PPARß/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells.

The role of peroxisome proliferator-activated receptor (PPAR)ß/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARß/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-ß (TGF-ß). The PPARß/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARß/δ activation abrogated TGF-ß1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-ß1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARß/δ agonist reduces TGF-ß1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.

Neurophysiological Pathways of Unconscious Emotion Processing in Depression: Insights from a simultaneous EEG-fMRI Measurement.

BACKGROUND: Major depressive disorder (MDD) is characterized by strong emotional dysregulation. Mechanisms driving the negative affect in depression may be fast processes existing on an unconscious level. METHODS: A priming task was conducted using simultaneous EEG-fMRI measurement involving presentation of facial expressions (happy, sad, neutral) to examine the neurophysiological pathway of biased unconscious emotion processing in MDD. Priming prior to a target emotion created unconscious (16.7 ms primer) and conscious (150 ms primer) trials. A large sample of N = 126 was recruited, containing healthy controls (HC; n = 66; 37 women) and MDD (n = 60; 31 women). RESULTS: HC showed a shorter reaction time in happy, but not in sad or neutral trials compared to MDD. N170 amplitudes were lower in trials with unconscious compared to conscious primer presentation. N170 amplitudes correlated with cortical (right fusiform gyrus (FFG), right middle temporal gyrus, right inferior temporal gyrus, left supplementary motor area, right middle frontal gyrus) and subcortical brain regions (right amygdala). The strength of N170 and brain activity correlation increased when the stimulus was consciously presented. Presented emotions did not affect the correlation of N170 values and brain activity. CONCLUSIONS: Our findings show that MDD may exhibit biased emotion regulation abilities at a behavioral and neurophysiological level. Face-sensitive event-related potentials demonstrate a correlation with heightened brain activity in regions associated with both face recognition (FFG) and emotion processing (amygdala). These findings are evident in both MDD and HC, with lower effect sizes in MDD indicating reduced emotion recognition and processing abilities.

Neural correlates of static and dynamic social decision-making in real-time sibling interactions.

In traditional game theory tasks, social decision-making is centered on the prediction of the intentions (i.e., mentalizing) of strangers or manipulated responses. In contrast, real-life scenarios often involve familiar individuals in dynamic environments. Further research is needed to explore neural correlates of social decision-making with changes in the available information and environmental settings. This study collected fMRI hyperscanning data (N = 100, 46 same-sex pairs were analyzed) to investigate sibling pairs engaging in an iterated Chicken Game task within a competitive context, including two decision-making phases. In the static phase, participants chose between turning (cooperate) and continuing (defect) in a fixed time window. Participants could estimate the probability of different events based on their priors (previous outcomes and representation of other's intentions) and report their decision plan. The dynamic phase mirrored real-world interactions in which information is continuously changing (replicated within a virtual environment). Individuals had to simultaneously update their beliefs, monitor the actions of the other, and adjust their decisions. Our findings revealed substantial choice consistency between the two phases and evidence for shared neural correlates in mentalizing-related brain regions, including the prefrontal cortex, temporoparietal junction (TPJ), and precuneus. Specific neural correlates were associated with each phase; increased activation of areas associated with action planning and outcome evaluation were found in the static compared with the dynamic phase. Using the opposite contrast, dynamic decision-making showed higher activation in regions related to predicting and monitoring other's actions, including the anterior cingulate cortex and insula. Cooperation (turning), compared with defection (continuing), showed increased activation in mentalizing-related regions only in the static phase, while defection, relative to cooperation, exhibited higher activation in areas associated with conflict monitoring and risk processing in the dynamic phase. Men were less cooperative and had greater TPJ activation. Sibling competitive relationship did not predict competitive behavior but showed a tendency to predict brain activity during dynamic decision-making. Only individual brain activation results are included here, and no interbrain analyses are reported. These neural correlates emphasize the significance of considering varying levels of information available and environmental settings when delving into the intricacies of mentalizing during social decision-making among familiar individuals.

Keratin 17 modulates the immune topography of pancreatic cancer.

BACKGROUND: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. METHODS: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. RESULTS: K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. CONCLUSIONS: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.

Keratin 17 is a prognostic and predictive biomarker in pancreatic ductal adenocarcinoma.

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. RESULTS: Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)-based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. CONCLUSIONS: The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU-based treatment was more likely than gemcitabine-based therapies to extend survival.

Keratin 17 modulates the immune topography of pancreatic cancer.

Background: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. Methods: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. Results: K17 expression had profound effects on the exclusion of intratumoral CD8 + T cells and was also associated with decreased numbers of peritumoral CD8 + T cells, CD16 + macrophages, and CD163 + macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8 + T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. Conclusions: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.

Integrating X-ray phase-contrast imaging and histology for comparative evaluation of breast tissue malignancies in virtual histology analysis.

Detecting breast tissue alterations is essential for cancer diagnosis. However, inherent bidimensionality limits histological procedures' effectiveness in identifying these changes. Our study applies a 3D virtual histology method based on X-ray phase-contrast microtomography (PhC µ CT), performed at a synchrotron facility, to investigate breast tissue samples including different types of lesions, namely intraductal papilloma, micropapillary intracystic carcinoma, and invasive lobular carcinoma. One-to-one comparisons of X-ray and histological images explore the clinical potential of 3D X-ray virtual histology. Results show that PhC µ CT technique provides high spatial resolution and soft tissue sensitivity, while being non-destructive, not requiring a dedicated sample processing and being compatible with conventional histology. PhC µ CT can enhance the visualization of morphological characteristics such as stromal tissue, fibrovascular core, terminal duct lobular unit, stromal/epithelium interface, basement membrane, and adipocytes. Despite not reaching the (sub) cellular level, the three-dimensionality of PhC µ CT images allows to depict in-depth alterations of the breast tissues, potentially revealing pathologically relevant details missed by a single histological section. Compared to serial sectioning, PhC µ CT allows the virtual investigation of the sample volume along any orientation, possibly guiding the pathologist in the choice of the most suitable cutting plane. Overall, PhC µ CT virtual histology holds great promise as a tool adding to conventional histology for improving efficiency, accessibility, and diagnostic accuracy of pathological evaluation.

A quasi-experimental study in sibling dyads: differential provocation-aggression patterns in the interactive taylor aggression paradigm.

Introduction: The Taylor Aggression Paradigm (TAP) is a well-established tool for assessing provocation-induced reactive aggression. We introduce an interactive version, the iTAP, with real-time opponents across 60 trials, including five simulated provocation trials in the middle. In this quasi-experimental study, we evaluate the effectiveness of the paradigm to investigate reactive aggression in interacting participants. The design allows us to employ the TAP in settings of high familiarity dyads, addressing an existing gap. Method: Twenty-eight healthy same-sex adult sibling pairs (N = 56) competed against each other in the iTAP, exemplifying high familiarity through their social and emotional co-development, and mutual knowledge. Additionally, we explore naturally arising aggression types in terms of sibling pairs' reciprocal aggression trajectories across trials. Lastly, we investigate situational and personal variables influencing reactive aggression on the iTAP within high familiarity dyads. Results: In line with non-interactive TAP versions, siblings employed a global "tit-for-tat" strategy in response to heightened provocation: Aggression increased during manipulated trials of increasing provocation, persisted during real interaction and declined in the final block, suggesting sibling co-regulation which was underscored by the convergence in within-pair aggression level. We found no gender differences in these dynamics but a trend for higher initial aggression levels within brother pairs and higher responsiveness to increased provocation in sister pairs. Overall aggression levels were related to situational variables including trial outcome (lost, won, and tie), Further, siblings' state anger correlated positively with aggression scores on the iTAP. Aggression was not reliably related to personal variables predicting aggression. We identified subgroups of sibling pairs with distinct provocation-aggression patterns related to differences in reported behavioral motivations and emotional states. The results highlight situational over personal variables in determining aggressive behavior on the task in this sample of healthy adults. While no direct link between sibling relationship quality and aggression was found, the overall behavior was likely influenced by the familiarity between siblings and the specific context of their relationship. Conclusion: The iTAP demonstrates promise as a tool for studying reciprocal aggressive behavior. The emergence of different interaction patterns underscores the ecological validity introduced by the interactive context, which complements the standard versions of the TAP.

Can people empathize with offenders and victims during violent scenes? Behavioral and brain correlates of affective and cognitive empathy considering victim vs. offender perspective using the Bochumer affective and cognitive empathy task (BACET).

Empathy is defined as the capacity to resonate with others' emotions and can be subdivided into affective and cognitive components. Few studies have focused on the role of perspective-taking within this ability. Utilizing the novel Bochumer Affective and Cognitive Empathy Task (BACET), the present study aims to determine the characteristics of specific empathy components, as well as the impact of offender vs. victim perspective-taking. A total of 21 male participants (mean age = 30.6) underwent functional magnetic resonance imaging (fMRI) while watching 60 videos showing two protagonists in neutral (n = 30) or violent interactions (n = 30) thereby adopting the perspective of the (later) offender or victim. Our data show that videos showing emotional (violent) content, compared to those with neutral content, were rated more emotionally negative and induced higher affective empathic involvement, particularly when adopting the victim's perspective compared to the offender's point of view. The correct assignment of people's appropriate emotion (cognitive empathy) was found to be more accurate and faster in the emotional condition relative to the neutral one. However, no significant differences in cognitive empathy performance were observed when comparing victim vs offender conditions. On a neural level, affective empathy processing, during emotional compared to neutral videos, was related to brain areas generally involved in social information processing, particularly in occipital, parietal, insular, and frontal regions. Cognitive aspects of empathy, relative to factual reasoning questions, were located in inferior occipital areas, fusiform gyrus, temporal pole, and frontal cortex. Neural differences were found depending on the perspective, i.e., empathizing with the victim, compared to the offender, during affective empathy activated parts of the right temporal lobe, whereas empathy towards the role of the offender revealed stronger activation in the right lingual gyrus. During cognitive empathy, empathy toward the victim, relative to the offender, enhanced activity of the right supramarginal and left precentral gyri. The opposite contrast did not show any significant differences. We conclude that the BACET can be a useful tool for further studying behavioral and neurobiological underpinnings of affective and cognitive empathy, especially in forensic populations since response patterns point to a significant impact of the observer's perspective.

Elafibranor upregulates the EMT-inducer S100A4 via PPARß/δ.

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and ß/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARß/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.

Promoting Empathy and Affiliation in Relationships (PEAR) study: protocol for a longitudinal study investigating the development of early childhood callous-unemotional traits.

INTRODUCTION: Children with callous-unemotional (CU) traits are at high lifetime risk of antisocial behaviour. Low affiliation (ie, social bonding difficulties) and fearlessness (ie, low threat sensitivity) are proposed risk factors for CU traits. Parenting practices (eg, harshness and low warmth) also predict risk for CU traits. However, few studies in early childhood have identified attentional or physiological markers of low affiliation and fearlessness. Moreover, no studies have tested whether parenting practices are underpinned by low affiliation or fearlessness shared by parents, which could further shape parent-child interactions and exacerbate risk for CU traits. Addressing these questions will inform knowledge of how CU traits develop and isolate novel parent and child targets for future specialised treatments for CU traits. METHODS AND ANALYSIS: The Promoting Empathy and Affiliation in Relationships (PEAR) study aims to establish risk factors for CU traits in children aged 3-6 years. The PEAR study will recruit 500 parent-child dyads from two metropolitan areas of the USA. Parents and children will complete questionnaires, computer tasks and observational assessments, alongside collection of eye-tracking and physiological data, when children are aged 3-4 (time 1) and 5-6 (time 2) years. The moderating roles of child sex, race and ethnicity, family and neighbourhood disadvantage, and parental psychopathology will also be assessed. Study aims will be addressed using structural equation modelling, which will allow for flexible characterisation of low affiliation, fearlessness and parenting practices as risk factors for CU traits across multiple domains. ETHICS AND DISSEMINATION: Ethical approval was granted by Boston University (#6158E) and the University of Pennsylvania (#850638). Results will be disseminated through conferences and open-access publications. All study and task materials will be made freely available on lab websites and through the Open Science Framework (OSF).

Utilización de evidencia científica en planificación del cuidado por el profesional de enfermería: Revisión Sistemática / Use of scientific evidence in care planning among nursing professionals: A Systematic Review

Objetivo: Determinar la utilización de evidencia científica disponible por el profesional de enfermería para planificar los cuidados otorgados. Metodología: Búsqueda en bases de datos: Proquest, Pubmed, Science Direct, Medline. Se seleccionó nueve artículos para análisis, publicados entre los años 2011 y 2021 en idiomas inglés y español, ajustados a requerimientos PRISMA. Resultados: Se obtuvieron 356 investigaciones, de las cuales 9 cumplieron con criterios de selección. Los artículos incluidos no miden el nivel de utilización de la Enfermería Basada en Evidencia (EBE) para la planificación de los cuidados, sin embargo, se describen factores facilitadores y barreras para su implementación. Conclusión: La evidencia disponible no es suficiente para determinar la utilización de la evidencia en los cuidados otorgados por parte del profesional de enfermería. Se describen barreras de tipo personales y organizacionales para su utilización. Para lograr una adecuada implementación de la EBE es necesario contar con estrategias efectivas en los entornos clínicos y esfuerzos multidisciplinarios para su utilización. Es necesario la realización de estudios de mayor calidad, para generar datos confiables que evidencien cómo impacta el conocimiento, el nivel de formación en investigación y el apoyo institucional en la utilización de la EBE en la práctica clínica. (AU)

Objective: To determine the use of the available scientific evidence among nursing professionals to plan the provision of care. Methods: A search was conducted in the following databases: ProQuest, PubMed, Science Direct, MEDLINE. Nine articles, published between 2011 and 2021 in English and Spanish, were selected for the analysis according to the PRISMA statement. Results: The search yielded a result of 356 articles, 9 of which met selection criteria. The included articles do not measure the level of utilization of Evidence-Based Nursing (EBN) for care planning, however, facilitating factors and barriers to its implementation are described. Conclusion: The available evidence is not sufficient to determine the utilization of evidence by nursing professionals in the provision of care. Barriers to its utilization, of both personal and organizational nature are described. In order to ensure an adequate implementation of EBN, it is necessary to adopt effective strategies in clinical settings and multidisciplinary efforts need to be made to promote its utilization. It is necessary to conduct higher-quality studies to produce reliable data that demonstrate the role that knowledge, the level of research training and institutional support have on the utilization of EBN in the clinical practice. (AU)

The role of dominance in sibling relationships: differences in interactive cooperative and competitive behavior.

Siblings strongly influence each other in their social development and are a major source of support and conflict. Yet, studies are mostly observational, and little is known about how adult sibling relationships influence social behavior. Previous tasks exploring dynamically adjusting social interactions have limitations in the level of interactivity and naturalism of the interaction. To address these limitations, we created a cooperative tetris puzzle-solving task and an interactive version of the chicken game task. We validated these two tasks to study cooperative and competitive behavior in real-time interactions (N = 56). Based on a dominance questionnaire (DoPL), sibling pairs were clustered into pairs that were both low in dominance (n = 7), both high in dominance (n = 8), or one low and one high in dominance (n = 13). Consistent with our hypothesis, there were significantly more mutual defections, less use of turn-taking strategies, and a non-significant trend for reduced success in solving tetris puzzles together among high dominance pairs compared to both other pair types. High dominant pairs also had higher Machiavellian and hypercompetitiveness traits and more apathetic sibling relationships. Both tasks constitute powerful and reliable tools to study personality and relationship influences on real and natural social interactions by demonstrating the different cooperative and competitive dynamics between siblings.

Representaciones sociales sobre la autonomía en la relación clínica de niños y niñas de 6 a 12 años de los y las profesionales de la salud en Uruguay / Social representations on the autonomy in the clinical relationship of children from 6 to 12 years and health professionals of the first level of care / Representações sociais sobre a autonomia na relação clínica de crianças de 6 a 12 anos dos profissionais de saúde do primeiro nível de atenção

El presente trabajo tiene como objetivo presentar la producción científica identificada en relación a las representaciones sociales de los profesionales de la salud acerca de la autonomía de niños y niñas para la toma de decisiones en la relación clínica. Se realiza desde una revisión integrativa, y la búsqueda se realiza en las bases Scientific Electronic Library Online (SciELO), Literatura Latinoamericana y del Caribe en Ciencias de la Salud (LILACS) y PubMed en el período de mayo a julio de 2022. A partir de la búsqueda realizada en las 3 bases de datos seleccionadas muestran un total de 10181 artículos consultados en una primera etapa, con una pre-selección de 79 artículos, atendiendo a la correlación de las temáticas abordadas por los títulos y los resúmenes de los artículos, de acuerdo a los objetivos generales y específicos de la revisión integrativa. A partir de una lectura completa de los artículos se seleccionan 35, y luego de eliminar los artículos que se reiteran en diferentes bases de datos, se seleccionan finalmente 24. La búsqueda realizada no identifica producción científica específica acerca de las representaciones de los y las profesionales de la salud respecto a la autonomía de niños y niñas para la toma de decisiones en salud. Se reafirma la importancia de producir conocimiento en esta área como forma de visibilizar aristas de los discursos y las prácticas en salud que no se explicitan, no obstante, podrían incidir en los modos de habilitar el ejercicio de la autonomía en la atención a la salud de niños y niñas.

This paper aims to present the scientific production identified in relation to the social representations of health teams about the autonomy of children for decision making in the clinical relationship. The integrative review was based on the publication from Scientific Electronic Library Online (SciELO), Latin American and Caribbean Literature in Ciências da Saúde (LILACS) and PubMed bases, during May and July,202. The final results, from the search carried out in the 3 selected databases show: i) a total of 10181 articles consulted in a first stage, ii) a pre-selection of 79, based on the correlation of the topics addressed by the titles and summaries of the articles with the general and specific objectives of the integrative review, iii) from a complete reading of the articles are selected 35, iv) after eliminating the articles that are repeated in different databases, finally selected 24. The search does not identify specific scientific production about the representations of health workers regarding the autonomy of children for health decision making. The importance of producing knowledge in this area is reaffirmed as a way to make visible the edges of the discourses and health practices that are not explained; however, they could influence the ways of enabling the exercise of autonomy in the health care of children.

Este artigo tem como objetivo apresentar a produção científica identificada em relação às representações sociais dos profissionais de saúde sobre a autonomia da criança para toma da de decisão na relação clínica. É realizado a partir de uma revisão integrativa, e a pesquisa é realizada nas bases da Scientific Electronic Library Online (SciELO), da América Latina e do Caribe em Ciências da Saúde (LILACS) e PubMed y PubMed no período de maio a julho de 2022.Os resultados finais, a partir da busca realizada nas 3bases de dados selecionadas, mostram: i) um total de 10181 artigos consultados em uma primeira etapa; ii) uma pré-seleção de 79, com base na correlação dos tópicos abordados por os títulos e resumos dos artigos com os objetivos gerais e específicos da revisão integrativa; iii) a partir de uma leitura completa dos artigos, são selecionados 35; iv)após a eliminação dos artigos repetidos em diferentes bases de dados; finalmente selecionado 24. A busca não identificou ou produção científica específica sobre as representações dos trabalhadores da saúde em relação à autonomia das crianças para a toma da de decisões em saúde. A importância de produzir conhecimento nessa área é reafirmada como forma de tornar visíveis as arestas dos discursos e práticas de saúde que não são explicadas, no entanto, podem influenciar as formas de viabilizar o exercício da autonomia no cuidado à saúde da criança.

Characterization of breast tissues in density and effective atomic number basis via spectral X-ray computed tomography.

Objective.Differentiation of breast tissues is challenging in X-ray imaging because tissues might share similar or even the same linear attenuation coefficientsµ. Spectral computed tomography (CT) allows for more quantitative characterization in terms of tissue density (ρ) and effective atomic number (Zeff) by exploiting the energy dependence ofµ. The objective of this study was to examine the potential ofρ/Zeffdecomposition in spectral breast CT so as to explore the benefits of tissue characterization and improve the diagnostic accuracy of this emerging 3D imaging technique.Approach.In this work, 5 mastectomy samples and a phantom with inserts mimicking breast soft tissues were evaluated in a retrospective study. The samples were imaged at three monochromatic energy levels in the range of 24-38 keV at 5 mGy per scan using a propagation-based phase-contrast setup at SYRMEP beamline at the Italian national synchrotron Elettra.Main results.A custom-made algorithm incorporating CT reconstructions of an arbitrary number of spectral energy channels was developed to extract the density and effective atomic number of adipose, fibro-glandular, pure glandular, tumor, and skin from regions selected by a radiologist.Significance.Preliminary results suggest that, via spectral CT, it is possible to enhance tissue differentiation. It was found that adipose, fibro-glandular and tumorous tissues have average effective atomic numbers (5.94 ± 0.09, 7.03 ± 0.012, and 7.40 ± 0.10) and densities (0.90 ± 0.02, 0.96 ± 0.02, and 1.07 ± 0.03 g cm-3) and can be better distinguished if both quantitative values are observed together.

Specific sequence mutations in a long-lasting rhIFN-α2b version reduce in vitro and in vivo immunogenicity and increase in vitro protein stability.

For decades, recombinant human interferon alpha (rhIFN-α2b) has been used to treat emerging and chronic viral diseases. However, rhIFN-α2b is immunogenic and has a short in vivo half-life. To solve these limitations, two long-lasting hyperglycosylated proteins with reduced immunogenicity were developed and designated as 4N-IFN(VAR1) and 4N-IFN(VAR3). Here, we continue to study the relevant characteristics of these therapeutic candidates. Thus, we demonstrated that both de-immunized IFN versions elicited significantly lower neutralizing antibody responses than the original molecule in HLA-DR1 transgenic mice, confirming our previous in vitro protein immunogenicity data. Also, we found that these biobetters exhibited remarkable stability when exposed to different physical factors that the protein product may encounter during its production process and storage, such as low pH, thermal stress, and repeated freezing/thawing cycles. Taking into consideration our previous and present results, 4N-IFN(VAR1) and 4N-IFN-4N(VAR3) appear to be valuable candidates for the treatment of human viral diseases.

A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.

BACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15. METHODS: Cultured hepatocytes and myotubes, and wild-type and Gdf15-/- mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin. RESULTS: A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15-/- mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS. CONCLUSION: Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.

Investigación científica en el campo de la infancia: consideraciones sobre la aplicabilidad de los requisitos éticos / Scientific research study on childhood: considerations on the applicability of ethical requirements / Pesquisa científica no campo da infância: considerações sobre a aplicabilidade dos requisitos éticos

El artículo aborda un tema particularmente sensible para la investigación científica como lo son los estudios que involucran directamente a niños y niñas. El valor social y la relevancia científica de la investigación en este campo es indudable, sin embargo, su justificación requiere especial detenimiento en las condiciones para el ejercicio de sus derechos antes, durante y después del proceso de investigación. La naturalización de su denominación como "población vulnerable" y el ejercicio de su autonomía relativa, son dos dimensiones principales aquí. El artículo navega por preguntas que no se resuelven aquí precisamente, ¿qué garantías para el proceso efectivo de asentimiento informado?, ¿cómo acompañar en la toma de decisiones sin sustituir al niño y la niña? Sin embargo, sí avanza en la instalación de dilemas y aspectos conceptuales y reflexivos sustantivos en la práctica científica.

The article deals with a particularly sensitive topic for scientific research, such as research studies that directly involve boys and girls. The social value and scientific relevance of research in this field is unquestionable; however, its justification requires special care regarding the conditions of children's rights before, during and after the research process. The naturalization of their denomination as a "vulnerable population" and the exercise of their relative autonomy are the two main dimensions of this study. This paper explores questions that are not answered in it precisely: what guarantees informed consent during the effective process? How to accompany the decision making process without replacing the boy and the girl? However, the study makes progress regarding the setting of substantive conceptual and reflective dilemmas and aspects in scientific practice.

O artigo trata de um tema particularmente sensível para a pesquisa científica, os estudos que envolvem diretamente meninos e meninas. O valor social e a relevância científica da pesquisa neste campo é inquestionável, porém, sua justificativa requer cuidados especiais nas condições de exercício dos direitos da criancas, durante e após o processo de pesquisa. A naturalização de sua denominação como "população vulnerável" e o exercício de sua autonomia relativa são as duas dimensões principais deste paper. O artigo explora por questões que não são aqui resolvidas de forma precisa: quais sao as garantias para o processo efetivo de assentimento informado? Como acompanhar o proceso da tomada de decisões sem substituir o menino e a menina? No entanto, realizamos um avanço na instalação de dilemas e aspectos conceituais e reflexivos substantivos na prática científica.

GDF15 mediates the metabolic effects of PPARß/δ by activating AMPK.

Peroxisome proliferator-activated receptor ß/δ (PPARß/δ) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examine whether PPARß/δ activation effects depend on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARß/δ activation increases GDF15 levels and ameliorates glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, and inflammation, and activates AMPK in HFD-fed mice, whereas these effects are abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway is involved in the PPARß/δ-mediated increase in GDF15, which in turn activates again AMPK. Consistently, Gdf15-/- mice show reduced AMPK activation in skeletal muscle, whereas GDF15 administration results in AMPK activation in this organ. Collectively, these data reveal a mechanism by which PPARß/δ activation increases GDF15 levels via AMPK and p53, which in turn mediates the metabolic effects of PPARß/δ by sustaining AMPK activation.