The Development of Novel Anti-folates: An Ongoing Battle Against Resistance

The development of drug compounds begins with the identification of well-validated targets. Conserved in bacterial, fungal, and mammalian species, the folate biosynthetic pathway performs critical processes to promote nucleic acid synthesis and maintain cellular function. Medicinal chemists have targeted dihydrofolate reductase (DHFR), an essential enzyme in this metabolic process, for several years. In fact, anti-folates acting on this pathway have potential roles against infectious diseases. This project examines a para-substituted drug compound called UCP111E, which is directed against dangerous fungal species, like Candida albicans and Candida glabrata. Since crystal structures of C. albicans DHFR (CaDHFR) and C. glabrata DHFR (CgDHFR) with UCP111E have already been solved, the main objective is to now deduce the structure of human DHFR (huDHFR) with the drug compound. Sample preparation procedures in this project used Qiagen EasyXtal 15-well trays to plate various conditions for crystallization. Buffer (i.e., Tris), salt (i.e., lithium sulfate), precipitant (i.e., PEG 4000), and additive (i.e., ethanol) remained constant for each well in the trays. However, non-volatile additives (i.e., 1,8-diaminooctane, strontium chloride, and calcium chloride) varied. Steps to improve the conditions with 1,8-diaminooctane produced plate-like crystals, while strontium chloride formed hexagon-shaped crystals, and calcium chloride, crystal rods. Only crystals formed with 1,8-diaminooctane and calcium chloride were large enough to diffract. However, diffraction patterns revealed the presence of salt, rather than protein, in the structures. Future projects hope to continue optimizing conditions with strontium chloride and calcium chloride to crystallize the huDHFR/UCP111E complex

Conflict Management in Culturally Diverse Workplaces : A lower-level manager’s perspective

This study discusses the intercultural workplace conflict management from lower-level manager’s point of view. The main objective of this study is to better understand how managers can develop the intercultural conflict management skills. The sub-objectives are to analyse workplace conflicts in intercultural context, determine crucial intercultural managerial skills, and understand the role of the manager as an interpreter with supervisory duties. Studying the workplace conflicts through intercultural lenses is important to understand the causes of conflicts in culturally diverse settings. Identifying the crucial managerial skills for conflict management shows the areas that require more attention. Thus, understanding how intercultural conflicts are created help to analyse different conflict management strategies and explore manager’s role. The theoretical background of the study follows the structure of culture-based social ecological conflict model and includes additional literature and theories related to the components. The empirical research is conducted by qualitative interviews of informants who meet the criteria. The semi-structured interviews of five informants were collected and transcribed. For the analysis of the data, thematic analysis method was selected. The findings of this study indicate that conflicts occurring at culturally diverse workplaces were related to apparent functional differences, which makes cultural differences an enhancing factor rather than a cause of conflicts. The study supports that lower-level managers have an important role in intercultural conflict settings in intervening conflict situations through interpretation. Yet the managerial skills are rather underappreciated and require self-learning because of insufficient training for the position. What is expected from the manager differ between different actors. Thus, responsibilities of a manager are vaguely determined, and the task-effectiveness was found to be valued over relational-effectiveness. The role of the manager as an interpreter and intervener is changing with the experiences, which highlights the importance of learning in the field through trial and error.Tässä tutkimuksessa käsitellään kulttuurienvälisten työpaikkakonfliktien hallintaa alemman tason johtajien näkökulmasta. Tutkimuksen päätavoitteena on ymmärtää paremmin, miten johtajat voivat kehittää kulttuurienvälisten konfliktien hallintataitoja. Alatavoitteina on analysoida työpaikkakonflikteja kulttuurienvälisessä kontekstissa, määrittää kulttuurienväliset johtamistaidot, jotka ovat ratkaisevia, ja ymmärtää johtajan rooli tulkkina, jolla on esimiestehtäviä. Työpaikkakonfliktien tutkiminen kulttuurienvälisen näkökulman kautta on tärkeää, jotta voidaan ymmärtää konfliktien syitä kulttuurisesti erilaisissa ympäristöissä. Konfliktinhallinnan kannalta ratkaisevien johtamistaitojen tunnistaminen osoittaa, mihin alueisiin on kiinnitettävä enemmän huomiota. Näin ollen kulttuurienvälisten konfliktien syntymisen ymmärtäminen auttaa analysoimaan erilaisia konfliktinhallintastrategioita ja tutkimaan johtajan roolia. Tutkimuksen teoreettinen tausta noudattaa kulttuuripohjaisen sosiaalis-ekologisen konfliktimallin rakennetta, ja siihen sisältyy osiin liittyvää lisäkirjallisuutta ja teorioita. Empiirinen tutkimus toteutetaan kriteerit täyttävien informanttien laadullisilla haastatteluilla. Viiden informantin puolistrukturoidut haastattelut kerättiin ja kirjoitettiin puhtaaksi. Aineiston analysointiin valittiin temaattinen analyysimenetelmä. Tutkimuksen tulokset osoittavat, että kulttuurisesti erilaisissa työpaikoissa esiintyvät konfliktit liittyivät ilmeisiin toiminnallisiin eroihin, mikä tekee kulttuurieroista pikemminkin konflikteja lisäävän tekijän kuin niiden syyn. Tutkimus tukee sitä, että alemman tason johtajilla on kulttuurienvälisissä konfliktiympäristöissä tärkeä rooli puuttua konfliktitilanteisiin tulkinnan kautta. Johtamistaitoja kuitenkin arvostetaan melko vähän, ja ne edellyttävät itseopiskelua, koska tehtävään ei ole riittävästi koulutusta. Se, mitä johtajalta odotetaan, vaihtelee eri toimijoiden välillä. Näin ollen johtajan vastuut ovat epämääräisesti määriteltyjä, ja tehtävän tehokkuus on arvotettu suhteelliseen tehokkuuteen nähden. Johtajan rooli tulkkina ja välittäjänä muuttuu kokemusten myötä, mikä korostaa kentällä kokeilujen ja erehdysten kautta tapahtuvan oppimisen merkitystä

Modelling value-added tax in the presence of multiproduction and differentiated exemptions

We develop a framework for economy-wide modelling of value-added tax systems. Our framework models a number of complexities of VAT systems as they are implemented by tax agencies. In particular, we model multiple rates, multiple exemptions, multiple degrees of refundability across commodity users, and multi-product enterprises. A detailed VAT framework is important for correct modelling of VAT within a general equilibrium model. Such a framework is also of value in correctly representing the distribution of indirect tax payments within the database of a general equilibrium model, a prerequisite of accurate welfare analysis. We use the model to analyse the effects of simplifying Vietnam’s complex VAT system. We simplify the system by moving from three tax rates to one budget-neutral rate, while also removing many discretionary exemptions.value added tax; dynamic CGE model; Vietnam; indirect tax reform

Travel to My Memory

Personal perception of beauty always changes over time. The repetitive circle of adopting the new thoughts and replacing the old ones is a natural process of human being

Untersuchung einer KCNJ5-Mutation beim Primären Hyperaldosteronismus in einem adrenokortikalen Zellmodell aus humanen induzierten pluripotenten Stammzellen

The adrenal cortex is a central site of steroidogenesis. Steroid hormones produced in the adrenal cortex regulate essential processes in the body, including electrolyte and fluid homeostasis, blood pressure, and stress-induced metabolisms. Defects in the structure and function of the adrenal cortex result in inappropriately low or high hormone secretion, leading to a number of diseases, including secondary hypertension due to hyperaldosteronism. Adrenocortical research has long suffered from a lack of adequate models, which has hampered advances in understanding disease mechanisms and developing therapies for adrenocortical disorders. Adrenocortical animal models and cell lines in many cases do not fully recapitulate the genotype-phenotype association of adrenocortical disorders. Criteria for ideal human-derived adrenocortical disease models include ease of genomic manipulation and adequate hormone production, which are currently unmet. Here, we developed an improved human induced pluripotent stem cell (hiPSC)-based differentiation system from intermediate mesoderm toward adrenocortical cells. Heterologous forced expression of steroidogenic factor-1 (SF-1) and the addition of adrenal cortex niche factors gave rise to cells that produced a wide range of adrenal steroids, including aldosterone and cortisol, and exhibited typical adrenocortical gene expression profiles. These cells maintained their proliferative capacity during extended cultivation. Using CRISPR/Cas9, we introduced a heterozygous somatic KCNJ5 mutation found in aldosterone-producing adenomas and familial hyperaldosteronism. Besides elevated aldosterone production, mutant cells showed increased proliferation, a hallmark of tumor development, that was missing in prior models. We conclude that our system is a valid tool for studying the pathophysiology of adrenocortical diseases.Die Nebennierenrinde ist ein zentraler Ort der Steroidogenese. In der Nebennierenrinde gebildete Steroidhormone regulieren wesentliche Prozesse im Körper, darunter die Elektrolyt- und Flüssigkeitshomöostase, den Blutdruck und den stressbedingten Stoffwechsel. Defekte in der Struktur und Funktion der Nebennierenrinde führen zu einer erhöhten oder erniedrigten Hormonausschüttung, die zu mehreren Erkrankungen, einschließlich sekundärem Bluthochdruck aufgrund eines Hyperaldosteronismus führen kann. Die Nebennierenrindenforschung leidet jedoch seit langem unter einem Mangel an geeigneten Modellen, was Fortschritte beim Verständnis der Krankheitsmechanismen und bei der Entwicklung von Therapien für Nebennierenrindenerkrankungen erschwert hat. Tiermodelle (Modelle zur Erforschung der Nebennierenrinde) und Zelllinien können die Genotyp-Phänotyp-Assoziation der genetischen Erkrankungen der humanen Nebennierenrinde in vielen Fällen nicht vollständig rekapitulieren. Idealerweise sollten humane Nebennierenrindenmodelle leicht genomisch zu manipulieren sein und eine nahezu physiologische Hormonproduktion aufweisen, Kriterien, die derzeit nicht erfüllt sind. Wir haben hier ein verbessertes System zur Differenzierung menschlicher induzierter pluripotenter Stammzellen (hiPSC) aus intermediärem Mesoderm in adrenokortikale Zellen entwickelt. Die heterologe Expression des steroidogenen Faktors 1 (SF-1) und Zugabe von Nischenfaktoren der Nebennierenrinde führten zu Zellen, die eine breite Palette von Nebennierensteroiden produzierten, einschließlich Aldosteron und Cortisol, und adrenokortikale Genexpressionsprofile aufwiesen. Diese Zellen behielten ihre Proliferationsfähigkeit auch bei längerer Kultivierung bei. Mithilfe von CRISPR/Cas9 haben wir eine heterozygote somatische KCNJ5-Mutation eingeführt, die bei Aldosteron produzierenden Adenomen und familiärem Hyperaldosteronismus vorkommt. Neben einer erhöhten Aldosteronproduktion zeigten die mutierten Zellen eine erhöhte Proliferation, ein Merkmal der Tumorentwicklung, das in früheren Modellen fehlte. Wir schließen daraus, dass unser System ein vielversprechender Ansatz für die Untersuchung der Pathophysiologie von Nebennierenrinden-erkrankungen ist

Towards a Rule-level Verification Framework for Property-Preserving Graph Transformations

International audienceWe report in this paper a method for proving that a graph transformation is property-preserving. Our approach uses a relational representation for graph grammar and a logical representation for graph properties with first-order logic formulas. The presented work consists in identifying the general conditions for a graph grammar to preserve graph properties, in particular structural properties. We aim to implement all the relevant notions of graph grammar in the Isabelle/HOL proof assistant in order to allow a (semi) automatic verification of graph transformation with a reasonable complexity. Given an input graph and a set of graph transformation rules, we can use mathematical induction strategies to verify statically if the transformation preserves a particular property of the initial graph. The main highlight of our approach is that such a verification is done without calculating the resulting graph and thus without using a transformation engine

HIGH SCHOOL STUDENTS’ PERCEPTIONS OF THE USE OF FACEBOOK-BASED E-PORTFOLIOS IN EFL WRITING: A CASE IN THE MEKONG DELTA, VIETNAM

Electronic portfolios (e-portfolios) have grown in popularity in ESL/EFL writing instruction for their contributions to students’ writing. However, selecting an electronic tool in e-portfolios is of concern to many researchers and teachers. The combination of Facebook and e-portfolios is a rather new implementation in educational research, especially in high school contexts. Therefore, the current research aimed at exploring (1) high school students’ perceptions of the use of Facebook-based e-portfolios in terms of their contributions in writing, and (2) problems in using Facebook-based e-portfolios in writing. Fifty grade 11 students at a high school in Soc Trang province, Vietnam participated in the research. Both quantitative and qualitative data were collected by using close-ended questionnaire and the interview. Prior to data collection, the students spent six weeks writing on Facebook close-typed groups. The results showed that the students highly appreciated the contributions of Facebook-based e-portfolios in terms of enhancing interaction, giving and receiving feedback, motivation and confidence in writing, writing skills, vocabulary, and grammar knowledge. No significant problems were found in using Facebook-based e-portfolios. The research is expected to shed light on implementing Facebook-based e-portfolios in improving the quality of teaching EFL/ESL writing in high school contexts.  Article visualizations

A Precondition Calculus for Correct-by-Construction Graph Transformations

We aim at assisting developers to write, in a Hoare style, provably correct graph transformations expressed in the ALCQ Description Logic. Given a postcondition and a transformation rule, we compute the weakest precondition for developers. However, the size and quality of this formula may be complex and hard to grasp. We seek to reduce the weakest precondition’s complexness by a static analysis based on an alias calculus. The refined precondition is presented to the developer in terms of alternative formulae, each one specifying a potential matching of the source graph. The developer chooses then the formulae that correspond to his intention to obtain finally a correct-byconstruction Hoare triple

MODÉLISATION DE PROCÉDÉS LOGICIELS À BASE DE PATRONS RÉUTILISABLES

This thesis investigates the reuse of software processes by an approach based on process patterns. The objective of our work is to make process patterns directly applicable in process modeling. The concept of process pattern is used to capture and reuse the proven solutions for recurring process problems. However, this attractive concept has still been poorly exploited due to the inadequate formalization and the lack of supporting methodology and tools. To promote the use of process patterns and reduce the modelling effort, we broaden the concept of process pattern for capturing various types of process knowledge at different abstract levels, and propose ways to reuse (semi-)automatically process patterns in process modelling. We define the process meta-model UML-PP to formalize the process pattern concept and the ways to apply patterns in process models. UML-PP allows describing the internal structure of a process pattern as well as the relations between process patterns, and enables the explicit representation of process patterns' applications in process models. We propose the meta-process PATPRO defining the modelling steps to elaborate a process model in UML-PP by reusing process patterns. To allow automated applications of process patterns, we define an operational semantics for the patterns reuse operators who carry out some tasks of the meta-process. We have developed the prototype PATPRO-MOD allowing to create and manage process patterns catalogues, and to elaborate process models in UML-PP by reusing (semi-)automatically process patterns.Cette thèse est consacrée à la réutilisation de procédés par une approche à base de patrons de procédé. Le concept de patron de procédé a été introduit pour capitaliser et réutiliser des solutions éprouvées des problèmes de procédés récurrents. Cependant cette approche est encore peu exploitée à cause du champ de définition limité, du manque de formalisation, de méthodologie et d'outils support. Pour promouvoir l'utilisation de patrons de procédé et réduire l'effort de modélisation, nous considérons le concept de patron de procédé à différents niveaux d'abstraction pour capturer divers types de connaissances sur les procédés, et proposons des moyens pour réutiliser de façon (semi-)automatique ces patrons dans la modélisation des procédés. Nous avons défini le méta-modèle de procédé UML-PP pour formaliser le concept de patron de procédé et la manière d'appliquer les patrons dans la modélisation de procédés. UML-PP permet de décrire la structure interne d'un patron de procédé ainsi que les relations entre patrons, et permet d'exprimer explicitement l'utilisation de patrons dans les modèles de procédé. Nous proposons le méta-procédé PATPRO définissant une démarche de modélisation pour élaborer un modèle de procédé UML-PP en réutilisant des patrons de procédé. Pour permettre une automatisation de l'application de patrons de procédé, nous définissons une sémantique opérationnelle des opérateurs de réutilisation de patrons qui réalisent l'imitation de patrons. Nous avons réalisé le prototype PATPRO-MOD permettant de créer et gérer des catalogues de patrons de procédé et d'élaborer des modèles de procédé UML-PP en réutilisant semi-automatiquement des patrons prédéfinis