Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates.

Influenza A virus (IAV) employs multiple strategies to manipulate cellular mechanisms and support proper virion formation and propagation. In this study, we performed a detailed analysis of the interplay between IAV and the host cells' proteostasis throughout the entire infectious cycle. We reveal that IAV infection activates the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response, and that this activation is important for an efficient infection. We further observed the accumulation of virus-induced insoluble protein aggregates, containing both viral and host proteins, associated with a dysregulation of the host cell RNA metabolism. Our data indicate that this accumulation is important for IAV propagation and favors the final steps of the infection cycle, more specifically the virion assembly. These findings reveal additional mechanisms by which IAV disrupts host proteostasis and uncovers new cellular targets that can be explored for the development of host-directed antiviral strategies.

Emerging roles of the Protein Phosphatase 1 (PP1) in the context of viral infections.

Protein Phosphatase 1 (PP1) is a major serine/threonine phosphatase in eukaryotes, participating in several cellular processes and metabolic pathways. Due to their low substrate specificity, PP1's catalytic subunits do not exist as free entities but instead bind to Regulatory Interactors of Protein Phosphatase One (RIPPO), which regulate PP1's substrate specificity and subcellular localization. Most RIPPOs bind to PP1 through combinations of short linear motifs (4-12 residues), forming highly specific PP1 holoenzymes. These PP1-binding motifs may, hence, represent attractive targets for the development of specific drugs that interfere with a subset of PP1 holoenzymes. Several viruses exploit the host cell protein (de)phosphorylation machinery to ensure efficient virus particle formation and propagation. While the role of many host cell kinases in viral life cycles has been extensively studied, the targeting of phosphatases by viral proteins has been studied in less detail. Here, we compile and review what is known concerning the role of PP1 in the context of viral infections and discuss how it may constitute a putative host-based target for the development of novel antiviral strategies.

Rheumatoid arthritis molecular targets and their importance to flavonoid-based therapy.

Rheumatoid arthritis (RA) is a progressive, chronic, autoimmune, inflammatory, and systemic condition that primarily affects the synovial joints and adjacent tissues, including bone, muscle, and tendons. The World Health Organization recognizes RA as one of the most prevalent chronic inflammatory diseases. In the last decade, there was an expansion on the available RA therapeutic options which aimed to improve patient's quality of life. Despite the extensive research and the emergence of new therapeutic approaches and drugs, there are still significant unwanted side effects associated to these drugs and still a vast number of patients that do not respond positively to the existing therapeutic strategies. Over the years, several references to the use of flavonoids in the quest for new treatments for RA have emerged. This review aimed to summarize the existing literature about the flavonoids' effects on the major pathogenic/molecular targets of RA and their potential use as lead compounds for the development of new effective molecules for RA treatment. It is demonstrated that flavonoids can modulate various players in synovial inflammation, regulate immune cell function, decrease synoviocytes proliferation and balance the apoptotic process, decrease angiogenesis, and stop/prevent bone and cartilage degradation, which are all dominant features of RA. Although further investigation is necessary to determine the effectiveness of flavonoids in humans, the available data from in vitro and in vivo models suggest their potential as new disease-modifying anti-rheumatic drugs. This review highlights the use of flavonoids as a promising avenue for future research in the treatment of RA.

The hidden RNA code: implications of the RNA epitranscriptome in the context of viral infections.

Emerging evidence highlights the multifaceted roles of the RNA epitranscriptome during viral infections. By modulating the modification landscape of viral and host RNAs, viruses enhance their propagation and elude host surveillance mechanisms. Here, we discuss how specific RNA modifications, in either host or viral RNA molecules, impact the virus-life cycle and host antiviral responses, highlighting the potential of targeting the RNA epitranscriptome for novel antiviral therapies.

The role of flavonoids in the regulation of epithelial-mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis.

One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.

2-Styrylchromones Prevent IL-1ß-Induced Pro-Inflammatory Activation of Fibroblast-like Synoviocytes while Increasing COX-2 Expression.

Rheumatoid arthritis (RA) is characterized by systemic immune and chronic inflammatory features, leading to the destruction of the joints. Presently, there are no effective drugs able to control synovitis and catabolism in the process of RA. 2-Styrylchromones (2-SC) are a small group of compounds characterized by the attachment of a styryl group to the chromone core that have already been associated to a wide range of biological activities, including antioxidant and anti-inflammatory activities. The present study investigated the effect of a set of six 2-SC on the interleukin-1ß (IL-1ß)-induced increase of nitric oxide (•NO), inducible form of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-3 (MMP-3) expression levels in human fibroblast-like synoviocytes (HFLS), pointing to the role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in the process. From a set of six 2-SC, presenting hydroxy and methoxy substituents, the one presenting two methoxy substituents at C-5 and C-7 of A ring and a catechol group on B ring, significantly reduced •NO production and the expression of its inducible synthase (iNOS). It also significantly reduced the catabolic MMP-3 protein expression. This 2-SC inhibited the NF-κB pathway by reversing the IL-1ß - induced levels of cytoplasmatic NF-kB inhibitor alpha (IκBα), and decreasing the p65 nuclear levels, suggesting the involvement of these pathways in the observed effects. The same 2-SC significantly increased the COX-2 expression, which may indicate a negative feedback loop mechanism of action. The properties of 2-SC may be of great value in the development of new therapies with improved efficacy and selectivity towards RA, and thus deserve further exploitation and evaluation to disclose the full potential of 2-SC.

Peroxisomes and Viruses: Overview on Current Knowledge and Experimental Approaches.

The general interest in the study of the interplay between peroxisomes and viruses has increased in recent years, with different reports demonstrating that distinct viruses modulate peroxisome-related mechanisms to either counteract the cellular antiviral response or support viral propagation. Nevertheless, mechanistical details are still scarce, and information is often incomplete. In this chapter, we present an overview of the current knowledge concerning the interplay between peroxisomes and different viruses. We furthermore present, compare, and discuss the most relevant experimental approaches and tools used in the different studies. Finally, we stress the importance of further, more detailed, and spatial-temporal analyses that encompass all the different phases of the viruses' infection cycles. These studies may lead to the discovery of novel peroxisome-related cellular mechanisms that can further be explored as targets for the development of novel antiviral therapies.

Tools to Investigate the Peroxisome-Dependent Antiviral Response.

The importance of peroxisomes in the context of viral infections has been increasingly demonstrated in recent years. The discovery that MAVS localizes at peroxisomes and that peroxisomal and mitochondrial MAVS perform complementing functions within the antiviral response has raised the interest in studying the peroxisome-dependent signaling in the context of infection by different viruses. To that end, specific experimental procedures should be applied, taking into consideration the endogenous localization of MAVS at both organelles. The analysis of peroxisomal MAVS activation requires, hence, the preliminar generation and validation of cell lines where MAVS localizes solely at peroxisomes, as well as other specific cellular tools. Here, we present a detailed protocol to analyse the peroxisome-dependent antiviral response, using virus-specific and virus-unspecific stimuli.

Determining the Importance of Peroxisomal Proteins for Viral Infections in Cultured Mammalian Cells.

Peroxisomes have recently been shown to play important roles in the context of viral infections. However, further and more detailed studies should be performed to unravel the specific mechanisms involved. The analysis of the relevance of particular peroxisomal components, such as peroxisomal proteins, for viral infections can be performed by comparing the production of new virus particles in the absence and presence of those specific components. Different methodologies are used to quantify the production of infectious virus particles, depending on the virus, cell type, and the specific characteristics of the viral infection to be analyzed. Here we provide a detailed protocol to study the importance of a putative peroxisomal protein on infection by viruses that induce the death of their host cells. We use the influenza A virus (IAV) infection in A549 cells as a model, and the quantification of the newly produced infectious virus particles is performed by a plaque assay.

Bis-chalcones: A review of synthetic methodologies and anti-inflammatory effects.

Chalcones are bioactive molecules of natural and synthetic sources, whose physicochemical properties, reactivity, and biological activities are well-known among the scientific community. However, there are many molecules strictly related to chalcones with significantly less recognition like bis-chalcones. Several studies indicated that bis-chalcones have advantages over chalcones in specific bioactivities like anti-inflammatory activity. This review article describes the chemical structure and chemical properties of bis-chalcones, as well as the methods reported in the literature for the synthesis of these compounds highlighting the most recent developments. Finally, the anti-inflammatory activity of bis-chalcones is described, emphasizing the active structures found in literature and their mechanisms of action.

Functional and patient-reported outcomes of bone-anchored hearing aids (BAHA): A prospective case series study.

Objective: The purpose of this study was to evaluate the functional and patient-reported outcomes, and their correlation, after percutaneous bone-anchored hearing aid (BAHA) implantation. Methods: A prospective study was conducted between January 2018 and December 2020 in a tertiary care center. All adult patients who were implanted with a percutaneous BAHA device during this evaluation period were included in the study. Complete auditory function and patients reported outcome measures (PROMs) were assessed in the preoperative period and 6 months after the implant activation. The PROMs included a generic form (Medical Outcome Study 36 Short Form Healthy Survey (MOS SF-36)), and three disease-specific forms (Hearing Handicap Inventory (HHI), Satisfaction with Amplification in Daily Life Scale (SADLS), and Tinnitus Handicap Inventory (THI)). Results: Twenty-two patients with an average age of 53 years were included in the study. The overall functional gain with the BAHA in sound-field pure tone average (PTA) was 29 dB, with no statistically significant differences according to surgical indication (F(3,18) = 2.319, p = 0.110). The greater the preoperative air-bone gap, the greater the functional gain obtained (r = 0.505, p < 0.05). In the PROMs, we found a significant improvement in HHI scores (p < 0.005) and a significant increase in overall SADLS scores (p < 0.05) with the use of percutaneous BAHA devices. We did not verify any statistically significant correlation between functional and PROMs results. Conclusions: The BAHA is a safe and effective alternative hearing rehabilitation option in selected patients. The PROMs results prove patient's overall satisfaction.

Urban Public Spaces as Restorative Environments: The Case of Ljubljana.

In this study, we used a survey to examine how urban residents in Ljubljana, Slovenia, value and use distinct urban public spaces. Specifically, we were interested to assess if urban public spaces in the city are used/perceived as restorative environments. To do this, we addressed the question: To what extent do restorative dimensions differ in nine selected urban public spaces, varying in size, design, amenities, number of visitors, and, most importantly, degree of naturalness? Results from survey allowed to determine to what extent the selected urban public spaces in Ljubljana differ in terms of their perceived degree of restoration. We hypothesized that urban public spaces with a higher degree of naturalness in the city have a higher restoration value than urban public spaces with a lower degree of naturalness. Surprisingly, the urban public space that was above average on most restorative dimensions was the Old Town. These results are somewhat at odds with the attentional restoration theory, which states that the combination of dimensions is most typical of natural environments. However, this could be an indicator of the effectiveness of the city's current policies to improve the quality of life for its citizens.

Determination of the lactose content in low-lactose milk using Fourier-transform infrared spectroscopy (FTIR) and convolutional neural network.

Demand for low lactose milk and milk products has been increasing worldwide due to the high number of people with lactose intolerance. These low lactose dairy foods require fast, low-cost and efficient methods for sugar quantification. However, available methods do not meet all these requirements. In this work, we propose the association of FTIR (Fourier Transform Infrared) spectroscopy with artificial intelligence to identify and quantify residual lactose and other sugars in milk. Convolutional neural networks (CNN) were built from the infrared spectra without preprocessing the data using hyperparameter adjustment and saliency map. For the quantitative prediction of the sugars in milk, a regression model was proposed, while for the qualitative assessment, a classification model was used. Raw, pasteurized and ultra-high temperature (UHT) milk was added with lactose, glucose, and galactose in six concentrations (0.1-7.0 mg mL-1) and, in total, 432 samples were submitted to convolutional neural network. Accuracy, precision, sensitivity, specificity, root mean square error, mean square error, mean absolute error, and coefficient of determination (R2) were used as evaluation parameters. The algorithms indicated a predictive capacity (accuracy) above 95% for classification, and R2 of 81%, 86%, and 92% for respectively, lactose, glucose, and galactose quantification. Our results showed that the association of FTIR spectra with artificial intelligence tools, such as CNN, is an efficient, quick, and low-cost methodology for quantifying lactose and other sugars in milk.

The physiological functions of human peroxisomes.

Peroxisomes are subcellular organelles that play a central role in human physiology by catalyzing a range of unique metabolic functions. The importance of peroxisomes for human health is exemplified by the existence of a group of usually severe diseases caused by an impairment in one or more peroxisomal functions. Among others these include the Zellweger spectrum disorders, X-linked adrenoleukodystrophy, and Refsum disease. To fulfill their role in metabolism, peroxisomes require continued interaction with other subcellular organelles including lipid droplets, lysosomes, the endoplasmic reticulum, and mitochondria. In recent years it has become clear that the metabolic alliance between peroxisomes and other organelles requires the active participation of tethering proteins to bring the organelles physically closer together, thereby achieving efficient transfer of metabolites. This review intends to describe the current state of knowledge about the metabolic role of peroxisomes in humans, with particular emphasis on the metabolic partnership between peroxisomes and other organelles and the consequences of genetic defects in these processes. We also describe the biogenesis of peroxisomes and the consequences of the multiple genetic defects therein. In addition, we discuss the functional role of peroxisomes in different organs and tissues and include relevant information derived from model systems, notably peroxisomal mouse models. Finally, we pay particular attention to a hitherto underrated role of peroxisomes in viral infections.

A decolonialidade na pesquisa e prática psicodramáticas: pela superação de epistemicídios históricos / Decoloniality in psychodramatic research and practice: overcoming historical epistemicides / La decolonialidad en la investigación y la práctica psicodramática: superando los epistemicidios históricos

RESUMO O presente artigo apresenta uma reflexão sobre o ancoramento científico da pesquisa e das práticas psicodramáticas, questionando a perspectiva colonial/moderna predominante no universo da ciência ocidental, e sugerindo uma aproximação com o pensamento decolonial que se desenvolve no século XXI, em que são retomadas epistemologias historicamente desconsideradas, como aquela em que se situam os princípios filosóficos morenianos. As questões discutidas acerca da pesquisa em Psicodrama podem ser transportadas para o campo das práticas, gerando questionamentos quanto ao lugar do psicodramatista na relação com o outro, a forma de elaboração dos problemas/hipóteses terapêuticas e o que se espera das intervenções, situando-as para além dos binarismos tradicionais modernos.

ABSTRACT This article reflects on the scientific anchoring of psychodramatic research and practice, questioning the colonial/modern perspective prevailing in the universe of Western science, and suggesting an approach to the decolonial thinking developed in the 21st century, in which historically disregarded epistemologies are resumed, such as the one in which the philosophical principles of Moreno's work are located. The questions discussed about research in Psychodrama can be transported to the field of practices, generating questions related to the place of the psychodramatist in the relationship with the other, the way of elaborating the therapeutic problems/hypotheses and what is expected of the interventions, placing them beyond traditional modern binarisms.

RESUMEN Este artículo reflexiona sobre el anclaje científico de la investigación y la práctica psicodramática, cuestionando la perspectiva colonial/moderna predominante en el universo de la ciencia occidental, y proponiendo una aproximación al pensamiento decolonial que se desarrolla en el siglo XXI, en el que se retoman epistemologías históricamente desconsideradas, como aquél en el que se ubican los principios filosóficos de la obra Moreniana. Las cuestiones discutidas sobre la investigación en Psicodrama pueden ser transportadas al campo de las prácticas, generando interrogantes sobre el lugar del psicodramatista en la relación con el otro, la forma de elaborar los problemas/hipótesis terapéuticas y lo que se espera de las intervenciones, ubicándolas más allá de los binarismos modernos tradicionales.

A machine learning proposal method to detect milk tainted with cheese whey.

Cheese whey addition to milk is a type of fraud with high prevalence and severe economic effects, resulting in low yield for dairy products, nutritional reduction of milk and milk-derived products, and even some safety concerns. Nevertheless, methods to detect fraudulent addition of cheese whey to milk are expensive and time consuming, and are thus ineffective as screening methods. The Fourier-transform infrared (FTIR) spectroscopy technique is a promising alternative to identify this type of fraud because a large number of data are generated, and useful information might be extracted to be used by machine learning models. The objective of this work was to evaluate the use of FTIR with machine learning methods, such as classification tree and multilayer perceptron neural networks to detect the addition of cheese whey to milk. A total of 520 samples of raw milk were added with cheese whey in concentrations of 1, 2, 5, 10, 15, 20, 25, and 30%; and 65 samples were used as control. The samples were stored at 7, 20, and 30°C for 0, 24, 48, 72, and 168 h, and analyzed using FTIR equipment. Complementary results of 520 samples of authentic raw milk were used. Selected components (fat, protein, casein, lactose, total solids, and solids nonfat) and freezing point (°C) were predicted using FTIR and then used as input features for the machine learning algorithms. Performance metrics included accuracy as high as 96.2% for CART (classification and regression trees) and 97.8% for multilayer perceptron neural networks, with precision, sensitivity, and specificity above 95% for both methods. The use of milk composition and freezing point predicted using FTIR, associated with machine learning techniques, was highly efficient to differentiate authentic milk from samples added with cheese whey. The results indicate that this is a potential method to be used as a high-performance screening process to detected milk adulterated with cheese whey in milk quality laboratories.