α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson's disease.

A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson's and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson's disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases.

Associations between sex, age and spiritual well-being scores on the EORTC QLQ-SWB32 for patients receiving palliative care for cancer: A further analysis of data from an international validation study.

OBJECTIVE: The EORTC QOL Group has recently completed the cross-cultural development and validation of a standalone measure of spiritual well-being (SWB) for cancer patients receiving palliative care: the EORTC QLQ-SWB32. The measure includes four scales: Relationships with Others, Relationship with Self, Relationship with Someone or Something Greater, and Existential, plus a Global-SWB item. This paper reports on further research investigating relationships between sex, age and SWB for patients receiving palliative care for cancer-adjusting for other socio-demographic, clinical and function variables, including WHO performance status and EORTC QLQ-C15-PAL emotional and physical function scores. METHODS: Cross-sectional data from the validation study were used, and chi-square, independent t tests, Mann-Whitney U tests and multiple regression analyses applied. RESULTS: The study included 451 participants with advanced and incurable cancer, from 14 countries. Adjusted analyses found better scores for female participants than males on three of the four EORTC QLQ-SWB32 subscales; Relationship with others, Relationship with Someone or Something Greater and Existential plus Global-SWB. Older age was positively associated with better Relationship with Self. CONCLUSION: The findings from our participants suggest that it might be beneficial if healthcare providers seeking to address patients' spiritual needs pay particular attention to male patients, younger patients and those with poor emotional functioning.

Caged luciferins enable rapid multicomponent bioluminescence imaging.

Bioluminescence is a sensitive technique for imaging biological features over time. Historically, though, the modality has been challenging to employ for multiplexed tracking due to a lack of resolvable luciferase-luciferin pairs. Recent years have seen the development of numerous orthogonal probes for multi-parameter imaging. While successful, generating such tools often requires complex syntheses and lengthy enzyme evolution campaigns. This work showcases an alternative strategy for multiplexed bioluminescence that takes advantage of already-orthogonal caged luciferins and established uncaging enzymes. These probes generate unique bioluminescent signals that can be distinguished via a linear unmixing algorithm. Caged luciferins enabled two- and three-component imaging on the minutes time scale. We further showed that the tools can be used in conjunction with endogenous enzymes for multiplexed studies. Collectively, this approach lowers the barrier to multicomponent bioluminescence imaging and can be readily adopted by the broader community.

Monitoring macrophage polarization with gene expression reporters and bioluminescence phasor analysis.

Macrophages exhibit a spectrum of behaviors upon activation and are generally classified as one of two types: inflammatory (M1) or anti-inflammatory (M2). Tracking these phenotypes in living cells can provide insight into immune function, but remains a challenging pursuit. Existing methods are mostly limited to static readouts or difficult to employ for multiplexed imaging in complex 3D environments while maintaining cellular resolution. We aimed to fill this void using bioluminescent technologies. Here we report genetically engineered luciferase reporters for long-term monitoring of macrophage polarization via spectral phasor analysis. M1- and M2- specific promoters were used to drive the expression of bioluminescent enzymes in macrophage cell lines. The readouts were multiplexed and discernable in both 2D and 3D formats with single cell resolution in living samples. Collectively, this work expands the toolbox of methods for monitoring macrophage polarization and provides a blueprint for monitoring other multifaceted networks in heterogeneous environments.

What do we know about the impact of economic recessions on mortality inequalities? A critical review.

Historically, there has been a debate on the effects of recessions on population health, and especially on mortality and its distribution across different social groups. This paper contributes to this discussion by means of a critical review of the research on the impact of economic recessions on mortality inequalities in the period 1980-2020. We analyzed 19 studies according to their mortality outcomes, socioeconomic indicators, design, analysis, and main findings. Twelve studies focused on European countries or urban areas, two on Asian countries, two on Russia, one on Asia and Europe, one on the USA, and one in Somalia. Five articles included cross-country comparisons (four between European countries or cities and one between Asian and European countries). The Great Recession of 2008 was the most researched economic crisis, followed by country-specific crises in the 90s, the fall of the Soviet Union, and some crises during the 80s. Most studies (n = 15) showed an overall or partial increase in mortality inequalities after an economic recession. However, two papers found a decrease in mortality inequalities due to the worsening of the health of the upper and middle classes, one article found a decrease in inequalities due to a general improvement in population health, and a study found a "slow-down" effect of pre-existent mortality inequalities.

Cancer pain management in Mexico.

BACKGROUND: Pain control is an essential component of high-quality palliative care. Unfortunately, many low-income and middle-income countries lack an appropriate infrastructure to provide palliative care and suffer from a severe lack of access to opioid analgesics to alleviate pain from various conditions such as cancer. OBJECTIVES: We aimed to review the history and current status of cancer pain management in Mexico, a middle-income Latin American country. Our objective was to identify existing barriers to proper, effective opioid use, as well as provide practical recommendations for improvement. METHODS: Using a search of EBSCOhost database, PubMed and Google, we found official documents and peer-reviewed articles related to health legislation, opioid consumption, palliative care infrastructure and palliative care training in Mexico. RESULTS: Despite advances in palliative care and access to opioids in Mexico, there are still several barriers that undermine effective pain management, showing a major gap between policy and practice. Although Mexican legislation and guidelines include adequate palliative care and pain control as a right for all patients with cancer, the lack of adequate infrastructure and trained personnel severely hampers the implementation of these policies. Additionally, there are important barriers to prescribing opioids, many of which are related to attempts at reducing the consumption of recreational drugs. CONCLUSIONS: Although Mexico has made significant improvements in pain control and palliative care, much needs to be done. Expansion of drug availability, improvement of palliative care training, and constant oversight of regulations and guidelines will help to strengthen Mexico's palliative care services.

Brincar e mediação na escola / Playing and mediation in school / El juego y la mediación en la escuela

Dentro da cultura da imobilização em que vivemos, perceber a importância do brincar na infância torna-se essencial, principalmente em instituições de educação infantil. Neste artigo pretendemos refletir sobre a questão da mediação do brincar na escola: como as diferentes formas de mediação do professor têm influência na qualidade do brincar das crianças. Para tal, em pesquisa qualitativa de caráter descritivo, observamos o cotidiano de uma turma em uma escola de educação infantil, enfocando especificamente o ambiente da sala de aula, chegando a três situações com formas diferentes de mediação do brincar.

In the culture of immobilization where we live, one perceives the importance of playing in childhood. Playing becomes essential, especially in early childhood education. In this article we intend to reflect the question of the mediation of playing at school. The different forms of mediation by the teacher influence the quality of playing at school. In order to achieve this, we will do a qualitative research, observing a group of young children on a daily basis, focusing the classroom environment. We found three situations with different forms of play mediations.

En una cultura que dificulta la libertad de movimiento, como en la que vivimos, percibir la relevancia del juego en la infancia es esencial, principalmente en escuelas para niños pequeños. En este artículo se pretende reflexionar sobre el asunto de cómo las diferentes formas de mediación del profesor influyen en la calidad del juego de los niños en la escuela. Para ello, una investigación cualitativa, de carácter descriptivo fue hecha en la cual observamos el día a día de una clase de niños de tres años en una escuela infantil, fijándonos especialmente en el ambiente dentro del aula y percibimos tres situaciones diferentes de mediación del juego.