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The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

Molecular Plant 2024年第7期17卷 1129-1150页

作者： paula berman Luis Alejandro de Haro Ana-Rita Cavaco Sayantan Panda Younghui Dong Nikolay Kuzmich Gabriel Lichtenstein Yoav Peleg Hila Harat Adam Jozwiaki Jianghua Cai Uwe Heinig Sagit Meir Ilana Rogachev Asaph Aharoni Department of Plant and Environmental Sciences Weizmann Institute of ScienceRehovot 7610001Israel Life Sciences Core Facilities Weizmann Institute of ScienceRehovot 7610001Israel The Maurice and Vivienne Wohl Institute for Drug Discovery Weizmann Institute of ScienceRehovot 7610001Israel Present address:Department of Cell and Metabolic Biology Leibniz Institute of Plant BiochemistryWeinberg 306120 Halle(Saale)Germany Department of Molecular&Cellular Pharmacology University of Miami Miler School of MedicineMiamiFL 33136USA Department of Botany and Plant Sciences University of California RiversideRiversideCA 92521USA Laboratory of Plant Hormones and Development Regulation of Chongqing School of Life SciencesChongqing UniversityChongqing 401331China

Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy ***,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be *** this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine *** employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway *** identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in ***,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline *** together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.

关键词： mescaline Lophophora williamsi Peyote biosynthetic pathway de novo genome sequencing mo-lecular modeling

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Antitumoral effects of cannabis in Notch1-mutated T-cell acute lymphoblastic leukemia

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Cancer Communications 2023年第6期43卷 711-715页

作者： Elazar Besser Anat Gelfand Gil Moshe Lewitus Hila Novak-Kotzer Shiri Procaccia paula berman Igal Louria-Hayon Inbar Shreiber-Livne Yishai Ofran David Meiri The Laboratory of Cancer Biology and Cannabinoid Research Faculty of BiologyTechnion-Israel Institute of TechnologyHaifaIsrael Department of Hematology and Bone Marrow Transplantation Rambam Health Care CampusHaifaIsrael

Dear Editor,In T-cell acute lymphoblastic leukemia(T-ALL),an aggressive hematologic cancer with poor clinical outcomes,more than 50%of cases show NOTCH1-driven transformation[1].The NOTCH1 receptor signaling pathway is activated through a series of proteolytic cleavages,ultimately causing the release of the active intracellular domain(NICD),which translocates to the nucleus where it promotes transcription of target genes involved in cell *** importance of NOTCH1 mutations in T-ALL has generated great interest in the development of anti-NOTCH1 targeted therapies.A new and promising emerging field in cancer treatment is medical *** evidence suggests the direct effects of cannabis on tumor progression in cell lines and animal models[2].Cannabis,and its unique secondary metabolites,known as phytocannabinoids,directly affect the propagation of cancer cells by modulating key cellsignaling pathways[3].We have previously demonstrated that different cannabis extracts,each containing a unique composition of metabolites,selectively impaired the survival of cancer cell lines depending on amatch between the chemical composition of the extract and the characteristics of the specific cancer cell line[4].In the present work,we set out to investigate whether cannabis extracts with unique phytocannabinoid profiles can selectively facilitate antitumor effects in T-ALL cells that harbor a Notch1 mutation.

关键词： Notch1 impaired lymphoblastic

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E2F transcription factors and their complementary roles during DNA damage responses

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Molecular Plant 2023年第9期16卷 1373-1375页

作者： paula Casati Centro de Estudios Fotosinteticos y Bioquimicos(CEFOBl) Universidad Nacional de RosarioSuipacha 5312000 RosarioArgentina

E2F transcription factors(TF)comprise a family of proteins that regulate the expression of genes required for S-phase progression,among *** genome encodes six E2F TFs(E2FA–F),which are classified as typical(E2FA–C)and atypical(E2FD–F)depending on their ability to interact with two DP interaction proteins(DPa and DPb)(Sablowski and Gutierrez,2022).While E2FA–C need to heterodimerize with either DPa or DPb to function,E2FD–F act independently of DP ***,the retinoblastoma-related1(RBR1)protein also binds and inhibits the typical E2F/DP TF complexes when bound to the promoter of genes,repressing their expression in the absence of a signal to enter a new cell *** general,E2FA and E2FB are considered transcriptional activators,while E2FC is generally considered a repressor of cell proliferation(Sablowski and Gutierrez,2022).In addition,it is well documented that E2FB at least,and probably E2FA,can also stimulate the G2/M transition.

关键词： damage E2F complementary

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3D City Models as a Visual Support Tool for the Analysis of Buildings Seismic Vulnerability: The Case of Lisbon

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International Journal of Disaster Risk Science 2017年第3期8卷 308-325页

作者： paula Redweik paula Teves-Costa Inês Vilas-Boas Teresa Santos Instituto Dom Luiz Faculdade de CiênciasUniversidade de Lisboa ESRI Portugal CICS.NOVA–Centro Interdisciplinar de Ciências Sociais Faculdade de Ciências Sociais e HumanasUniversidade Nova de Lisboa

3D city models associate a database of a city to a rigorous geospatial representation that is close to the visible reality by combining appearance, geometry, and semantics. As such, these models may include tools that convey attribute analysis, not only at the statistical level but also in terms of visual appearance of the objects, thus allowing the generation of new knowledge about a phenomenon or its effects. Lisbon is a city with a moderate level of seismic risk, and has been hit in the past by strong earthquakes. Several seismic vulnerability studies of buildings have been carried out in Lisbon. These studies generate different scenarios that consider the magnitude and source location of potential earthquakes. The results of these studies were presented as maps obtained from crossing information contained in 2D layers and presented in a GIS environment. In the present study a seismic vulnerability assessment of Lisbon's buildings held in 2D is extended to the third dimension, which refines the resolution and the set of parameters and explores the gains of spatial analysis in 3D representations. The numerous parameters that contribute to assess seismic vulnerability of buildings may be analyzed individually or simultaneously as well as in multiple seismic scenarios. Although covering all residential buildings in Lisbon, the application of the 3Dcity model is demonstrated with more detail in three pilot areas.

关键词： 3D-GIS 3D models Building vulnerability Lisbon Seismic scenarios

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Striatum-specific mechanisms regulate neuronal cell cycle re-entry:the choice between life and death

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Neural Regeneration Research 2023年第3期18卷 523-524页

作者： paula Dietrich Ioannis Dragatsis Department of Physiology The University of TennesseeHealth Science CenterMemphisTNUSA

Mitochondria dysfunction occurs in the aging brain as well as in several neurodegenerative disorders and predisposes neuronal cells to enhanced sensitivity to *** particular,defects in any of the mitochondria respiratory chain complexes lead to impaired adenosine triphosphate production resulting in diseases that often affect the central nervous *** instance,innate deficits in succinate dehydrogenase(SDH)mitochondria respiratory chain complex II activity caused by genetic mutations in SDH subunits lead to early-onset neurodegeneration(Jain-Ghai et al.,2013),while several adult-onset genetic neurodegenerative disorders are associated with variable levels of complex II deficiency in the central nervous system(Túnez et al.,2010).Also,chemically induced complex II deficiency leads to neurodegeneration.

关键词： SDH impaired cycle

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Forecasting patient demand at urgent care clinics using explainable machine learning

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CAAI Transactions on Intelligence Technology 2023年第3期8卷 712-733页

作者： Teo Susnjak paula Maddigan School of Mathematical and Computational Sciences Massey UniversityAucklandNew Zealand

Urgent care clinics and emergency departments around the world periodically suffer from extended wait times beyond patient expectations due to surges in patient *** delays arising from inadequate staffing levels during these periods have been linked with adverse clinical *** research into forecasting patient flows has mostly used statistical *** studies have also predominately focussed on short‐term forecasts,which have limited practicality for the resourcing of medical *** study joins an emerging body of work which seeks to explore the potential of machine learning algorithms to generate accurate forecasts of patient *** research uses datasets covering 10 years from two large urgent care clinics to develop long‐term patient flow forecasts up to one quarter ahead using a range of state‐of‐the‐art algo-rithms.A distinctive feature of this study is the use of eXplainable Artificial Intelligence(XAI)tools like Shapely and LIME that enable an in‐depth analysis of the behaviour of the models,which would otherwise be *** analysis tools enabled us to explore the ability of the models to adapt to the volatility in patient demand during the COVID‐19 pandemic lockdowns and to identify the most impactful variables,resulting in valuable insights into their *** results showed that a novel combination of advanced univariate models like Prophet as well as gradient boosting,into an ensemble,delivered the most accurate and consistent solutions on *** approach generated improvements in the range of 16%-30%over the existing in‐house methods for esti-mating the daily patient flows 90 days ahead.

关键词： data mining explainable AI forecasting machine learning patient flow urgent care clinics

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King's College criteria and the Clichy-Villejuif criteria require adjustments for assessing acute liver failure due to yellow fever

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World Journal of Transplantation 2025年第1期15卷 124-134页

作者： Bruno da Silva Athanasio Antonio Marcio de Faria Andrade Vivian Vasconcelos Costa Juliano Felix Castro Silverio Leonardo Macedo Garcia Mauro Martins Teixeira Daniele da Gloria Souza paula Vieira Teixeira Vidigal Cristiano Xavier Lima Department of Surgery Federal University of Minas GeraisBelo Horizonte 30130-100Minas GeraisBrazil Liver Transplantation Unit Felicio Rocho HospitalBelo Horizonte 30110-934Minas GeraisBrazil Department of Morphology Federal University of Minas GeraisBelo Horizonte 31270-901Minas GeraisBrazil Department of Biochemistry and Immunology Federal University of Minas GeraisBelo Horizonte 31270-901Minas GeraisBrazil Department of Pathology Federal University of Minas GeraisBelo Horizonte 30130-100Minas GeraisBrazil

BACKGROUND Acute liver failure(ALF)is a severe condition characterized by rapid deterioration of liver function in individuals without preexisting liver *** transplantation(LT)is the most impactful *** fever(YF)is an infectious disease that primarily affects the liver and has a high mortality ***,LT can be a viable option for treating rare cases with extensive liver ***,the criteria for assessing the severity of ALF and determining the indications for transplantation have not been specifically validated for cases caused by *** To present necessary adjustments to established scoring systems for ALF secondary to *** This was an observational,retrospective,single-center *** consecutive patients with confirmed ALF due to YF were monitored in the intensive care unit by a specialized liver transplant team during a three-month epidemic outbreak in *** hospitalization,general supportive therapeutic measures were implemented,and the patients were regularly assessed using the King's College criteria and the Clichy-Villejuif criteria to determine the severity of liver *** is considered a viable measure for patients with signs of end-stage liver *** Eight of 14(57%)patients developed severe neurological alterations within the first 96 hours after hospital *** patients underwent emergency LT,and despite a moderate viral infection of the graft after transplantation,the 5-year survival rate was 50%.Although the King's College criteria and the Clichy-Villejuif criteria are the main scoring systems for ALF,they are insufficient for predicting the risk of mortality in this context,primarily because of low serum bilirubin levels in the final stage of the disease and significant disparities between coagulation abnormalities and patient *** To ensure good applicability in cases of YF-induced ALF,the authors suggest adaptations to the King's College and Clichy-Vill

关键词： Yellow fever Acute liver failure Liver transplantation King's College criteria Clichy-Villejuif criteria

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Impact of weather conditions and building design on contaminant infiltration from crawl spaces in Swedish schools-Numerical modeling using Monte Carlo method

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Building Simulation 2022年第5期15卷 845-858页

作者： Fredrik Domhagen paula Wahlgren Carl-Eric Hagentoft Department for Architecture and Civil Engineering Division of Building TechnologyChalmers University of TechnologySE-41296GothenburgSweden

Some Swedish school buildings built in the 1960s and 1970s experience indoor air quality problems,where the contaminants are suspected to come from the crawl space underneath the *** poor indoor air quality causes discomfort among pupils and *** an exhaust fan to maintain a negative pressure difference in the crawl space relative to indoors or increasing the ventilation in the classroom are two examples of common measures taken to improve the indoor air ***,these measures are not always effective,and sometimes the school building has to be *** relation between pressure distribution,contaminant concentration in the classroom,outdoor temperature,wind,mechanical ventilation,and air leakage distribution is complex.A better understanding of these relations is crucial for making decisions on the most efficient measure to improve the indoor air *** this paper,a model for contaminant infiltration from the crawl space is used together with the Monte Carlo method to study these *** are performed for several cases where different building shapes,building orientations,shielding conditions,and geographical locations are *** show,for example,that for a building with an imbalanced ventilation system,air is leaking from the crawl space to the classroom for the majority of cases and that concentration levels in the classroom are usually the highest during mild and calm days.

关键词： airtightness air permeability Monte Carlo method infiltration model crawl space indoor air quality

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Numerical Approach of a Coupled Pressure-Saturation Model Describing Oil-Water Flow in Porous Media

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Communications on Applied Mathematics and Computation 2023年第2期5卷 946-964页

作者： paula Luna Arturo Hidalgo ISIS Neutron and Muon Source Rutherford Appleton LaboratoryDidcot OX110QXUK Departamento de Ingeniería Geológica y Minera Escuela Técnica Superior de Ingenieros de Minas y EnergíaCenter for Computational SimulationUniversidad Politécnica de MadridRíos Rosas2128003 MadridSpain

Two-phase flow in porous media is a very active field of research,due to its important applications in groundwater pollution,CO_(2)sequestration,or oil and gas production from petroleum reservoirs,just to name a few of *** flow equations,which make use of Darcy's law,for describing the movement of two immiscible fluids in a porous medium,are among the most relevant mathematical models in reservoir *** work aims to solve a fractional flow model formed by an elliptic equation,representing the spatial distribution of the pressure,and a hyperbolic equation describing the space-time evolution of water *** numerical solution of the elliptic part is obtained using a finite-element(FE)scheme,while the hyperbolic equation is solved by means of two dif-ferent numerical approaches,both in the finite-volume(FV)*** is based on a monotonic upstream-centered scheme for conservation laws(MUSCL)-Hancock scheme,whereas the other makes use of a weighted essentially non-oscillatory(ENO)*** both cases,a first-order centered(FORCE)-αnumerical scheme is applied for inter-cell flux reconstruction,which constitutes a new contribution in the field of fractional flow models describing oil-water movement.A relevant feature of this work is the study of the effect of the parameterαon the numerical solution of the models *** also show that,in the FORCE-αmethod,when the parameterαincreases,the errors diminish and the order of accuracy is more properly attained,as verified using a manufactured solution technique.

关键词： Two-phase flow Reservoir simulation Porous media FORCE-α Finite volume

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Identification of Pu and U isotopic composition and its applications in environmental and CBRN research

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Defence Technology（防务技术） 2021年第3期17卷 728-740页

作者： Susanna Salminen-Paatero paula Vanninen Jussi Paatero Department of Chemistry RadiochemistryP.O.Box 55FI-00014University of HelsinkiFinland VERIFIN-Finnish Institute for the Verification of the Chemical Weapons Convention Department of ChemistryP.O.Box 55FI-00014University of HelsinkiFinland Finnish Meteorological Institute Observation ServicesP.O.Box 503FI-00101HelsinkiFinland

This paper describes the most common presently used methods for detecting uranium and plutonium isotopes after their introduction to environment. Known isotope ratios of U and Pu in different nuclear events are important tool for characterizing the sources of nuclear material. Detection techniques both in field and in laboratory are presented, as well as different models that can be used for identifying the origin and age of the nuclear material. Identification of the source of nuclear material in environmental samples is needed for estimating the quality and quantity of the nuclear hazard. This information is essential in risk assessment and crisis management, in chemical, biological, radiological and nuclear(CBRN) research after e.g. a terrorist attack, in radioecology and environmental radioactivity research.

关键词： CBRN Nuclear contamination Plutonium isotope ratios Uranium isotope ratios Nuclear fingerprinting Nuclear particle

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