Nanomedicines Meet Disordered Proteins: A Shift from Traditional Materials and Concepts to Innovative Polymers

Water-soluble nanomedicines have been widely studied for the targeted delivery of drugs for a very long time. As a notable example, biomaterials based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers have been under investigation for nearly half a century. In particular, anticancer drug carriers have been developed under the assumption that the leading mechanism with a therapeutic impact on solid tumors is the enhanced permeability and retention (EPR) effect, which dates back more than three decades. Nevertheless, these (and other) materials and concepts have encountered several barriers in their successful translation into clinical practice, and future nanomedicines need improvements in both passive and active targeting to their site of action. Notions borrowed from recent studies on intrinsically disordered proteins (IDPs) seem promising for enhancing the self-assembly, stimuli-responsiveness, and recognition properties of protein/peptide-based copolymers. Accordingly, IDP-based nanomedicines are ready to give new impetus to more traditional research in this field

Instructional experiment on Lenz's law

We present a visual manifestation of Lenz’s Law. The setup is composed of two coils connected by a central linear metal nucleus. Each of them has a LED plugged in parallel to its terminals. The primary is fed with a pulsating external voltage. We recorded a slow-motion video (960Hz) of the two blinking LEDs. It is possible to observe a complete out-of-phase fade-in/fade-out behavior of them, which is a direct consequence of the minus sign present in the electromagnetic induction equation. We also discuss how to introduce the apparatus in a classroom activity. The mathematical modeling and the numerical results are instructively derived along with the text. There is also a review of the technical features that must be taken into account to study the observation of high-frequency blinking LEDs

Intrinsically disordered inhibitor of glutamine synthetase is a functional protein with random-coil-like pKa values

The sequential action of glutamine synthetase (GS) and glutamate synthase (GOGAT) in cyanobacteria allows the incorporation of ammonium into carbon skeletons. In the cyanobacterium Synechocystis sp. PCC 6803, the activity of GS is modulated by the interaction with proteins, which include a 65-residue-long intrinsically disordered protein (IDP), the inactivating factor IF7. This interaction is regulated by the presence of charged residues in both IF7 and GS. To understand how charged amino acids can affect the binding of an IDP with its target and to provide clues on electrostatic interactions in disordered states of proteins, we measured the pKa values of all IF7 acidic groups (Glu32, Glu36, Glu38, Asp40, Asp58, and Ser65, the backbone C-terminus) at 100 mM NaCl concentration, by using NMR spectroscopy. We also obtained solution structures of IF7 through molecular dynamics simulation, validated them on the basis of previous experiments, and used them to obtain theoretical estimates of the pKa values. Titration values for the two Asp and three Glu residues of IF7 were similar to those reported for random-coil models, suggesting the lack of electrostatic interactions around these residues. Furthermore, our results suggest the presence of helical structure at the N-terminus of the protein and of conformational changes at acidic pH values. The overall experimental and in silico findings suggest that local interactions and conformational equilibria do not play a role in determining the electrostatic features of the acidic residues of IF7.Ministerio de Economía y Competitividad CTQ 2015-64445-R, BFU2013- 41712-P, BIO2016-75634PJunta de Andalucía BIO-284Generalitat Valenciana Prometeo 018/201

The C Terminus of the Ribosomal-Associated Protein LrtA Is an Intrinsically Disordered Oligomer

The 191-residue-long LrtA protein of Synechocystis sp. PCC 6803 is involved in post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family, intervening in protein synthesis. The protein consists of two domains: The N-terminal region (N-LrtA, residues 1-101), which is common to all the members of the HPF, and seems to be well-folded; and the C-terminal region (C-LrtA, residues 102-191), which is hypothesized to be disordered. In this work, we studied the conformational preferences of isolated C-LrtA in solution. The protein was disordered, as shown by computational modelling, 1D-H-1 NMR, steady-state far-UV circular dichroism (CD) and chemical and thermal denaturations followed by fluorescence and far-UV CD. Moreover, at physiological conditions, as indicated by several biochemical and hydrodynamic techniques, isolated C-LrtA intervened in a self-association equilibrium, involving several oligomerization reactions. Thus, C-LrtA was an oligomeric disordered protein.This research was funded by Spanish Ministry of Economy and Competitiveness [CTQ2015-64445-R (to J.L.N.) and MAT2015-63704-P (to A.A.), with Fondo Social Europeo (ESF)], and by the Basque Government [IT-654-13 (to A.A.)

The C Terminus of the Ribosomal-Associated Protein LrtA Is an Intrinsically Disordered Oligomer

The 191-residue-long LrtA protein of Synechocystis sp. PCC 6803 is involved in post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family, intervening in protein synthesis. The protein consists of two domains: The N-terminal region (N-LrtA, residues 1-101), which is common to all the members of the HPF, and seems to be well-folded; and the C-terminal region (C-LrtA, residues 102-191), which is hypothesized to be disordered. In this work, we studied the conformational preferences of isolated C-LrtA in solution. The protein was disordered, as shown by computational modelling, 1D-H-1 NMR, steady-state far-UV circular dichroism (CD) and chemical and thermal denaturations followed by fluorescence and far-UV CD. Moreover, at physiological conditions, as indicated by several biochemical and hydrodynamic techniques, isolated C-LrtA intervened in a self-association equilibrium, involving several oligomerization reactions. Thus, C-LrtA was an oligomeric disordered protein.This research was funded by Spanish Ministry of Economy and Competitiveness [CTQ2015-64445-R (to J.L.N.) and MAT2015-63704-P (to A.A.), with Fondo Social Europeo (ESF)], and by the Basque Government [IT-654-13 (to A.A.)

Quadro Didático AC: um produto didático para o ensino por investigação nas aulas práticasde circuitos elétricos e eletromagnetismo

In this paper we present the Quadro AC. It is an educational technology, that is registered in the INPI ( BR 302012002737-3). It is used with the purpose of easing the teaching of alternating current electric circuits. It can be apllied in regular High school courses or even in undergraduate introductory disciplines. The main points of the device are safety for the user and easy handling. With the Quadro, it is possible to approach the Kirchhoff's laws and Faraday induction law in an investigative way. In this work, we explain the detailed operation of each part of the product and two methods of classroom application are presented. One of them allows the teacher to use it in classroom with many students in such a way that all of them will be doing some work related to the Quadro during all the time. The main point is to get engagement of the students.Neste trabalho apresentamos o Quadro AC. É uma tecnologia educacional que possui registro no INPI, sob o número BR 302012002737-3, que tem a finalidade de facilitar o ensino de circuitos elétricos com corrente alternada. Ele pode ser utilizado em cursos regulares do Ensino Médio, cursos técnicos e superiores. Os pontos principais do produto são a segurança para o usuário e o fácil manuseio. Com ele é possível abordar a lei das malhas, a lei dos nós (leis de Kirchhoff) e a lei da indução de Faraday de forma investigativa. Neste texto explicamos o funcionamento detalhado de cada parte do produto e são apresentados dois métodos de aplicação em sala de aula. Um deles permite que ele seja utilizado por uma turma com muitos alunos de tal forma que todos participem durante toda a aula. O foco principal é gerar engajamento da turma na atividade e nos resultados produzidos por cada um dos alunos ao executar tarefas

AÑO INTERNACIONAL DE LA ASTRONOMÍA EN AMAZONAS: POPULARIZACIÓN DE LA ASTRONOMÍA EN UNA ACTIVIDAD DE EXTENSIÓN COMO UNA INICIACIÓN A CIENCIA

Em comemoração dos 400 anos das observações de Galileu Galilei com o telescópio, o ano de 2009 foi escolhido pela UNESCO como o Ano Internacional da Astronomia. Inserido nesta celebração, foi desenvolvido um projeto de divulgação científica e de popularização da Astronomia na cidade de Coari no estado do Amazonas. Procurando melhorar a integração entre a universidade e a comunidade em geral, bem como despertar o interesse dos jovens pela Astronomia e Física, além de relacionar conhecimentos teóricos e práticos dos estudantes envolvidos no projeto. Desenvolvemos atividades extensionistas de divulgação científica, palestras, observações do céu noturno e minicursos. Neste artigo pretendemos apresentar as atividades desenvolvidas no projeto, suas implicações e seus desdobramentos.In celebration of the 400th anniversary of Galileo Galilei's observations with the telescope, the year 2009 was chosen by UNESCO as the International Year of Astronomy. As part of this initiative, we undertook a project to increase the awareness of science, based on the popularization of astronomy, in the city of Coari in the State of Amazonas. The objective was to improve integration between the university and the community, and attract the interest of young people in astronomy and physics, as well as to draw together the theoretical and practical knowledge of the students involved in the project. The activities included lectures, observations of the night sky, and courses. In this article, we describe the project in terms of the different activities, its implications, and its consequences.En la celebración del 400 aniversario de las primeras observaciones de Galileo Galilei con el telescopio, el año 2009 fue elegido por la UNESCO como Año Internacional de la Astronomía. Por la celebración de este hecho histórico, se desarrolló un proyecto para la difusión científica y la divulgación de la astronomía en la ciudad de Coari en el Estado de Amazonas, Brasil, con el fin de mejorar la integración entre la universidad y la comunidad y atraer el interés de los jóvenes por la astronomía y la física, así como asimilar los conocimientos teóricos y prácticos de los estudiantes que participan en el proyecto. Desarrollamos en este proyecto algunas actividades de difusión científica: conferencias, observaciones del cielo nocturno y talleres. En este artículo presentamos las actividades desarrolladas en el proyecto y sus consecuencias

AÑO INTERNACIONAL DE LA ASTRONOMÍA EN AMAZONAS: POPULARIZACIÓN DE LA ASTRONOMÍA EN UNA ACTIVIDAD DE EXTENSIÓN COMO UNA INICIACIÓN A CIENCIA

Em comemoração dos 400 anos das observações de Galileu Galilei com o telescópio, o ano de 2009 foi escolhido pela UNESCO como o Ano Internacional da Astronomia. Inserido nesta celebração, foi desenvolvido um projeto de divulgação científica e de popularização da Astronomia na cidade de Coari no estado do Amazonas. Procurando melhorar a integração entre a universidade e a comunidade em geral, bem como despertar o interesse dos jovens pela Astronomia e Física, além de relacionar conhecimentos teóricos e práticos dos estudantes envolvidos no projeto. Desenvolvemos atividades extensionistas de divulgação científica, palestras, observações do céu noturno e minicursos. Neste artigo pretendemos apresentar as atividades desenvolvidas no projeto, suas implicações e seus desdobramentos.In celebration of the 400th anniversary of Galileo Galilei's observations with the telescope, the year 2009 was chosen by UNESCO as the International Year of Astronomy. As part of this initiative, we undertook a project to increase the awareness of science, based on the popularization of astronomy, in the city of Coari in the State of Amazonas. The objective was to improve integration between the university and the community, and attract the interest of young people in astronomy and physics, as well as to draw together the theoretical and practical knowledge of the students involved in the project. The activities included lectures, observations of the night sky, and courses. In this article, we describe the project in terms of the different activities, its implications, and its consequences.En la celebración del 400 aniversario de las primeras observaciones de Galileo Galilei con el telescopio, el año 2009 fue elegido por la UNESCO como Año Internacional de la Astronomía. Por la celebración de este hecho histórico, se desarrolló un proyecto para la difusión científica y la divulgación de la astronomía en la ciudad de Coari en el Estado de Amazonas, Brasil, con el fin de mejorar la integración entre la universidad y la comunidad y atraer el interés de los jóvenes por la astronomía y la física, así como asimilar los conocimientos teóricos y prácticos de los estudiantes que participan en el proyecto. Desarrollamos en este proyecto algunas actividades de difusión científica: conferencias, observaciones del cielo nocturno y talleres. En este artículo presentamos las actividades desarrolladas en el proyecto y sus consecuencias

The old adapts to the modern: checking the Astronomical Unity value by reproducing the Venus transit with the Stellarium software

The distance between the Earth and the Sun, known as the Astronomical Unit (AU), has a fundamental role to Astronomy: it provides a scale distance inside our solar system and supports the measure from the Sun to near stars. Then, in this work we present one of the methods to obtain the AU using the Venus transits in front of the Sun. This is an adaptation to the Halley's method and was applied with the help of the free software of Astronomy Stellarium. We found (1, 4 ± 0, 3) ⋅ 108km, which gives 93, 6% of accordance with the literature. The revision of the method of obtaining the AU using the planet's transit meets either pedagogical and scientific reasons: the work proposed here may be easily reproduced in classrooms from high-school to the college, in courses related to Astronomy. Besides, the Venus transit itself from June 2012 was used to measure the solar radius with an uncertainty of only 15km, which justifies its study. Finally, this work checks the consistence of Stellarium for we have determined via geometrical means the AU inserted into the program.A distância Terra-Sol, conhecida como Unidade Astronômica (UA), tem papel fundamental para a Astronomia: ela fornece uma escala de distâncias dentro do nosso sistema solar e serve como base para a medida de distâncias entre o Sol e estrelas próximas. Neste trabalho, apresentamos uma das maneiras para se obter a UA a partir dos trânsitos de Vênus pelo disco solar. Esta é uma adaptação do método de Halley e foi aplicado a partir das imagens obtidas pelo software livre de Astronomia Stellarium. Encontramos o valor (1, 4±0, 3)⋅108km, em concordância de 93, 6% com o valor aceito pela literatura. A revisão do método de obtenção da Unidade Astronômica a partir do trânsito de planetas fundamenta-se por razões tanto pedagógicas quanto científicas: este trabalho pode ser facilmente reproduzido em salas de aula tanto do ensino médio quanto superior em cursos de introdução à Astronomia. Além disso, o trânsito de Vênus de 2012 foi utilizado para a determinação do raio do Sol com incerteza de apenas 15km, justificando assim o seu estudo. Por fim, este trabalho fornece um teste de autoconsistência do Stellarium, uma vez que determinamos por meios geométricos o valor da UA utilizado pelo programa

Dynamics of the Intrinsically Disordered Inhibitor IF7 of Glutamine Synthetase in Isolation and in Complex with its Partner

Glutamine synthetase (GS) catalyzes the ATP-dependent formation of glutamine from glutamate and ammonia. The activity of Synechocystis sp. PCC 6803 GS is regulated, among other mechanisms, by protein-protein interactions with a 65-residue-long, intrinsically disordered protein (IDP), named IF7. IDPs explore diverse conformations in their free states and, in some cases, in their molecular complexes. We used both nuclear magnetic resonance (NMR) at 11.7 T and small angle X-ray scattering (SAXS) to study the size and the dynamics in the picoseconds-to-nanosecond (ps-ns) timescale of: (i) isolated IF7; and (ii) the IF7/GS complex. Our SAXS findings, together with MD results, show: (i) some of the possible IF7 structures in solution; and, (ii) that the presence of IF7 affected the structure of GS in solution. The joint use of SAXS and NMR shows that movements of each amino acid of IF7 were uncorrelated with those of its neighbors. Residues of IF7 with the largest values of the relaxation rates (R1, R2 and ηxy), in the free and bound species, were mainly clustered around: (i) the C terminus of the protein; and (ii) Ala30. These residues, together with Arg8 (which is a hot-spot residue in the interaction with GS), had a restricted mobility in the presence of GS. The C-terminal region, which appeared more compact in our MD simulations of isolated IF7, seemed to be involved in non-native contacts with GS that help in the binding between the two macromolecules.Ministerio de Economía y Competitividad RTI 2018-097991- BI0