22,530 research outputs found
Giardia cyst wall protein 1 is a lectin that binds to curled fibrils of the GalNAc homopolymer.
No full textThe infectious and diagnostic stage of Giardia lamblia (also known as G. intestinalis or G. duodenalis) is the cyst. The Giardia cyst wall contains fibrils of a unique beta-1,3-linked N-acetylgalactosamine (GalNAc) homopolymer and at least three cyst wall proteins (CWPs) composed of Leu-rich repeats (CWP(LRR)) and a C-terminal conserved Cys-rich region (CWP(CRR)). Our goals were to dissect the structure of the cyst wall and determine how it is disrupted during excystation. The intact Giardia cyst wall is thin (approximately 400 nm), easily fractured by sonication, and impermeable to small molecules. Curled fibrils of the GalNAc homopolymer are restricted to a narrow plane and are coated with linear arrays of oval-shaped protein complex. In contrast, cyst walls of Giardia treated with hot alkali to deproteinate fibrils of the GalNAc homopolymer are thick (approximately 1.2 microm), resistant to sonication, and permeable. The deproteinated GalNAc homopolymer, which forms a loose lattice of curled fibrils, is bound by native CWP1 and CWP2, as well as by maltose-binding protein (MBP)-fusions containing the full-length CWP1 or CWP1(LRR). In contrast, neither MBP alone nor MBP fused to CWP1(CRR) bind to the GalNAc homopolymer. Recombinant CWP1 binds to the GalNAc homopolymer within secretory vesicles of Giardia encysting in vitro. Fibrils of the GalNAc homopolymer are exposed during excystation or by treatment of heat-killed cysts with chymotrypsin, while deproteinated fibrils of the GalNAc homopolymer are degraded by extracts of Giardia cysts but not trophozoites. These results show the Leu-rich repeat domain of CWP1 is a lectin that binds to curled fibrils of the GalNAc homopolymer. During excystation, host and Giardia proteases appear to degrade bound CWPs, exposing fibrils of the GalNAc homopolymer that are digested by a stage-specific glycohydrolase
CE Challenges: Work to Do
No full textCE has been used for more than two decades now. Despite many successes and advantages, there are still many challenges to be addressed. These challenges are both technical and organisational. In the paper we will address the current challenges of CE. Many challenges are related to the exchange of data and knowledge and to the systems that make data and knowledge exchange possible. Although much progress has been made in enabling extensive data and knowledge exchange and use, much remains to be wished. For example, there are still barriers to data exchange. Technically, these barriers may consist of different formats, differences in infrastructures and systems, and different semantics. There are also organisational and political barriers. For example, investment in information system may heavily impact upstream suppliers, while revenues of better information exchange may predominantly be gained by downstream actors. Without sharing costs and revenues, chain-wide information exchange will not be easily realised. Another barrier is the possible lack of willingness to share information, because of potential misuse of knowledge and loss of power. The paper is organised as follows. First we will describe the current manifestation of CE as described in a recent book. Second, we will list current trends in CE. Third, we will present some Critical Success Factors (CSFs) that are considered relevant for implementing and adapting CE practices. Last, we indicate some research and practical questions to be addressed, especially for areas that have a high potential and actual impact. </p
Redox modulation and hematological malignancies : from preclinical study of an aldehyde dehydrogenase inhibitor to phase I trial
No full textNous développerons cette thèse en 4 temps :1) par un article donnant notre vision des mécanismes d’échappement tumoral aux thérapies ciblées grâce à une approche préliminaire par l’analyse tumorale en technique de « cellule seule », nous émettons des hypothèses quant aux options stratégiques de traitement des leucémies, 2) nous nous intéresserons à l’impact du DIMATE sur les effecteurs du système immunitaire, puisque les approches d’immunothérapie sont devenues à l’heure actuelle complémentaires des chimiothérapies,3) nous tenterons de comprendre les altérations redox complexes des cellules blastiques tout en identifiant le mécanisme d'action du DIMATE. Nous nous efforcerons d’'identifier de nouveaux biomarqueurs dans la LAM en relation avec le statut redox des cellules leucémiques grâce à une vaste cohorte prospective d'échantillons de patients atteints de LAM, tout en mettant au point des tests-compagnons de la réponse aux médicaments,4) l’ensemble de ce travail étant la base de l’essai clinique de phase I que nous espérons débuter fin 2021-2022 (PI et coordonateur national, Pr R. Costello ; responsable essai CLIPP AP-HM, Dr J Colle).We will develop this thesis in 4 steps:1) Through a paper giving our vision of the mechanisms of tumor escape to targeted therapies thanks to a preliminary approach by tumor analysis in "cell-only" technique, we hypothesize about strategic options for leukemia treatment,2) We will investigate the impact of DIMATE on immune system effectors, as immunotherapy approaches have become complementary to chemotherapies,3) We will try to understand the complex redox alterations of blast cells while identifying the mechanism of action of DIMATE. We will strive to identify new biomarkers in AML related to the redox status of leukemic cells through a large prospective cohort of AML patients, while developing companion assays for drug response,4) All of this work being the basis of the phase I clinical trial that we hope to start in late 2022 (PI and national coordinator, Pr R. Costello; CLIPP AP-HM trial manager, Dr J Colle)
Bioenergetic and molecular analysis of Costello Syndrome pathophysiology
No full textLes mutations germinales activatrices de la voie RAS sont responsables de maladies rares regroupées sous le nom de RASopathies : le Syndrome de Noonan, le Syndrome de Noonan avec de Multiples Lentigines, la Neurofibromatose de type 1, le Syndrome de Malformations Capillaires et Malformations Artério-Veinseuses, le Syndrome Cardio-Facio-Cutané, le Syndrome de Legius et le Syndrome de Costello. Cette thèse s’intéresse au syndrome de Costello causé par une mutation hétérozygote de novo du gène HRAS. Ce syndrome est révélé dans les premiers mois de la vie et se caractérise par un retard de croissance postnatal, des traits du visage épais, un déficit intellectuel, des anomalies cutanées, ainsi qu’une prédisposition à développer des tumeurs. De plus, les patients atteints du syndrome de Costello développent une cardiomyopathie hypertrophique, de l’hypertension, une hypotonie et une myopathie d'origine moléculaire inconnue. En lien avec une association de malade et le service de génétique du CHU de Bordeaux, nous avons mené une exploration des anomalies protéomiques dans les tissus d’une souris modèle du syndrome de Costello ainsi que dans des fibroblastes de patients et des cellules modèles exprimant les formes mutées de HRASG12S et HRASG12A. Cette analyse globale et sans a priori a révélé des altérations au niveau du métabolisme énergétique et plus particulièrement de la composition des mitochondries. Le déficit fonctionnel des mitochondries, centrale énergétique du corps humain, a été caractérisé par des approches de biochimie, de bioénergétique et de biologie cellulaire. De plus, l’analyse des données ‘omiques’ a permis de suggérer une nouvelle hypothèse dans la physiopathologie du syndrome de Costello. Cette hypothèse considère l’implication d’un micro-ARN, le miR-221* dans l’inhibition du métabolisme oxydatif. Les analyses génétiques réalisées sur les cellules de patients et les cellules modèles ont démontré l’inhibition de l’expression de la protéine AMPK, un régulateur majeur du métabolisme mitochondrial, par le miR-221* sous le contrôle de HRASG12S et HRASG12A. Ces découvertes ont permis d’élaborer une stratégie thérapeutique visant à réduire la cardiomyopathie dans le syndrome de Costello. Les analyses précliniques effectuées sur les modèles cellulaires et le modèle murin ont permis d’évaluer l’efficacité d’une stimulation pharmacologique du métabolisme mitochondrial. Cette thèse révèle donc l’implication des mitochondries dans le syndrome de Costello et l’analyse moléculaire réalisée propose une série de données ‘Omiques’ qui permettront de progresser dans la compréhension de cette maladie rare.Germline activating mutations of the RAS pathway are responsible for rare diseases grouped under the name of RASopathies: Noonan Syndrome, Noonan Syndrome with multiple Lentigines, Type 1-neurofibromatosis, Capillaries malformations and arteriovenous malformations syndrome, Cardio-Facio-Cutaneous Syndrome, Legius Syndrome and Costello Syndrome. This Ph.D thesis focuses on Costello syndrome that is caused by a heterozygous de novo mutation of the HRAS gene. This syndrome is revealed in the first months of life and is characterized by postnatal growth retardation, thick facial features, intellectual deficit, skin abnormalities, and a predisposition to developing tumors. In addition, patients with Costello syndrome develop hypertrophic cardiomyopathy, hypertension, hypotonia and myopathy of unknown molecular origin. In connection with a patients association and the genetics department of Bordeaux University Hospital, we conducted an exploration of proteomic abnormalities in the tissues of a mouse model of the Costello syndrome as well as in patients’ fibroblasts and cell models expressing mutated forms of HRASG12S and HRASG12A. This global and unbiased analysis revealed alterations in energy metabolism and more particularly in the composition of mitochondria. The functional deficiency of mitochondria, energy plants of the human body, has been characterized by biochemistry, bioenergetics and cell biology approaches. In addition, the 'omic' analysis of Costello syndrome suggested a new pathophysiology hypothesis that considered the involvement of a microRNA, miR-221* in the alteration of oxidative metabolism. Functional genetic analyzes performed on patient cells and cell models demonstrated the inhibition of the expression of the major mitochondrial metabolism regulator AMPK protein by miR-221* under the control of HRASG12S and HRASG12A. These findings led to the development of a preclinical therapeutic strategy to reduce cardiomyopathy in Costello syndrome. Preclinical investigations performed on the cellular models and the murine model made it possible to evaluate the efficacy of a pharmacological stimulation of mitochondrial metabolism. This thesis thus reveals the involvement of mitochondria in Costello syndrome and the molecular analysis carried out makes available a series of 'Omics' data that will allow progress in the understanding of this rare disease
Synthesis optimization and charge carrier transfer mechanism in LiLuSiO<sub>4</sub>:Ce, Tm storage phosphor
No full textLiLuSiO4:Ce and LiLuSiO4:Ce, Tm show very efficient charge carrier storage properties upon beta irradiation after samples have received treatment in vacuum. They outperform the commercial storage phosphor BaFBr(I):Eu2+ in many aspects. The influence of the synthesis conditions, Ce and Tm concentration, nonstoichiometry and codoping with Ca, Hf, Al and Ge are reported. Based on the results of the synthesis optimization, thermoluminescence (TL) emission and TL excitation spectra a mechanism of charge carrier transfer, storage, and recombination during irradiation and thermal or optical readout is proposed.Accepted Author ManuscriptRST/Fundamental Aspects of Materials and EnergyRST/Luminescence Material
Chymotrypsin C is a co-activator of human pancreatic procarboxypeptidases A1 and A2.
No full textHuman digestive carboxypeptidases CPA1, CPA2, and CPB1 are secreted by the pancreas as inactive proenzymes containing a 94–96-amino acid-long propeptide. Activation of procarboxypeptidases is initiated by proteolytic cleavage at the C-terminal end of the propeptide by trypsin. Here, we demonstrate that subsequent cleavage of the propeptide by chymotrypsin C (CTRC) induces a nearly 10-fold increase in the activity of trypsin-activated CPA1 and CPA2, whereas CPB1 activity is unaffected. Other human pancreatic proteases such as chymotrypsin B1, chymotrypsin B2, chymotrypsin-like enzyme-1, elastase 2A, elastase 3A, or elastase 3B are inactive or markedly less effective at promoting procarboxypeptidase activation. On the basis of these observations, we propose that CTRC is a physiological co-activator of proCPA1 and proCPA2. Furthermore, the results confirm and extend the notion that CTRC is a key regulator of digestive zymogen activation
The impact of P(NDI2OD-T2) crystalline domains on the open-circuit voltage of bilayer all-polymer solar cells with an inverted configuration
No full textWe fabricated P(NDI2OD-T2)/PTB7 bilayer all-polymer solar cells with an inverted configuration, where the annealing temperature was systematically varied. The current density-voltage behavior was investigated and the structural properties of the P(NDI2OD-T2) layers were characterized. Absorption spectroscopy, surface morphology, and crystallite analysis showed that increasing phase segregation of P(NDI2OD-T2) films occurred as the annealing temperature increased. We found that, as the P(NDI2OD-T2) stacking improved, with larger domains, the open-circuit voltage decreased and the saturation dark current density increased. This work provides a guide for the processing of P(NDI2OD-T2) layers to maximize the power conversion efficiency of all-polymer solar cells. (C) 2015 Author(s).open1186sciescopu
Data and code for: Variational Graph Author Topic Modeling
No full textThis is the tensorflow implementation of KDD-2022 paper "Variational Graph Author Topic Modeling" by Delvin Ce Zhang and Hady W. Lauw.
VGATM is a Graph Neural Network model that extracts interpretable topics for documents with authors and venues. Topics of documents then fulfill document classification, citation prediction, etc.
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Updated analytical solutions of continuity equation for electron beams precipitation – I. Pure collisional and pure ohmic energy losses
No full textWe present updated analytical solutions of continuity equations for power-law beam electrons precipitating in (a) purely collisional losses and (b) purely ohmic losses. The solutions of continuity equation (CE) normalized on electron density presented in Dobranskis & Zharkova are found by method of characteristics eliminating a mistake in the density characteristic pointed out by Emslie et al. The corrected electron beam differential densities (DD) for collisions are shown to have energy spectra with the index of −(γ + 1)/2, coinciding with the one derived from the inverse problem solution by Brown, while being lower by 1/2 than the index of −γ/2 obtained from CE for electron flux. This leads to a decrease of the index of mean electron spectra from −(γ − 2.5) (CE for flux) to −(γ − 2.0) (CE for electron density). The similar method is applied to CE for electrons precipitating in electric field induced by the beam itself. For the first time, the electron energy spectra are calculated for both constant and variable electric fields by using CE for electron density. We derive electron DD for precipitating electrons (moving towards the photosphere, μ = +1) and ‘returning’ electrons (moving towards the corona, μ = −1). The indices of DD energy spectra are reduced from −γ − 1 (CE for flux) to −γ (CE for electron density). While the index of mean electron spectra is increased by 0.5, from −γ + 0.5 (CE for flux) to −γ + 1(CE for electron density). Hard X-ray intensities are also calculated for relativistic cross-section for the updated differential spectra revealing closer resemblance to numerical Fokker–Planck (FP) solutions
Analyse bioénergétique et moléculaire de la physiopathologie du Syndrome de Costello
No full textGermline activating mutations of the RAS pathway are responsible for rare diseases grouped under the name of RASopathies: Noonan Syndrome, Noonan Syndrome with multiple Lentigines, Type 1-neurofibromatosis, Capillaries malformations and arteriovenous malformations syndrome, Cardio-Facio-Cutaneous Syndrome, Legius Syndrome and Costello Syndrome. This Ph.D thesis focuses on Costello syndrome that is caused by a heterozygous de novo mutation of the HRAS gene. This syndrome is revealed in the first months of life and is characterized by postnatal growth retardation, thick facial features, intellectual deficit, skin abnormalities, and a predisposition to developing tumors. In addition, patients with Costello syndrome develop hypertrophic cardiomyopathy, hypertension, hypotonia and myopathy of unknown molecular origin. In connection with a patients association and the genetics department of Bordeaux University Hospital, we conducted an exploration of proteomic abnormalities in the tissues of a mouse model of the Costello syndrome as well as in patients’ fibroblasts and cell models expressing mutated forms of HRASG12S and HRASG12A. This global and unbiased analysis revealed alterations in energy metabolism and more particularly in the composition of mitochondria. The functional deficiency of mitochondria, energy plants of the human body, has been characterized by biochemistry, bioenergetics and cell biology approaches. In addition, the 'omic' analysis of Costello syndrome suggested a new pathophysiology hypothesis that considered the involvement of a microRNA, miR-221* in the alteration of oxidative metabolism. Functional genetic analyzes performed on patient cells and cell models demonstrated the inhibition of the expression of the major mitochondrial metabolism regulator AMPK protein by miR-221* under the control of HRASG12S and HRASG12A. These findings led to the development of a preclinical therapeutic strategy to reduce cardiomyopathy in Costello syndrome. Preclinical investigations performed on the cellular models and the murine model made it possible to evaluate the efficacy of a pharmacological stimulation of mitochondrial metabolism. This thesis thus reveals the involvement of mitochondria in Costello syndrome and the molecular analysis carried out makes available a series of 'Omics' data that will allow progress in the understanding of this rare disease.Les mutations germinales activatrices de la voie RAS sont responsables de maladies rares regroupées sous le nom de RASopathies : le Syndrome de Noonan, le Syndrome de Noonan avec de Multiples Lentigines, la Neurofibromatose de type 1, le Syndrome de Malformations Capillaires et Malformations Artério-Veinseuses, le Syndrome Cardio-Facio-Cutané, le Syndrome de Legius et le Syndrome de Costello. Cette thèse s’intéresse au syndrome de Costello causé par une mutation hétérozygote de novo du gène HRAS. Ce syndrome est révélé dans les premiers mois de la vie et se caractérise par un retard de croissance postnatal, des traits du visage épais, un déficit intellectuel, des anomalies cutanées, ainsi qu’une prédisposition à développer des tumeurs. De plus, les patients atteints du syndrome de Costello développent une cardiomyopathie hypertrophique, de l’hypertension, une hypotonie et une myopathie d'origine moléculaire inconnue. En lien avec une association de malade et le service de génétique du CHU de Bordeaux, nous avons mené une exploration des anomalies protéomiques dans les tissus d’une souris modèle du syndrome de Costello ainsi que dans des fibroblastes de patients et des cellules modèles exprimant les formes mutées de HRASG12S et HRASG12A. Cette analyse globale et sans a priori a révélé des altérations au niveau du métabolisme énergétique et plus particulièrement de la composition des mitochondries. Le déficit fonctionnel des mitochondries, centrale énergétique du corps humain, a été caractérisé par des approches de biochimie, de bioénergétique et de biologie cellulaire. De plus, l’analyse des données ‘omiques’ a permis de suggérer une nouvelle hypothèse dans la physiopathologie du syndrome de Costello. Cette hypothèse considère l’implication d’un micro-ARN, le miR-221* dans l’inhibition du métabolisme oxydatif. Les analyses génétiques réalisées sur les cellules de patients et les cellules modèles ont démontré l’inhibition de l’expression de la protéine AMPK, un régulateur majeur du métabolisme mitochondrial, par le miR-221* sous le contrôle de HRASG12S et HRASG12A. Ces découvertes ont permis d’élaborer une stratégie thérapeutique visant à réduire la cardiomyopathie dans le syndrome de Costello. Les analyses précliniques effectuées sur les modèles cellulaires et le modèle murin ont permis d’évaluer l’efficacité d’une stimulation pharmacologique du métabolisme mitochondrial. Cette thèse révèle donc l’implication des mitochondries dans le syndrome de Costello et l’analyse moléculaire réalisée propose une série de données ‘Omiques’ qui permettront de progresser dans la compréhension de cette maladie rare
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