Nuevos nanocompuestos para aplicaciones biológicas: óxido de grafeno como plataforma de biosensado y aglomerados de pocos átomos metálicos como agentes oxidantes con potencial biocida

Esta tesis doctoral se enfoca en el estudio de dos grupos de nanomateriales y sus potenciales aplicaciones en sistemas biológicos: el óxido de grafeno como plataforma para el desarrollo de biosensores, y los aglomerados de pocos átomos de plata como agente biocida. El desarrollo de este trabajo comprende la caracterización exhaustiva de los nanomateriales empleados y el análisis de sus propiedades fisicoquímicas, especialmente de aquellas relevantes para sus posibles aplicaciones. Uno de los aspectos de interés de esta tesis comprende la síntesis, caracterización y aplicación de diferentes óxidos de grafeno para la optimización de superficies que actúen como plataformas sensoras, utilizando como modelo la detección de glucosa mediante la inmovilización enzimática. A lo largo del trabajo se analizan cada una de las variables que intervienen en el desarrollo de este objetivo, realizando ensamblados controlados mediante el uso de balanza de Langmuir-Blodgett y su posterior caracterización a través de técnicas de rayos X, microscopías y técnicas electroquímicas y espectroscopías ópticas. Estos ensamblados son optimizados a través de la reducción del óxido de grafeno y se estudia su interacción con nanoestructuras metálicas. A su vez, se analiza la funcionalidad de las superficies para la detección de glucosa a través de la transducción electroquímica y las características cinéticas en el proceso de reconocimiento. Por otra parte, se aborda el estudio en el efecto de aglomerados atómicos de plata sobre moléculas con interés biológico, en particular diversos modelos moleculares con grupos tioles en su estructura química. Con este fin se utilizaron técnicas avanzadas para la caracterización de nanomateriales, que involucran fuentes de luz sincrotrón para el análisis cuali-cuantitativo de la catálisis de los aglomerados metálicos sobre estas moléculas de interés biológico. Las técnicas de absorción de rayos X permiten realizar estudios in-situ y evaluar las reacciones catalíticas realizando una caracterización precisa de las especies moleculares intervinientes. Esta información se utiliza para proponer mecanismos que no se encuentran descriptos hasta el momento. A su vez, se realizaron estudios preliminares en membranas celulares para evaluar la manera en la que interactúan con estos sistemas, y las implicancias de dichas interacciones en la posible aplicación de estos nanomateriales como agentes biocidas, a partir de su estudio en líneas celulares tumorales.Facultad de Ciencias Exacta

Silver clusters of five atoms as highly selective antitumoral agents through irreversible oxidation of thiols

Low atomicity clusters present properties dependent on the size, due to the quantum confinement, with well-defined electronic structures and high stability. Here it is shown that Ag5 clusters catalyze the complete oxidation of sulfur to S+6. Ag5 catalytic activity increases with different oxidant species in the order O2 ≪ H2O2 < OH•. Selective oxidation of thiols on the cysteine residues of glutathione and thioredoxin is the primary mechanism human cells have to maintain redox homeostasis. Contingent upon oxidant concentration, Ag5 catalyzes the irreversible oxidation of glutathione and thioredoxin, triggering apoptosis. Modification of the intracellular environment to a more oxidized state to mimic conditions within cancer cells through the expression of an activated oncogene (HRASG12V) or through ARID1A mutation, sensitizes cells to Ag5 mediated apoptosis. While cancers evolve to evade treatments designed to target pathways or genetic mutations that drive them, they cannot evade a treatment that takes advantage of aberrant redox homeostasis, which is essential for tumor progression and metastasis. Ag5 has antitumor activity in mice with orthotopic lung tumors reducing primary tumor size, and the burden of affected lymphatic nodes. The findings suggest the unique intracellular redox chemistry of Ag5 may lead to new redox-based approaches to cancer therapyThis research was partially supported by 1) “la Caixa” Foundation, Ref. LCF/PR/PR12/11070003 to F.D. and M.A.L.Q.; 2) Ministerio de Ciencia, Innovación y Universidades (MAT2017-89678-R, AEI/FEDER, UE) to F.D. and A.V.; 3) the Consellería de Educación (Xunta de Galicia), Grants No. Grupos Ref. Comp. ED431C 2017/22, ED431C 2019/13 and AEMAT-ED431E2018/08 to M.A.L.Q.; and ED431C 2019/13 to A.V. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme (Bac-To-Fuel) under Grant Agreement No. 825999 (M.A.L.Q.). J.C.H. acknowledge financial support from European Union's Horizon 2020 research and innovation programme under grant agreement no. 823717-ESTEEM3, and the MICIIN (projects PID2019-107578GA-100 and PID-110018GA-100). J.M.D, L.J.G., and F.G.R. thank to the ANPCyT (PICT 2015-2285 and 2017-3944), UNLP (Project 11/X790) and the partial support by the Laboratório Nacional de Luz Síncrotron (LNLS, Brazil) under proposal SXS-20180280. G.B. acknowledges the CINECA Award N. IsC51, year 2017, under the ISCRA initiative, for the availability of high-performance computing resources and support. D.B. expresses gratitude for a postdoctoral grant from Xunta de Galicia, Spain (POS-A/2013/018). B.D. expresses gratitude for a predoctoral grant from MICINN, Spain (BES-2016-076765). F.D. and A.V. also acknowledged Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022 ref ED431G 2019/02) and the European Union (European Regional Development Fund – ERDF). Work in M.P.M.'s lab was supported by the Medical Research Council UK (MC_U105663142). T.G.C. gratefully acknowledges the technical assistance of María José Otero-Fraga (FIDIS)S

Silver Clusters of Five Atoms as Highly Selective Antitumoral Agents Through Irreversible Oxidation of Thiols

Abstract: Low atomicity clusters present properties dependent on the size, due to the quantum confinement, with well‐defined electronic structures and high stability. Here it is shown that Ag5 clusters catalyze the complete oxidation of sulfur to S+6. Ag5 catalytic activity increases with different oxidant species in the order O2 ≪ H2O2 < OH•. Selective oxidation of thiols on the cysteine residues of glutathione and thioredoxin is the primary mechanism human cells have to maintain redox homeostasis. Contingent upon oxidant concentration, Ag5 catalyzes the irreversible oxidation of glutathione and thioredoxin, triggering apoptosis. Modification of the intracellular environment to a more oxidized state to mimic conditions within cancer cells through the expression of an activated oncogene (HRASG12V) or through ARID1A mutation, sensitizes cells to Ag5 mediated apoptosis. While cancers evolve to evade treatments designed to target pathways or genetic mutations that drive them, they cannot evade a treatment that takes advantage of aberrant redox homeostasis, which is essential for tumor progression and metastasis. Ag5 has antitumor activity in mice with orthotopic lung tumors reducing primary tumor size, and the burden of affected lymphatic nodes. The findings suggest the unique intracellular redox chemistry of Ag5 may lead to new redox‐based approaches to cancer therapy

Analisis Kinerja Keuangan Sebelum dan Sesudah Akuisisi PT. Pakoakuina oleh PT. Astra Otoparts, Tbk

Akuisisi merupakan salah satu jenis penggabungan usaha dimana proses pengambilalihannya, keseluruhan atau sebagian sistem dan kepemilikan perusahaan yang diakuisisi menjadi milik perusahaan pengakuisisi, dan setelah proses akuisisi maka masing-masing perusahaan tetap melanjutkan kegiatannya. Penelitian ini untuk menilai dan menganalisis kinerja keuangan sebelum dan sesudah akuisisi pada PT Astra Otoparts, Tbk. Kinerja keuangan diukur menggunakan rasio keuangan yang terdiri dari rasio likuiditas (current ratio, quick ratio), rasio solvabilitas (total debt to equity ratio, total debt to asset ratio), rasio profitabilitas (net profit margin, return on equity, return on asset), rasio aktvitas (total asset turn over), dan rasio nilai pasar (earning per share). Keseluruhan nilai rasio ini menunjukkan adanya penurunan setelah melakukan akuisisi dibandingkan sebelum melakukan akuisisi. Uji statistik yang digunakan, Paired Sample t- Test untuk mengetahui perbedaan kinerja keuangan sebelum dan sesudah akuisisi. Pada current ratio, quick ratio, net profit margin, return on equity, return on asset, total asset turn over, dan earning per share yang diuji dengan Paired Sample t-Test menunjukkan bahwa tidak terdapat perbedaan yang signifikan antara sebelum dan sesudah akuisisi. Sedangkan, pada total debt to equity ratio dan total debt to asset ratio menunjukkan bahwa terdapat perbedaan yang signifikan antara sebelum dan sesudah akuisisi pada PT Astra Otoparts, Tbk

Indirect strain and compassion fatigue : a qualitative study of workingconditions in social work

Abstract Authors: Veronica Axeborg &amp; Malin Devida Carlsson Title: Indirect strain and compassion fatigue- a qualitative study of working conditions in social work Supervisor: Roddy Nilsson Assessor: Rickard Ulmestig   High levels of sick leave can often be detected in social work, especially within the group of social workers that have contact and relationship building professions. Direct collaboration with clients requires that the social worker uses him or herself as a tool. On top of a heavy workload with complex cases that are time consuming and the pressure of getting tasks ready on time, these social workers are also exposed to an indirect workload when they listen to the suffering and pain of their clients’ problems. Compassion fatigue is a phenomenon and condition that can occur when a person repeatedly hears about difficulties without experiencing it for themselves.  The purpose of this study was to investigate social workers views and experiences with indirect strain and compassion fatigue and also how these phenomena are made aware of and handled or not handled in the workplace. This study consists of six semi-structured interviews with social workers that have a contact and relationship building profession. The results of the interviews are presented through prominent themes and analysed with Antonovskys theory of Sense of coherence.  Results showed that several of the respondents has experiences of indirect strain, sometimes so invisible they don´t notice or reflect over it themselves. Only one respondent experience compassion fatigue due to contact with clients whereas the others are aware of the existence of the phenomenon but do not suffer from it. Both indirect strain and compassion fatigue arises at times in workplaces but nothing structural is organised to prevent or handle the phenomena. Collegial support has proven to be the chosen way of dealing with it. A prominent conclusion of this study is that the direct workload and time pressure is what’s burdening in the social worker´s profession and that the line between the indirect and direct strain sometimes is difficult to draw. They often go into each other’s fields or become each other’s consequences.

Indirect strain and compassion fatigue : a qualitative study of workingconditions in social work

Abstract Authors: Veronica Axeborg &amp; Malin Devida Carlsson Title: Indirect strain and compassion fatigue- a qualitative study of working conditions in social work Supervisor: Roddy Nilsson Assessor: Rickard Ulmestig   High levels of sick leave can often be detected in social work, especially within the group of social workers that have contact and relationship building professions. Direct collaboration with clients requires that the social worker uses him or herself as a tool. On top of a heavy workload with complex cases that are time consuming and the pressure of getting tasks ready on time, these social workers are also exposed to an indirect workload when they listen to the suffering and pain of their clients’ problems. Compassion fatigue is a phenomenon and condition that can occur when a person repeatedly hears about difficulties without experiencing it for themselves.  The purpose of this study was to investigate social workers views and experiences with indirect strain and compassion fatigue and also how these phenomena are made aware of and handled or not handled in the workplace. This study consists of six semi-structured interviews with social workers that have a contact and relationship building profession. The results of the interviews are presented through prominent themes and analysed with Antonovskys theory of Sense of coherence.  Results showed that several of the respondents has experiences of indirect strain, sometimes so invisible they don´t notice or reflect over it themselves. Only one respondent experience compassion fatigue due to contact with clients whereas the others are aware of the existence of the phenomenon but do not suffer from it. Both indirect strain and compassion fatigue arises at times in workplaces but nothing structural is organised to prevent or handle the phenomena. Collegial support has proven to be the chosen way of dealing with it. A prominent conclusion of this study is that the direct workload and time pressure is what’s burdening in the social worker´s profession and that the line between the indirect and direct strain sometimes is difficult to draw. They often go into each other’s fields or become each other’s consequences.