technology(防务技术) 2023年第7期25卷 60-68页

作者： therese Schunck Dominique Eckenfels Laurent Sinniger French-German Research Institute of Saint-Louis ISL5 Rue Du General Cassagnou68300Saint-LouisFrance

In this work, blast disruption and mitigation using 3D grids/perforated plates were tested for underbelly and side protection of vehicles. Two vehicle simulants were used: a small-scale one for side vehicle protection assessment and a true-to-scale simulant for underbelly protection testing. The deformation of target plates was assessed. These were either unprotected or protected by three different types of disruptors. The first disruptor was made of a sandwich structure of two perforated plates filled with a thin aluminum structure allowing the air to pass through. The two other disruptors were made of pieces of cast metallic foam. Two different kinds of foams were used: one with large cells and the second one with small cells. Beforehand, the mitigation efficiency of the disruptors was evaluated using an explosivedriven shock tube(EDST). The experiments showed that blast disruption/mitigation by 3D grid/perforated plate structures was not suitable for vehicle side protection. However, 3D grids/perforated structures proved to be relatively effective for underbelly protection compared to an equivalent mass of steel.

关键词： Blast Mitigation Perforated plates 3D grids Vehicle protection

酒精和精神兴奋剂依赖的遗传药理学治疗(英文)

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中国药物依赖性杂志 2009年第4期18卷 241-248,282页

作者： Thomas R.kosten therese kosten Colin HAILE Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine

遗传药理学使用基因检测的方法预测药物治疗对酒精或阿片类物质依赖患者个体的有效性。酒精和阿片类物质产生强化效应和依赖的共同神经生物学基础是增加β-内啡肽释放。酒精和阿片类物质引起的生理和主观效应都与β-内啡肽和μ阿片受体... 详细信息

遗传药理学使用基因检测的方法预测药物治疗对酒精或阿片类物质依赖患者个体的有效性。酒精和阿片类物质产生强化效应和依赖的共同神经生物学基础是增加β-内啡肽释放。酒精和阿片类物质引起的生理和主观效应都与β-内啡肽和μ阿片受体有密切的关系。纳曲酮治疗是一种对酒精和阿片依赖均有效的治疗方法,其能增加β-内啡肽的基础释放量,从而抑制酒精引起的β-内啡肽进一步释放。纳曲酮在治疗酒精依赖中的作用被认为与μ阿片受体基因(Al18G)的功能性单核苷酸多态性(SNP)有关。具有这种单核苷酸多态性的酒精依赖患者使用纳曲酮治疗后复发率低。这种单核苷酸多态性在中国北方人中较为常见,因此提示了纳曲酮治疗酒精依赖在中国的重要性。另一个与精神活性物质或其他药物依赖相关的重要基因多态性多发生于编码多巴胺β-羟化酶(DβH)基因的启动子区域。这种基因多态性可导致多巴胺β-羟化酶水平降低10 -100倍,使神经元中的多巴胺转化为去甲肾上腺素。多巴胺β-羟化酶水平正常的精神活性物质依赖患者采用多巴胺β-羟化酶抑制剂治疗能明显减少药物滥用,而多巴胺β-羟化酶水平低的患者采用该疗法治疗无效。遗传药理学在改善治疗效果方面有巨大的潜力。我们已经鉴别出能影响药效学和药代动力学因素的基因变异体。这些变异能够指导药物治疗的选择,使酒精和精神活性物质滥用患者得到最优化的治疗,降低戒断后的复吸率。

关键词：遗传药理学治疗酒精兴奋剂

Review on Dynamic Bandwidth Allocation of GPON and EPON

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Journal of Electronic Science and Technology 2020年第4期18卷 297-307页

作者： Theresal Thangappan Brintha therese Adi Suvarnamma Gadda Sai Swapna School of Electronics and Communication Engineering Vellore Institute of Technology(Chennai Campus)Chennai 632014 School of Electronics and Communication Engineering Vels UniversityChennai 600117 School of Electronics and Communication Engineering Government Polytechnic CollegeAdhoni 518301

The passive optical network(PON)technology has been drastically improved in recent *** spite of using the optical technology,the utilization of the entire bandwidth is a very challenging *** main categories of PON are the Ethernet passive optical network(EPON)and gigabit passive optical network(GPON).These two networks use the dynamic bandwidth allocation(DBA)algorithm to attain the maximum usage of bandwidth,which is provided in the network dynamically according to the need of the customers with the support of the service level agreement(SLA).This paper will provide a clear review about the DBA algorithm of both technologies as well as the comparison。

关键词： Dynamic bandwidth allocation(DBA) Ethernet passive optical network(EPON) gigabit passive optical network(GPON)