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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

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

Congenital diaphragmatic hernia survival in an English regional ECMO center

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World Journal of Pediatric Surgery 2023年第2期6卷 77-84页

作者： Elizabeth O'connor Ryo Tamura therese Hannon Sundeep Harigopal Bruce Jaffray Paediatric surgery The Great North Children's HospitalNewcastle upon TyneTyne&WearUK Fetal medicine and obstetrics Royal Victoria InfirmaryNewcastle upon TyneTyne&WearUK Neonatal medicine Royal Victoria InfirmaryNewcastle upon TyneTyne&WearUK

Introduction Congenital diaphragmatic hernia(CDH)remains a cause of neonatal *** aims are to describe contemporary rates of survival and the variables associated with this outcome,contrasting these with our study of two decades earlier and recent *** and methods A retrospective review of all infants diagnosed in a regional center between January 2000 and December 2020 was *** outcome of interest was *** explanatory variables included side of defect,use of complex ventilatory or hemodynamic strategies(inhaled nitric oxide(iNO),high-frequency oscillatory ventilation(HFOV),extracorporeal membrane oxygenation(ECMO),and Prostin),presence of antenatal diagnosis,associated anomalies,birth weight,and *** changes were studied by measuring outcomes in each of four consecutive 63-month *** A total of 225 cases were *** was 60%(134 of 225).Postnatal survival was 68%(134 of 198 liveborn),and postrepair survival was 84%(134 of 159 who survived to repair).Diagnosis was made antenatally in 66%of *** associated with mortality were the need for complex ventilatory strategies(iNO,HFOV,Prostin,and ECMO),antenatal diagnosis,right-sided defects,use of patch repair,associated anomalies,birth weight,and *** has improved from our report of a prior decade and did not vary during the study *** survival has improved despite fewer *** multivariate analysis,the need for complex ventilation was the strongest predictor of death(OR=50,95%CI 13 to 224,p<0.0001),and associated anomalies ceased to be *** Survival has improved from our earlier report,despite reduced numbers of *** may be related to increased use of complex ventilatory strategies.

关键词： Survival termination sided

Pharmacogenetic Treatments for Alcohol and Stimulants

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Pharmacogenetic Treatments for Alcohol and Stimulants

The mutational dynamics of the SARS-CoV-2 virus in serial passages in vitro

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

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Virologica Sinica 2022年第2期37卷 198-207页

作者： Sissy therese Sonnleitner Stefanie Sonnleitner Eva Hinterbichler Hannah Halbfurter Dominik BCKopecky Stephan Koblmüller Christian Sturmbauer Wilfried Posch Gernot Walder Dr.Gernot Walder GmbH Medical LaboratoryDepartment of VirologyAusservillgraten9931Austria Division of Hygiene and Medical Microbiology Medical University of InnsbruckInnsbruck6020Austria Institute of Biology University of GrazGraz8010Austria

Since its outbreak in 2019,Severe Acute Respiratory Syndrome Coronavirus 2(SARS-Co V-2)keeps surprising the medical community by evolving diverse immune escape mutations in a rapid and effective *** gain deeper insight into mutation frequency and dynamics,we isolated ten ancestral strains of SARS-Co V-2 and performed consecutive serial incubation in ten replications in a suitable and common cell line and subsequently analysed them using RT-q PCR and whole genome *** those lines we hoped to gain fundamental insights into the evolutionary capacity of SARS-Co V-2 in *** results identified a series of adaptive genetic changes,ranging from unique convergent substitutional mutations and hitherto undescribed *** region coding for spike proved to be a mutational hotspot,evolving a number of mutational changes including the already known substitutions at positions S:484 and S:*** discussed the evolution of all specific adaptations as well as possible reasons for the seemingly inhomogeneous potential of SARS-Co V-2 in the adaptation to cell *** combination of serial passage in vitro with whole genome sequencing uncovers the immense mutational potential of some SARS-Co V-2 *** observed genetic changes of SARS-Co V-2 in vitro could not be explained solely by selectively neutral mutations but possibly resulted from the action of directional selection accumulating favourable genetic changes in the evolving variants,along the path of increasing potency of the *** among a high number of quasi-species in the SARS-Co V-2 in vitro population gene pool may reinforce directional selection and boost the speed of evolutionary change.

关键词： SARS-CoV-2 Whole genome sequencing(WGS) Mutational dynamics Adaptation Serial passage in vitro

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

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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

Testing of a Full-Scale Composite Floor Plate

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Engineering 2019年第2期5卷 223-233页

作者： Dennis Lam Xianghe Dai therese Sheehan School of Engineering University of Bradford Bradford BD7 IDP United Kingdom

A full-scale composite floor plate was tested to investigate the flexural behavior and in-plane effects of the floor slab in a grillage of composite beams that reduces the tendency for longitudinal splitting of the concrete slab along the line of the primary beams. This is important in cases where the steel decking is discontinuous when it is orientated parallel to the beams. In this case, it is important to demonstrate that the amount of transverse reinforcement required to transfer local forces from the shear connectors can be reduced relative to the requirements of Eurocode 4. The mechanism under study involved in-plane compression forces being developed in the slab due to the restraining action of the floor plate, which was held in position by the peripheral composite beams;while the secondary beams acted as transverse ties to resist the forces in the floor plate that would otherwise lead to splitting of the slab along the line of the primary beams. The tendency for cracking along the center line of the primary beam and at the peripheral beams was closely monitored. This is the first large floor plate test that has been carried out under laboratory conditions since the Cardington tests in the early 1990s, although those tests were not carried out to failure. This floor plate test was designed so that the longitudinal force transferred by the primary beams was relatively high (i.e., it was designed for full shear connection), but the transverse reinforcement was taken as the minimum of 0.2% of the concrete area. The test confirmed that the primary beams reached their plastic bending resistance despite the discontinuous decking and transverse reinforcement at the minimum percentage given in Eurocode 4. Based on this test, a reduction factor due to shear connectors at edge beams without U-bars is proposed.

关键词： Floor plate test Composite beams Edge beams Eurocode 4 In-plane effect Column removal Robustness