OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function.

Ubiquitylation entails the concerted action of E1, E2, and E3 enzymes. We recently reported that OTUB1, a deubiquitylase, inhibits the DNA damage response independently of its isopeptidase activity. OTUB1 does so by blocking ubiquitin transfer by UBC13, the cognate E2 enzyme for RNF168. OTUB1 also inhibits E2s of the UBE2D and UBE2E families. Here we elucidate the structural mechanism by which OTUB1 binds E2s to inhibit ubiquitin transfer. OTUB1 recognizes ubiquitin-charged E2s through contacts with both donor ubiquitin and the E2 enzyme. Surprisingly, free ubiquitin associates with the canonical distal ubiquitin-binding site on OTUB1 to promote formation of the inhibited E2 complex. Lys48 of donor ubiquitin lies near the OTUB1 catalytic site and the C terminus of free ubiquitin, a configuration that mimics the products of Lys48-linked ubiquitin chain cleavage. OTUB1 therefore co-opts Lys48-linked ubiquitin chain recognition to suppress ubiquitin conjugation and the DNA damage response.

An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.

Structure-function analysis of core STRIPAK Proteins: a signaling complex implicated in Golgi polarization.

Cerebral cavernous malformations (CCMs) are alterations in brain capillary architecture that can result in neurological deficits, seizures, or stroke. We recently demonstrated that CCM3, a protein mutated in familial CCMs, resides predominantly within the STRIPAK complex (striatin interacting phosphatase and kinase). Along with CCM3, STRIPAK contains the Ser/Thr phosphatase PP2A. The PP2A holoenzyme consists of a core catalytic subunit along with variable scaffolding and regulatory subunits. Within STRIPAK, striatin family members act as PP2A regulatory subunits. STRIPAK also contains all three members of a subfamily of Sterile 20 kinases called the GCKIII proteins (MST4, STK24, and STK25). Here, we report that striatins and CCM3 bridge the phosphatase and kinase components of STRIPAK and map the interacting regions on each protein. We show that striatins and CCM3 regulate the Golgi localization of MST4 in an opposite manner. Consistent with a previously described function for MST4 and CCM3 in Golgi positioning, depletion of CCM3 or striatins affects Golgi polarization, also in an opposite manner. We propose that STRIPAK regulates the balance between MST4 localization at the Golgi and in the cytosol to control Golgi positioning.

Quality Of Life and Associated Factors in Latin American Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: The objective of this study was to determine whether individuals with hip osteoarthritis who undergo THA have higher HRQOL scores than those awaiting the procedure; An additional aim was to investigate associated factors exerting an impact on HRQOL. MATERIALS AND METHODS: A cross-sectional study was conducted. Participants were divided into two groups: pre-THA and post-THA. Functional capacity was assessed using the Harris Hip Score, and HRQOL was measured using a validated and adapted version of the WOMAC questionnaire. A multivariate analysis of the WOMAC results was used to identify the main variables associated with HRQOL in both groups. RESULTS: The post-THA group had higher HRQOL scores (100.4 ± 88.5) than the pre-THA group (197.8 ± 54.1). The domains Pain (68.0 ± 19.0 versus 34.7 ± 30.8), Stiffness (61.2 ± 28.9 versus 29.9 ± 33.1), and Physical Activity (68.6 ± 16.1 versus 36.6 ± 30.2) also had higher scores in the post-THA group. Pain was the variable most frequently associated with the increase in post-THA HRQOL scores. Other variables such as occupation, time of diagnosis, joint function, and body weight also had an impact on the HRQOL of both groups. CONCLUSIONS: 1. Individuals who underwent THA had higher scores for HRQOL compared to those still awaiting the procedure. 2. Pain was the variable most strongly associated with quality of life.

Quality of Life and Associated Factors in Latin American Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: The objective of this study was to determine whether individuals with hip osteoarthritis who undergo THA have higher HRQOL scores than those awaiting the procedure; An additional aim was to investigate associated factors exerting an impact on HRQOL. MATERIALS AND METHODS: A cross-sectional study was conducted. Participants were divided into two groups: pre-THA and post-THA. Functional capacity was assessed using the Harris Hip Score, and HRQOL was measured using a validated and adapted version of the WOMAC questionnaire. A multivariate analysis of the WOMAC results was used to identify the main variables associated with HRQOL in both groups. RESULTS: The post-THA group had higher HRQOL scores (100.4 ± 88.5) than the pre-THA group (197.8 ± 54.1). The domains Pain (68.0 ± 19.0 versus 34.7 ± 30.8), Stiffness (61.2 ± 28.9 versus 29.9 ± 33.1), and Phy-sical Act--vity (68.6 ± 16.1 versus 36.6 ± 30.2) also had higher scores in the post-THA group. Pain was the variable most frequently associated with the increase in post-THA HRQOL scores. Other variables such as occupation, time of diagnosis, joint function, and body weight also had an impact on the HRQOL of both groups. CONCLUSIONS: 1. Individuals who had undergone THA showed higher HRQOL scores in all domains when compared to those still awaiting the procedure, and pain reduction was the variable most strongly associated with the improvement in quality of life of those patients. 2. Occupation and mobility were associated with the Stiffness domain of QOL; Occupation also had a bearing on health-related quality of life as a whole. 3. Physical Activity of the WOMAC instrument was associated with time of diagnosis, patient's body weight, and function as assessed by the HHS.

AlbuCORE: an albumin-based molecular scaffold for multivalent biologics design.

As biologics have become a mainstay in the development of novel therapies, protein engineering tools to expand on their structural advantages, namely specificity, affinity, and valency are of interest. Antibodies have dominated this field as the preferred scaffold for biologics development while there has been limited exploration into the use of albumin with its unique physiological characteristics as a platform for biologics design. There has been a great deal of interest to create bispecific and more complex multivalent molecules to build on the advantages offered by protein-based therapeutics relative to small molecules. Here, we explore the use of human serum albumin (HSA) as a scaffold for the design of multispecific biologics. In particular, we describe a structure-guided approach to the design of split HSA molecules we refer to as AlbuCORE, that effectively and spontaneously forms a native albumin-like molecule, but in a heterodimeric state upon co-expression. We show that the split AlbuCORE designs allow the creation of novel fusion entities with unique alternate geometries. We also show that, apart from these AlbuCORE fusion entities, there is an opportunity to explore their albumin-like small hydrophobic molecule carrying capacity as a drug conjugate in these designs.

Effectiveness of commercial inhibitors against subtype F HIV-1 protease.

Subtype F wild type HIV protease has been kinetically characterized using six commercial inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) commonly used for HIV/AIDS treatment, as well as inhibitor TL-3 and acetyl-pepstatin. We also obtained kinetic parameters for two multi-resistant proteases (one of subtype B and one of subtype F) harboring primary and secondary mutations selected by intensive treatment with ritonavir/nelfinavir. This newly obtained biochemical data shows that all six studied commercially available protease inhibitors are significantly less effective against subtype F HIV proteases than against HIV proteases of subtype B, as judged by increased K(i) and biochemical fitness (vitality) values. Comparison with previously reported kinetic values for subtype A and C HIV proteases show that subtype F wild type proteases are significantly less susceptible to inhibition. These results demonstrate that the accumulation of natural polymorphisms in subtype F proteases yields catalytically more active enzymes with a large degree of cross-resistance, which thus results in strong virus viability.

Vulnerabilidade moral entre estranhos morais: limites do princípio da permissão / Moral vulnerability among moral strangers: limits of the principle of permission / Vulnerabilidad moral entre extraños morales: límites del principio de permiso

Resumo Este artigo apresenta uma análise crítica da obra de Tristram Engelhardt, com foco no princípio da permissão. Argumenta-se que, em contextos de intensas desigualdades sociais e negação de direitos, a aplicação da ética de procedimentos baseada apenas no princípio da permissão pode resultar na vulnerabilidade moral de indivíduos e grupos que não compartilham de determinada moralidade. Isso pode levá-los a serem expostos a diferentes formas de negação de direitos, violência, exploração, exclusão e estigmatização. Diante dessa realidade, destaca-se a importância de fortalecer uma bioética comprometida com a defesa da dignidade, da diversidade, dos direitos humanos e da justiça social.

Abstract This article presents a critical analysis of Tristram Engelhardt's work, focusing on the principle of permission. It is argued that, in a context of intense social inequalities and denial of rights, the application of procedural ethics based solely on the principle of permission can result in the moral vulnerability of individuals and groups who do not share a certain morality. This can expose them to different forms of denial of rights, violence, exploitation, exclusion, and stigmatization. Given this reality, the importance of strengthening a bioethics committed to defending dignity, diversity, human rights, and social justice is highlighted.

Resumen Este artículo presenta un análisis crítico de la obra de Tristram Engelhardt, centrándose en el principio de permiso. Se arguye que, en un contexto de intensas desigualdades sociales y negación de derechos, la aplicación de la ética de procedimientos basada solo en el principio de permiso puede generar vulnerabilidad moral en los individuos y grupos que no comparten cierta moralidad. Esto puede llevarlos a verse expuestos a diferentes formas de negación de derechos, violencia, explotación, exclusión y estigmatización. Ante esta realidad, se destaca la importancia de fortalecer una bioética comprometida con la defensa de la dignidad, la diversidad, los derechos humanos y la justicia social.

The crystal structure of the human Mov34 MPN domain reveals a metal-free dimer.

The 26S proteasome is a large protein complex involved in protein degradation. We have shown previously that the PSMD7/Mov34 subunit of the human proteasome contains a proteolytically resistant MPN domain. MPN domain family members comprise subunits of the proteasome, COP9-signalosome and translation initiation factor 3 complexes. Here, the crystal structure of two C-terminally truncated proteins, MPN 1-186 and MPN 1-177, were solved to 1.96 and 3.0 A resolution, respectively. MPN 1-186 is formed by nine beta-strands surrounded by three alpha-helices plus a fourth alpha-helix at the C terminus. This final alpha-helix emerges from the domain core and folds along with a symmetrically related subunit, typical of a domain swap. The crystallographic dimer is consistent with size-exclusion chromatography and DLS analysis showing that MPN 1-186 is a dimer in solution. MPN 1-186 shows an overall architecture highly similar to the previously reported crystal structure of the Archaeal MPN domain AfJAMM of Archaeoglobus fulgidus. However, previous structural and biophysical analyses have shown that neither MPN 1-186 nor full-length human Mov34 bind metal, in opposition to the zinc-binding AfJAMM structures. The zinc ligand residues observed in AfJAMM are conserved in the yeast Rpn11 proteasome and Csn5 COP-signalosome subunits, which is consistent with the isopeptidase activity described for these proteins. The results presented here show that, although the MPN domain of Mov34 shows a typical metalloprotease fold, it is unable to coordinate a metal ion. This finding and amino acid sequence comparisons can explain why the MPN-containing proteins Mov34/PSMD7, RPN8, Csn6, Prp8p and the translation initiation factor 3 subunits f and h do not show catalytic isopeptidase activity, allowing us to propose the hypothesis that in these proteins the MPN domain has a primarily structural function.

Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development.

Although a majority of HIV-1 infections in Brazil are caused by the subtype B virus (also prevalent in the United States and Western Europe), viral subtypes F and C are also found very frequently. Genomic differences between the subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. The current anti-HIV drugs have been developed primarily against subtype B and the effects arising from the combination of drug-resistance mutations with the naturally existing polymorphisms in non-B HIV-1 subtypes are only beginning to be elucidated. To gain more insights into the structure and function of different variants of HIV proteases, we have determined a 2.1 A structure of the native subtype F HIV-1 protease (PR) in complex with the protease inhibitor TL-3. We have also solved crystal structures of two multi-drug resistant mutant HIV PRs in complex with TL-3, from subtype B (Bmut) carrying the primary mutations V82A and L90M, and from subtype F (Fmut) carrying the primary mutation V82A plus the secondary mutation M36I, at 1.75 A and 2.8 A resolution, respectively. The proteases Bmut, Fwt and Fmut exhibit sevenfold, threefold, and 54-fold resistance to TL-3, respectively. In addition, the structure of subtype B wild type HIV-PR in complex with TL-3 has been redetermined in space group P6(1), consistent with the other three structures. Our results show that the primary mutation V82A causes the known effect of collapsing the S1/S1' pockets that ultimately lead to the reduced inhibitory effect of TL-3. Our results further indicate that two naturally occurring polymorphic substitutions in subtype F and other non-B HIV proteases, M36I and L89M, may lead to early development of drug resistance in patients infected with non-B HIV subtypes.

Imigração de haitianos: enfoque na comunicação em saúde / Haitian immigration: focus on health communication / Inmigración haitiana: enfoque en la comunicación de salud

Pesquisa sobre a adaptação dos imigrantes haitianos à realidade brasileira e ao Sistema Único de Saúde (SUS) e a forma como se processam as relações interpessoais no ambiente de saúde. O objetivo foi compreender como os imigrantes haitianos, usuários do sistema de saúde, se apresentam e são percebidos nas relações estabelecidas com os profissionais de saúde em uma Unidade Básica de Saúde (UBS) da Região Metropolitana de Curitiba. Foi uma etnografia com observação participante, com utilização de diário de campo. Resultados apontam dificuldades por parte dos imigrantes haitianos ao acesso ao sistema de saúde, pelas peculiaridades de sua cultura, e por parte dos profissionais de saúde, a língua e a cultura se tornam as principais barreiras para os atendimentos, permeada por preconceitos, decorrentes de falta de preparo de alguns profissionais. Contudo, tais dificuldades podem ser contornadas por meio de estratégias eficazes e uma melhor preparação para acolher essa população.

Research on the adaptation of Haitian immigrants to the Brazilian reality and to the Brazilian Public Health System (SUS) and on the way interpersonal relationship is processed in the health environment. The objective was to understand how Haitian immigrants, users of the health system, present themselves and are perceived in the relationships established with health professionals in a Primary Health Unit in the Metropolitan Region of Curitiba. It was an ethnography with participant observation, using a field diary. Results indicate difficulties for Haitian immigrants to access the health system, due to the peculiarities of their culture, and for the health professionals, as language and culture become the main barrier to care, being permeated by prejudice resulting from lack of training of some professionals. However, such difficulties can be overcome through effective strategies and better preparation to embrace this population.

Investigación sobre la adaptación de los inmigrantes haitianos a la realidad brasileña y al Sistema Único de Salud y la forma en que se procesan las relaciones interpersonales en el entorno de la salud. El objetivo fue comprender cómo los inmigrantes haitianos se presentan y son percibidos en las relaciones establecidas con los profesionales de salud en una Unidad Básica de Salud de la Región Metropolitana de Curitiba. Fue una etnografía con observación participante utilizando un diario de campo. Resultados señalan dificultades por parte de los inmigrantes haitianos para acceder al sistema de salud, por las peculiaridades de su cultura, y por parte de los profesionales de la salud, el idioma y la cultura se convierten en la principal barrera para la atención, permeada por prejuicios, derivados de la falta de formación de algunos profesionales. Tales dificultades pueden superarse mediante estrategias eficaces y una mejor preparación para acoger a esta población.

Cuidados paliativos em terapia intensiva: revisão integrativa / Palliative care in intensive care units: an integrative review / Cuidados paliativos en cuidados intensivos: revisión integradora

Resumo Trata-se de revisão integrativa com o objetivo de identificar decisões terapêuticas de cuidados paliativos em unidade de terapia intensiva. A busca foi realizada na Biblioteca Virtual em Saúde com os descritores "cuidados paliativos", "unidades de terapia intensiva" e "atenção à saúde", e encontrou 1.579 pesquisas, das quais sete constituíram a amostra final. O material foi analisado por meio do software Interface de R pour les Analyses Multidimensionnelles de Textes et de Questionnaires . Uma árvore de similitude foi produzida a partir dos principais resultados e dos vocábulos "paciente", "término", "família", "unidade de terapia intensiva", "cuidados paliativos", "hospital", resultando em duas categorias e quatro subcategorias. Na atualidade, com avanços das doenças crônicas não transmissíveis e aumento da expectativa de vida, vislumbra-se a possibilidade de utilizar esses cuidados em grande escala, gerando melhorias na qualidade de vida, assistencial e acadêmica.

Abstract Our integrative review sought to identify therapeutic decisions for palliative care in intensive care units. Bibliographic search conducted on the Virtual Health Library using the descriptors "palliative care," "intensive care units" and "delivery of health care" returned 1,579 studies, of which seven were included in the final sample. Textual analysis was performed using the Iramuteq software. From the main results and words—"patient," "end of life," "family," "intensive care unit," "hospital"—we produced a co-occurrences tree, resulting in two categories and four subcategories. Currently, the spread of chronic noncommunicable diseases and increased life expectancy call for the large-scale use of this type of care, improving quality of life, care and academia.

Resumen Esta revisión integradora pretende identificar las decisiones terapéuticas de cuidados paliativos en una unidad de cuidados intensivos. La búsqueda se realizó en la Biblioteca Virtual de Salud, con los descriptores "cuidados paliativos", "unidades de cuidados intensivos" y "cuidado de la salud", la cual resultó en 1.579 estudios, de los cuales siete compusieron la muestra final. Para el análisis del material se utilizó el software Interface de R pour les Analyses Multidimensionnelles de Textes et de Questionnaires. Se elaboró un árbol de similitud desde los resultados principales y las palabras "paciente", "finitud", "familia", "unidad de cuidados intensivos", "cuidados paliativos", "hospital", lo que dio como resultado dos categorías y cuatro subcategorías. Teniendo en cuenta los actuales avances en las enfermedades crónicas no transmisibles y el aumento de la esperanza de vida, este tipo de cuidados puede utilizarse a gran escala, pues genera mejoras en la calidad de vida, asistencial y académica.

Caracterização atual da objeção de consciência: proposta crítica e renovada / Current characterization of conscientious objection: a critical and renewed proposal / Caracterización actual de la objeción de conciencia: propuesta crítica y renovada

Resumo O artigo caracteriza a "objeção de consciência" - cercada por controvérsias e marcada pela ausência de definição unificada - e os limites de seu exercício. O objetivo da pesquisa, baseada na abordagem de revisão crítica de literatura, é propor uma definição para o termo. Para isso, identificaram-se situações em que a objeção de consciência é erroneamente invocada ou serve de pretexto para comportamentos antiéticos, e se procurou estabelecer os elementos que verdadeiramente compõem tal objeção. O conceito proposto pretende contribuir para esclarecer o assunto e estabelecer limites justos ao exercício ético desse direito.

Abstract This article characterizes "conscientious objection" - surrounded by controversies and marked by the absence of a unified definition - and the limits of its exercise. From a critical literature review approach, the objective is to propose a definition for the term. For such, situations where conscientious objection is wrongly invoked or serves as a pretext for unethical behavior were identified, and an attempt to establish the elements that truly compose such objection was made. The proposed concept intends to contribute to clarifying the matter and establishing fair limits to the ethical exercise of this right.

Resumen El artículo caracteriza la "objeción de conciencia", rodeada de controversias y marcada por la ausencia de una definición unificada, y los límites de su ejercicio. El objetivo de la investigación, basada en el enfoque de la revisión crítica de la literatura, es proponer una definición para el término. Para ello, se identificaron situaciones en las que la objeción de conciencia se invoca erróneamente o sirve de pretexto para conductas poco éticas, y se intentó establecer los elementos que verdaderamente componen dicha objeción. El concepto propuesto pretende contribuir a clarificar el tema y establecer límites justos al ejercicio ético de este derecho.

Participação masculina no planejamento familiar: revisão integrativa da literatura / Male involvement in family planning: an integrative literature review / Participación masculina en la planificación familiar: revisión integrativa de la literatura

Este artigo trata de uma revisão integrativa de literatura sobre a participação masculina no planejamento familiar. Foram analisados 15 artigos de pesquisas empíricas realizadas com homens, disponíveis no Portal de Periódicos Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) e nas bases de dados US National Library of Medicine (Pubmed) e Scientific Electronic Library Online (SciELO), com recorte de 1995 a 2019. Os resultados foram organizados em cinco categorias: comportamento masculino em relação ao planejamento familiar (PF); quem deve ser responsável pelo PF versus envolvimento masculino atual; como os homens participam do PF; fatores que influenciam a participação; fatores que dificultam a participação. Evidenciou-se a limitada participação masculina no PF, porém com sinais de mudanças em culturas com relações de gênero mais igualitárias. Por esse e outros fatores, ressalta-se a necessidade de investimentos em políticas públicas que visem melhor inserção masculina no PF.(AU)

This article presents the results of an integrative literature review of male involvement in family planning (FP). We analyzed 15 articles of studies conducted with men between 1995 and 2019 available on CAPES' Journal Portal and the PubMed and SciELO databases. The results were organized into five categories: male behavior in relation to FP; who should be responsible for FP versus current male involvement; how men participate in FP; factors that influence involvement; and factors that hinder involvement. The findings showed that although male involvement in FP was limited, there are signs of change in culture resulting in greater gender equality. Our findings and other factors highlight the need to invest in public policies designed to increase male involvement in FP.(AU)

Este artículo contiene una revisión integrativa de literatura sobre la participación masculina en la planificación familiar. Se analizaron 15 artículos de investigaciones empíricas realizadas con hombres, disponibles en el Portal de Periódicos CAPES y en las bases de datos Pubmed y SciELO, con recorte de 1995 a 2019. Los resultados se organizaron en cinco categorías: comportamiento masculino con relación a la planificación familiar (PF): quién debe ser responsable por la PF versus envolvimiento masculino actual; cómo los hombres participan en la PF; factores que influyen en la participación; factores que dificultan la participación. Resultó evidente la limitada participación que ellos tienen en la PF, pero con señales de cambio cultural con relaciones de género más igualitarias. Por ese y otros factores, se subraya la necesidad de inversiones en políticas públicas con el objetivo de una mejor inserción masculina en la PF.(AU)

O lugar do desejo de aborto na parentalidade: uma reflexão bioética / The place of desire for abortion in parenting: a bioethical reflection

O aborto é um tema dilemático e sensível. Dessa forma, seus aspectos demográficos são ainda elusivos. O objetivo dessa pesquisa foi obter/ analisar dados demográficos do risco do desejo de aborto. Foi aplicado no Estado do Paraná o instrumento "Planejamento da Parentalidade no Contexto da Bioética". Dos 1608 participantes (74,2% se identificaram como mulheres e 24,94% como homens) 4,5% responderam ter desejado fortemente o aborto. Para os pais que não planejaram a gravidez (39,9% dos participantes) o forte desejo do aborto correspondeu a 51,4%. Ao correlacionar esse desejo com as demais variáveis, fica evidente que a vulnerabilidade deve ser considerada no desenvolvimento da parentalidade, pois impacta o planejamento familiar e o desejo de aborto, para além das questões sociais e de gênero. Este estudo aponta a necessidade de ampliação de estudos demográficos do desejo do aborto, bem como utilização da Bioética como ferramenta nos programas de planejamento familiar.

Abortion is a dilemmatic and sensitive issue. Thus, its demographic aspects are still elusive. The objective of this research is to obtain and analyze demographic data on the risk of the desire for abortion. In the State of Paraná the research instrument "Parenting Planning in the Context of Bioethics" was applied. Among 1608 participants (74.2% identified as women and 24.94% as men), 4.5% responded to have strongly desired an abortion. For parents who did not plan for pregnancy (39.9% of participants) the strong desire for an abortion corresponded to 51.4%. When correlating this desire with other variables, it is evident that vulnerability must be considered in the development of parenting, as it impacts family planning and the desire for abortion, in addition to social and gender issues. This study points out the need to expand demographic studies on the desire for abortion, as well as the use of Bioethics as a tool for family planning programs.

Perspectivas bioéticas sobre tomada de decisão em tempos de pandemia / Bioethical perspectives on decision-making in times of pandemic / Perspectivas bioéticas sobre la toma de decisiones en tiempos de pandemia

Resumo Este artigo busca identificar contribuições da bioética para enfrentar conflitos relacionados à tomada de decisão em tempos de pandemia. Trata-se de texto elaborado a partir de reflexões pessoais dos autores em diálogo com a literatura de diferentes perspectivas da bioética. Com fundamento em relatos históricos, argumenta-se que, durante epidemias, a sociedade passa a atuar em modo de excepcionalidade, o que exige argumentação mais apurada para se posicionar ante os conflitos que surgem. Analisam-se então diferentes vertentes teóricas - principialismo, personalismo, utilitarismo e bioética social -, recolhendo de cada uma elementos que podem nortear a tomada de decisão. Com base nessas contribuições, propõem-se parâmetros para a atuação dos profissionais da saúde, reconhecendo igual valor em cada vida humana, com o propósito de salvar o maior número de pessoas possível. Por fim, aponta-se para a responsabilidade de agentes políticos.

Abstract This article aims to identify the contribution of bioethics to resolve decision-making conflicts in healthcare in times of pandemic. The research was based on the authors' personal reflections in a dialogue with the literature and different bioethical perspectives. Historical accounts show that when a society is experiencing an epidemic it starts to function in a mode of social exceptionality, reinforcing the need for a more appropriate form of reasoning before the ethical conflicts that may arise from this situation. Some approaches to bioethics - principlism, personalism, utilitarianism and social bioethics - are briefly examined in order to obtain the elements for guiding the decision-making process. Finally, we suggest some parameters for health professionals, recognizing the value of all human lives, to save as many lives as possible.

Resumen Este artículo tiene como objetivo identificar la contribución de la bioética para hacer frente a los conflictos relacionados con la toma de decisiones en tiempos de pandemia. Se trata de un texto elaborado con base en las reflexiones personales de los autores en diálogo con la literatura de diferentes perspectivas de la bioética. Con base en los relatos históricos, se argumenta que, durante epidemias, la sociedad pasa a actuar en modo de excepcionalidad, lo que requiere una argumentación más precisa para posicionarse ante los conflictos que surgen. Se analizan entonces diferentes vertientes teóricas -el principialismo, el personalismo, el utilitarismo y la bioética social-, recogiendo de cada una los elementos que pueden orientar la toma de decisiones. Con base en dichas contribuciones, se proponen parámetros para la actuación de los profesionales de la salud, reconociendo el mismo valor en cada vida humana, con el propósito de salvar al mayor número posible de personas. Por fin, se apunta hacia la responsabilidad de los agentes políticos.

Visões antropológicas divergentes em artigos científicos de bioética no Brasil / Visiones antropológicas divergentes en artículos científicos de bioética en Brasil / Divergent Anthropological Views in Scientific Articles on Bioethics in Brazil

Resumo O objetivo deste estudo é caracterizar de forma antropológica as produções brasileiras em bioética, em específico artigos científicos. A questão norteadora da pesquisa é: qual a caracterização antropológica presente nos artigos científicos em bioética no Brasil? As teorias bioéticas proeminentes apresentam indicadores de antropologia restritiva, isto é, que atribuem dignidade apenas a membros da espécie humana que sejam detentores de alguns atributos, dentre eles, consciência e autoconsciência, em contraponto com indicadores de antropologia integral em relação com os seres humanos, ou seja, que atribuem igual dignidade a todos os membros da espécie Homo sapiens. Conclui-se a proeminência de indicadores de antropologia integral e a divergência teórica nas temáticas relacionadas ao início da vida, principalmente entre utilitarismo e personalismo. .

Resumen El objeto del estudio es caracterizar de forma antropológica las producciones brasileñas en bioética, en específico artículos científicos. La cuestión orientadora de la investigación es: ¿cuál es la caracterización antropológica presente en los artículos científicos en bioética en Brasil? Las teorías bioéticas prominentes presentan indicadores de antropología restrictiva, es decir, que atribuyen dignidad solo a miembros de la especie humana que sean detentores de algunos atributos, entre ellos, conciencia y autoconciencia, en contraposición con indicadores de antropología integral en relación con los seres humanos, o sea, que atribuyen igual dignidad a todos los miembros de la especie Homo sapiens. Se concluye la prominencia de indicadores de antropología integral y la divergencia teórica en las temáticas relacionadas con el inicio de la vida, sobre todo entre utilitarismo y personalismo.

Abstract The aim of the study is to characterize Brazilian bioethics outputs anthropologically, specifically scientific articles. The guiding question of this research is: What is the anthropological characterization present in scientific articles on bioethics in Brazil? Prominent bioethical theories show restrictive anthropology indicators; i.e., dignity is given only to members of the human species that have certain attributes, including conscience and self-consciousness, as opposed to comprehensive anthropology indicators in relation to human beings; i.e., dignity is equally assigned to all members of the Homo sapiens species. In conclusion, comprehensive anthropology indicators and theoretical divergence in relation to the origin of life, especially between utilitarianism and personalism, prevail.

Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.

Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.

Vulnerabilidade moral: leitura das exclusões no contexto da bioética / Moral vulnerability: a view of exclusions in the context of bioethics / Vulnerabilidad moral: lectura de las exclusiones en el contexto de la bioética

Resumo Este artigo aborda a vulnerabilidade humana, apontando que as discussões sobre vulnerabilidade social e existencial não são suficientes para compreender determinadas situações de discriminação e exclusão a que algumas pessoas são submetidas. Trata-se de revisão teórica da temática estudada, a partir de abordagem interdisciplinar, como é próprio da bioética. A literatura deste campo já apresenta a distinção entre ser vulnerável, elemento próprio da condição humana, e estar vulnerável, indicando circunstâncias específicas. As situações de estar vulnerável revelam a chamada "vulnerabilidade social"; no entanto, há cenários em que a condição de vulnerabilidade de algumas pessoas é construída a partir de elementos abertamente morais, culturais, teóricos e, por isso, é defendida explicitamente. O artigo trata do conceito de vulnerabilidade moral, no âmbito da bioética, como uma chave de leitura para compreender a exclusão e discriminação a que alguns grupos são submetidos na atualidade, principalmente negros, mulheres e homossexuais.

Abstract This article proposes the discussion of human vulnerability, pointing out that the discussion of social and existential vulnerability is not enough to understand certain situations of discrimination and exclusion to which some people are submitted. It is a theoretical review of the studied subject, with an interdisciplinary approach, as it is used in bioethics. The literature on bioethics already shows the distinction between being vulnerable, an element of human condition and living a situation of specific vulnerability. Being involved in a vulnerable situation indicates the so called 'social vulnerability'. However, there are situations where the condition of vulnerability of some people is explicitly built from moral, cultural and theoretical elements, that are explicitly espoused and defended. The article approaches the concept of 'moral vulnerability' within the framework of bioethics, as a key to understand exclusion and discrimination to which some groups are presently submitted, especially black people, women and homosexuals.

Resumen Este artículo aborda la vulnerabilidad humana, señalando que la discusión sobre la vulnerabilidad social y existencial no es suficiente para comprender ciertas situaciones de discriminación y exclusión a las que algunas personas se ven sometidas. Se trata de una revisión teórica de la materia estudiada, a partir de un enfoque interdisciplinario, propio de la bioética. La literatura de este campo ya presenta la distinción entre ser vulnerable, lo cual es propio de la condición humana, y estar vulnerable, indicando situaciones específicas. Las situaciones en las que se está vulnerable revelan lo conocido como "vulnerabilidad social", sin embargo, hay situaciones en las que la condición de vulnerabilidad de algunas personas se construye a partir de elementos abiertamente morales, culturales, teóricos y, por ese motivo, se defiende explícitamente. El artículo aborda el concepto de vulnerabilidad moral, en el ámbito de la bioética, como una clave de lectura para comprender la exclusión y la discriminación a la que algunos grupos son sometidos hoy en día, principalmente negros, mujeres y homosexuales.

Structural and physiological analyses of the alkanesulphonate-binding protein (SsuA) of the citrus pathogen Xanthomonas citri.

BACKGROUND: The uptake of sulphur-containing compounds plays a pivotal role in the physiology of bacteria that live in aerobic soils where organosulfur compounds such as sulphonates and sulphate esters represent more than 95% of the available sulphur. Until now, no information has been available on the uptake of sulphonates by bacterial plant pathogens, particularly those of the Xanthomonas genus, which encompasses several pathogenic species. In the present study, we characterised the alkanesulphonate uptake system (Ssu) of Xanthomonas axonopodis pv. citri 306 strain (X. citri), the etiological agent of citrus canker. METHODOLOGY/PRINCIPAL FINDINGS: A single operon-like gene cluster (ssuEDACB) that encodes both the sulphur uptake system and enzymes involved in desulphurisation was detected in the genomes of X. citri and of the closely related species. We characterised X. citri SsuA protein, a periplasmic alkanesulphonate-binding protein that, together with SsuC and SsuB, defines the alkanesulphonate uptake system. The crystal structure of SsuA bound to MOPS, MES and HEPES, which is herein described for the first time, provides evidence for the importance of a conserved dipole in sulphate group coordination, identifies specific amino acids interacting with the sulphate group and shows the presence of a rather large binding pocket that explains the rather wide range of molecules recognised by the protein. Isolation of an isogenic ssuA-knockout derivative of the X. citri 306 strain showed that disruption of alkanesulphonate uptake affects both xanthan gum production and generation of canker lesions in sweet orange leaves. CONCLUSIONS/SIGNIFICANCE: The present study unravels unique structural and functional features of the X. citri SsuA protein and provides the first experimental evidence that an ABC uptake system affects the virulence of this phytopathogen.