Theoretical models of staurosporine and analogs uncover detailed structural information in biological solution.

Staurosporine and its analogs (STA-analogs) are indolocarbazoles (ICZs) compounds able to inhibit kinase proteins in a non-specific way, while present antimicrobial and cytostatic properties. The knowledge of molecular features associated to the complexation, including the ligand shape in solution and thermodynamics of complexation, is substantial to the development of new bioactive ICZs with improved therapeutic properties. In this context, the empirical approach of GROMOS force field is able to accurately reproduce condensed phase physicochemical properties of molecular systems after parameterization. Hence, through parameterization under GROMOS force field and molecular simulations, we assessed STA-analogs dynamics in aqueous solution, as well as its interaction with water to probe conformational and structural features involved in complexation to therapeutic targets. The coexistence of multiple conformers observed in simulations, and confirmed by metadynamics calculations, expanding the conformational space knowledge of these ligands with potential implications in understanding the ligand conformational selection during complexation. Also, changes in availability to H-bonding concerning the different substituents and water can reflect on effects at complexation free energy due to variation at the desolvation energetic costs. Based on these results, we expect the obtained structural data provide systemic framework for rational chemical modification of STA-analogs.

Mitochondrial genome study in blood of maternally inherited ALS cases.

BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer's and Parkinson's diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.

Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

Spreading of alpha-synuclein between different cell types.

Aggregation of alpha-synuclein (α-syn) is central in Parkinson's disease as well as in other synucleinopathies. Recent evidence suggests that not only intracellular aggregation of α-syn plays an important role for disease pathogenesis but also cell-to-cell propagation of α-syn seems to significantly contribute to pathological changes in synucleinopathies. In this mini-review we summarize current aspects of spreading of α-syn between brain cell types and its role in pathology.

Psicodrama público sp on-line durante a pandemia de covid-19 / Public psychodrama sp on-line during the covid-19 pandemic / Psicodrama público sp on-line durante la pandemia del covid-19

RESUMO O objetivo deste trabalho é apresentar reflexões sobre as sessões de Psicodrama Público SP On-line ocorridas entre agosto de 2020 e dezembro de 2021. O procedimento utilizado foi a análise qualitativa de entrevistas com a unidade funcional, o anfitrião e alguns participantes, gravadas após a realização dos psicodramas. Foram criadas quatro categorias a partir dos temas protagônicos apresentados. Foram identificados dois movimentos complementares: um em direção ao desequilíbrio e outro em direção à tentativa de restaurá-lo,além de uma retroalimentação entre as categorias e entre os períodos analisados. Observou-se que se instauraram novos processos de subjetivação no contexto grupal marcados pelos múltiplos sofrimentos vivenciados no período pandêmico da COVID-19, facilitados pela liberação da espontaneidade e criatividade.

ABSTRACT This paper aims to present reflections on the Psicodrama Público SP On-line sessions that took place between August 2020 and December 2021. The procedure used was the qualitative analysis of interviews, with the functional unit, the host and some participants, recorded after the realization of psychodramas. Four categories were created from the main themes presented. Two complementary movements were identified: one towards the imbalance and the other towards the attempt to restore it, in addition to a feedback between the categories and between the analyzed periods. It was observed that new processes of subjectivation were established in the group context marked by many sufferings in the pandemic period of COVID-19, facilitated by the release of spontaneity and creativity.

RESUMEN El objetivo de este trabajo es presentar reflexiones sobre las sesiones de Psicodrama Público SP On-line que se desarrollaron entre agosto de 2020 y diciembre de 2021. El procedimiento utilizado fue el análisis cualitativo de entrevistas, con la unidad funcional, el conductor y algunos participantes, grabadas después de la realización de psicodramas. Se crearon cuatro categorías a partir de los principales temas presentados. Se identificaron dos movimientos complementarios: uno hacia el desequilibrio y otro hacia el intento de restaurarlo, además de una retroalimentación entre las categorías y entre los periodos analizados. Se observó que se establecieron nuevos procesos de subjetivación en el contexto grupal marcado por los muchos sufrimientos en el período de pandemia por la COVID-19, facilitados por la liberación de la espontaneidad y la creatividad.

Comparative genomics and antibiotic resistance of Yersinia enterocolitica obtained from a pork production chain and human clinical cases in Brazil.

Previous work found a high similarity of macro-restriction patterns for isolates of Yersinia enterocolitica 4/O:3 obtained at a pork production chain from Minas Gerais, Brazil. Herein we aimed to determine the clonality and the antibiotic resistance profiles of a subset of these isolates (n = 23) and human clinical isolates (n = 3). Analysis based on whole genome sequencing (WGS) showed that the isolates were distributed into two major clades based on single nucleotide polymorphisms (SNP) with one isolate defining Clade A (isolate R31) and remaining isolates (n = 25, 96.2%) defining Clade B. Seven clonal groups were identified. The inclusion of isolate R31 as a distinct clonal group was due to the presence of several phage-related genes, allowing its characterization as serotype O:5 by WGS. Disk-diffusion assays (14 antibiotics) identified 13 multidrug resistant isolates (50.0%). Subsequent sequence analysis identified 17 different antibiotic resistance related genes. All isolates harbored blaA (y56 beta-lactamase), vatF, rosA, rosB and crp, while nine isolates harbored a high diversity of antibiotic resistance related genes (n = 13). The close genetic relationship among Y. enterocolitica obtained from a pork production chain and human clinical isolates in Brazil was confirmed, and we can highlight the role of swine in the potential transmission of an antibiotic-resistant clones of a pathogenic bio-serotype to humans, or the transmission of these resistant bacteria from people to animals. The role of veterinary antibiotic use in this process is unclear.

Correction: On the relation between transversal and longitudinal scaling in cities.

[This corrects the article DOI: 10.1371/journal.pone.0233003.].

Gene doping and genomic science in sports: where are we?

The misuse of sport-related gene transfer methods in elite athletes is a real and growing concern. The success of gene therapy in the treatment of hereditary diseases has been most evident since targets in gene therapy products can be used in healthy individuals to improve sports performance. Performing these practices threatens the sporting character of competitions and may pose potential health hazards. Since the World Anti-Doping Agency pronouncement on the prohibition of such practices in 2003, several researchers have been trying to address the challenge of developing an effective method for the detection of genetic doping. This review presents an overview of the published methods developed for this purpose, the advantages and limitations of technologies and the putative target genes. At last, we present the perspective related to the application of the detection methods in the doping control field.

On the relation between transversal and longitudinal scaling in cities.

Does the scaling relationship between population sizes of cities with urban metrics like economic output and infrastructure (transversal scaling) mirror the evolution of individual cities in time (longitudinal scaling)? The answer to this question has important policy implications, but the lack of suitable data has so far hindered rigorous empirical tests. In this paper, we advance the debate by looking at the evolution of two urban variables, GDP and water network length, for over 5500 cities in Brazil. We find that longitudinal scaling exponents are city-specific. However, they are distributed around an average value that approaches the transversal scaling exponent provided that the data is decomposed to eliminate external factors, and only for cities with a sufficiently high growth rate. We also introduce a mathematical framework that connects the microscopic level to global behaviour, finding good agreement between theoretical predictions and empirical evidence in all analyzed cases. Our results add complexity to the idea that the longitudinal dynamics is a micro-scaling version of the transversal dynamics of the entire urban system. The longitudinal analysis can reveal differences in scaling behavior related to population size and nature of urban variables. Our approach also makes room for the role of external factors such as public policies and development, and opens up new possibilities in the research of the effects of scaling and contextual factors.

Current Status of Carbohydrates Information in the Protein Data Bank.

Carbohydrates are well known for their physicochemical, biological, functional, and therapeutic characteristics. Unfortunately, their chemical nature imposes severe challenges for the structural elucidation of these phenomena, impairing not only the depth of our understanding of carbohydrates but also the development of new biotechnological and therapeutic applications based on these molecules. In the recent past, the amount of structural information, obtained mainly from X-ray crystallography, has increased progressively, as well as its quality. In this context, the current work presents a global analysis of the carbohydrate information available in the Protein Data Bank (PDB). From high quality structures, it is clear that most of the data are highly concentrated on a few sets of residue types, on their monosaccharidic forms, and connected by a small diversity of glycosidic linkages. The geometries of these linkages can be mostly associated with the types of linkages instead of residues, while the level of puckering distortion was characterized, quantified, and located in a pseudorotational equilibrium landscape, not only to local minima but also to transitional states. These qualitative and quantitative analyses offer a global picture of the carbohydrate structural content in the PDB, potentially supporting the building of new models for carbohydrate-related biological phenomena at the atomistic level, including new developments on force field parameters.

Evolution of urban scaling: Evidence from Brazil.

During the last years, the new science of cities has been established as a fertile quantitative approach to systematically understand the urban phenomena. One of its main pillars is the proposition that urban systems display universal scaling behavior regarding socioeconomic, infrastructural and individual basic services variables. This paper discusses the extension of the universality proposition by testing it against a broad range of urban metrics in a developing country urban system. We present an exploration of the scaling exponents for over 60 variables for the Brazilian urban system. Estimating those exponents is challenging from the technical point of view because the Brazilian municipalities' definition follows local political criteria and does not regard characteristics of the landscape, density, and basic utilities. As Brazilian municipalities can deviate significantly from urban settlements, urban-like municipalities were selected based on a systematic density cut-off procedure and the scaling exponents were estimated for this new subset of municipalities. To validate our findings we compared the results for overlaying variables with other studies based on alternative methods. It was found that the analyzed socioeconomic variables follow a superlinear scaling relationship with the population size, and most of the infrastructure and individual basic services variables follow expected sublinear and linear scaling, respectively. However, some infrastructural and individual basic services variables deviated from their expected regimes, challenging the universality hypothesis of urban scaling. We propose that these deviations are a product of top-down decisions/policies. Our analysis spreads over a time-range of 10 years, what is not enough to draw conclusive observations, nevertheless we found hints that the scaling exponent of these variables are evolving towards the expected scaling regime, indicating that the deviations might be temporally constrained and that the urban systems might eventually reach the expected scaling regime.

Crack, é possível vencer!? Sociodrama, drogas e políticas públicas / Crack, it is possible to win!? Sociodrama, drugs and public policy / Crack, es posible vencer!? Sociodrama, drogas y políticas públicas

Este artigo apresenta uma narrativa e uma análise da experiência sociodramática realizada junto ao Ministério da Justiça pelo Sistema Nacional de Políticas Públicas sobre Drogas (SISNAD), que criou o Plano Integrado de Enfretamento ao Crack e outras Drogas. E, posteriormente, originou o programa "Crack, é Possível Vencer!", que propunha ações sustentadas em três eixos: prevenção, cuidado e autoridade, junto a policiais militares em capitais brasileiras em 2013/2014. O sociodrama promovia uma sensibilização e uma reflexão do usuário de crack como um cidadão doente social. A meta foi criar uma mudança na mentalidade e despertar para uma nova política pública de tratamento.

This article presents a narrative and an analysis of the sociodramatic experience held by the Ministry of Justice through the National System of Public Policies on Drugs (SISNAD), which formulated the Integrated Plan to Combat Crack and Other Drugs. And later, it created the "Crack, it's possible to win!" program, which proposed actions based on three axes: prevention, care and authority, together with police officers in Brazilian capitals in 2013/2014. The sociodrama promoted awareness and reflection in relation to the crack user as a socially sick citizen. The goal was to create a change in mentality and to raise awareness to a new public treatment policy.

Este artículo presenta una narrativa y un análisis de la experiencia sociodramática realizada junto al Ministerio de Justicia por el Sistema Nacional de Políticas Públicas sobre Drogas (SISNAD), que creó el Plan Integrado de Enfrentamiento al Crack y otras Drogas. Y, posteriormente, originó el programa "Crack, es posible vencer!", que proponía acciones sostenidas en tres ejes: prevención, cuidado y autoridad, junto a las policías militares en capitales brasileñas en 2013/2014. El sociodrama promovía una sensibilización y una reflexión del usuario de crack como un ciudadano enfermo social. La meta fue crear un cambio en la mentalidad y conciencia sobre una nueva política pública de tratamiento.

Cities, from Information to Interaction.

From physics to the social sciences, information is now seen as a fundamental component of reality. However, a form of information seems still underestimated, perhaps precisely because it is so pervasive that we take it for granted: the information encoded in the very environment we live in. We still do not fully understand how information takes the form of cities, and how our minds deal with it in order to learn about the world, make daily decisions, and take part in the complex system of interactions we create as we live together. This paper addresses three related problems that need to be solved if we are to understand the role of environmental information: (1) the physical problem: how can we preserve information in the built environment? (2) The semantic problem: how do we make environmental information meaningful? and (3) the pragmatic problem: how do we use environmental information in our daily lives? Attempting to devise a solution to these problems, we introduce a three-layered model of information in cities, namely environmental information in physical space, environmental information in semantic space, and the information enacted by interacting agents. We propose forms of estimating entropy in these different layers, and apply these measures to emblematic urban cases and simulated scenarios. Our results suggest that ordered spatial structures and diverse land use patterns encode information, and that aspects of physical and semantic information affect coordination in interaction systems.

A model of urban scaling laws based on distance dependent interactions.

Socio-economic related properties of a city grow faster than a linear relationship with the population, in a log-log plot, the so-called superlinear scaling. Conversely, the larger a city, the more efficient it is in the use of its infrastructure, leading to a sublinear scaling on these variables. In this work, we addressed a simple explanation for those scaling laws in cities based on the interaction range between the citizens and on the fractal properties of the cities. To this purpose, we introduced a measure of social potential which captured the influence of social interaction on the economic performance and the benefits of amenities in the case of infrastructure offered by the city. We assumed that the population density depends on the fractal dimension and on the distance-dependent interactions between individuals. The model suggests that when the city interacts as a whole, and not just as a set of isolated parts, there is improvement of the socio-economic indicators. Moreover, the bigger the interaction range between citizens and amenities, the bigger the improvement of the socio-economic indicators and the lower the infrastructure costs of the city. We addressed how public policies could take advantage of these properties to improve cities development, minimizing negative effects. Furthermore, the model predicts that the sum of the scaling exponents of social-economic and infrastructure variables are 2, as observed in the literature. Simulations with an agent-based model are confronted with the theoretical approach and they are compatible with the empirical evidences.

RIMSA 12. Propuesta para la creación de la Comisión Panamericana de Inocuidad de Alimentos (COPAIA)

En este documento se analiza la situación relacionada con la inocuidad de los alimentos en los países de la Región de las Américas y se estabelecen las bases para la creación de una Comisión Panamericana de Inocuidad de Alimentos, COPAIA, así como su Plan de Acción cuyo objetivo principal apunte al logro de los principios básicos de la OPS de Equidad y Panamericanismo y actúe como um foro de alto nivel político en la Región de las Américas.