Measuring prion propagation in single bacteria elucidates a mechanism of loss.

Prions are self-propagating protein aggregates formed by specific proteins that can adopt alternative folds. Prions were discovered as the cause of the fatal transmissible spongiform encephalopathies in mammals, but prions can also constitute nontoxic protein-based elements of inheritance in fungi and other species. Prion propagation has recently been shown to occur in bacteria for more than a hundred cell divisions, yet a fraction of cells in these lineages lost the prion through an unknown mechanism. Here, we investigate prion propagation in single bacterial cells as they divide using microfluidics and fluorescence microscopy. We show that the propagation occurs in two distinct modes. In a fraction of the population, cells had multiple small visible aggregates and lost the prion through random partitioning of aggregates to one of the two daughter cells at division. In the other subpopulation, cells had a stable large aggregate localized to the pole; upon division the mother cell retained this polar aggregate and a daughter cell was generated that contained small aggregates. Extending our findings to prion domains from two orthologous proteins, we observe similar propagation and loss properties. Our findings also provide support for the suggestion that bacterial prions can form more than one self-propagating state. We implement a stochastic version of the molecular model of prion propagation from yeast and mammals that recapitulates all the observed single-cell properties. This model highlights challenges for prion propagation that are unique to prokaryotes and illustrates the conservation of fundamental characteristics of prion propagation.

Next-generation sequencing to genetically diagnose a diverse range of inherited eye disorders in 15 consanguineous families from Pakistan.

Inherited retinal dystrophies (IRDs) are characterized by photoreceptor dysfunction or degeneration. Clinical and phenotypic overlap between IRDs makes the genetic diagnosis very challenging and comprehensive genomic approaches for accurate diagnosis are frequently required. While there are previous studies on IRDs in Pakistan, causative genes and variants are still unknown for a significant portion of patients. Therefore, there is a need to expand the knowledge of the genetic spectrum of IRDs in Pakistan. Here, we recruited 52 affected and 53 normal individuals from 15 consanguineous Pakistani families presenting non-syndromic and syndromic forms of IRDs. We employed single molecule Molecular Inversion Probes (smMIPs) based panel sequencing and whole genome sequencing to identify the probable disease-causing variants in these families. Using this approach, we obtained a 93% genetic solve rate and identified 16 (likely) causative variants in 14 families, of which seven novel variants were identified in ATOH7, COL18A1, MERTK, NDP, PROM1, PRPF8 and USH2A while nine recurrent variants were identified in CNGA3, CNGB1, HGSNAT, NMNAT1, SIX6 and TULP1. The novel MERTK variant and one recurrent TULP1 variant explained the intra-familial locus heterogeneity in one of the screened families while two recurrent CNGA3 variants explained compound heterozygosity in another family. The identification of variants in known disease-associated genes emphasizes the utilization of time and cost-effective screening approaches for rapid diagnosis. The timely genetic diagnosis will not only identify any associated systemic issues in case of syndromic IRDs, but will also aid in the acceleration of personalized medicine for patients affected with IRDs.

Sleep and circadian disruption in bipolar disorders: From psychopathology to digital phenotyping in clinical practice.

Sleep and biological rhythms are integral to mood regulation across the lifespan, particularly in bipolar disorder (BD), where alterations in sleep phase, structure, and duration occur in all mood states. These disruptions are linked to poorer quality of life, heightened suicide risk, impaired cognitive function, and increased relapse rates. This review highlights the pathophysiology of sleep disturbances in BD and aims to consolidate understanding and clinical applications of these phenomena. It also summarizes the evolution of sleep and biological rhythms assessment methods, including ecological momentary assessment (EMA) and digital phenotyping. It underscores the importance of recognizing circadian rhythm involvement in mood regulation, suggesting potential therapeutic targets. Future research directions include elucidating circadian clock gene mechanisms, understanding environmental impacts on circadian rhythms, and investigating the bidirectional relationship between sleep disturbances and mood regulation in BD. Standardizing assessment methods and addressing privacy concerns related to EMA technology and digital phenotyping are essential for advancing research. Collaborative efforts are crucial for enhancing clinical applicability and understanding the broader implications of biological rhythms in BD diagnosis and treatment. Overall, recognizing the significance of sleep and biological rhythms in BD offers promise for improved outcomes through targeted interventions and a deeper understanding of the disorder's underlying mechanisms.

[Barriers and facilitators in accessing and using primary health care centers for people experiencing homelessness]. / Barreras y facilitadores en el acceso y la utilización de los centros de atención primaria para las personas en situación de sinhogarismo.

OBJECTIVE: To identify barriers and facilitators for the access and use of primary care centers for people experiencing homelessness. DESIGN: Qualitative study, phenomenological theoretical-methodological approach. Between May 19 and July 27, 2023. LOCATION: Besòs Primary Health Care Center and Gregal social dining (Besòs and Maresme neighborhood, Barcelona). PARTICIPANTS: People experiencing homelessness attending the Gregal social dining and professionals from the Besòs Primary Health Care Center. METHOD: Theoretical purposive sampling. Individual and group interviews and open non-participant observation. Thematic content analysis, triangulation by independent analysis of three members of the research team and triangulation of methods. Discourse saturation was achieved through variability of discourse and techniques. RESULTS: Eleven individual interviews, three group interviews and two observations. Different barriers and facilitators were identified. These were classified into five categories: (1)concept and identification of people experiencing homelessness; (2)personal factors of people experiencing homelessness; (3)behaviors and attitudes of professionals; (4)structural factors related to health system regulation, anf (5)internal organizational factors of primary health care centers. CONCLUSIONS: People experiencing homelessness face multiple barriers to access primary health care, although there are also facilitators such as trusting relationships and multidisciplinary and intersectoral work that can be enhanced from primary health care centers to contribute to health equity.

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study.

BACKGROUND: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. METHODS: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. RESULTS: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. CONCLUSIONS: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.

A Hollow Tridimensional Silicone Template for Microtia Reconstruction and Postoperative Scar Compression.

Microtia poses a great challenge in auricular reconstruction, due to a great number of anatomical details on the anterior aspect, and its tridimensional shape. Numerous techniques have been described in an attempt to optimize results. We have designed a hollow tridimensional silicon template to serve as an intrasurgical guide for ear's anatomy, size and projection, according to the normal side, which allows better results of auricular reconstruction. It also can be used as a customized post-operative compression method. We believe it could be a valuable tool for microtia reconstruction surgery. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Effect of linear and branched fructans on growth and probiotic characteristics of seven Lactobacillus spp. isolated from an autochthonous beverage from Chiapas, Mexico.

The effect that the fructans of Cichorium intybus and Agave salmiana have on health, as well as on the growth of some Lactobacillus species, has been demonstrated. The aim of this work was to evaluate the effect of linear and branched fructans on the growth of seven strains and some probiotic characteristics. The molecular identification of seven strains was performed. Moreover, the growth, resistance to antibiotics and simulated gastrointestinal conditions were also evaluated when these microorganisms were grown in a culture medium containing agave and chicory fructans. The strains were identified as Lactiplantibacillus plantarum, Lactiplantibacillus pentosus, Lactiplantibacillus fabifermentans and Lactiplantibacillus paraplantarum. The results suggest that the seven Lactobacillus strains were able to grow using agave (branched) and chicory (linear) fructans. The linear and branched fructans statistically influenced the kinetic parameters. The specific growth rate varied between 0.270 and 0.573 h-1 and the generation time between 1.21 and 2.45 h for all strains and culture media. All strains showed a growth of 9 Log CFU/mL in all the culture media. Production of lactic, acetic, propionic, butyric, formic and succinic acid was influenced by linear and branched fructans (p < 0.05). All the strains survived simulated gastrointestinal conditions greater than 83%. The resistance of Lactobacillus against ciprofloxacin and rifaximin was significantly affected by linear and branched fructans, but survival to gastrointestinal conditions was not affected by the type of substrate. These results highlight the use of the seven strains, which have probiotic potential; therefore, these could be applied in several biotechnological products.

Applying reflective multicriteria decision analysis to understand the value of therapeutic alternatives in the management of gestational and peripartum anaemia in Spain.

BACKGROUND: The objective of the FeminFER project was to assess the value of ferric carboxymaltose following a multicriteria decision analysis in obstetrics and gynaecology in Spain. METHODS: Ferric carboxymaltose (FCM) and ferrous sulphate were evaluated using the EVIDEM framework. Ten stakeholders participated to collect different perspectives. The framework was adapted considering evidence retrieved with a PICO-S search strategy and grey literature. Criteria/subcriteria were weighted by level of relevance and an evidence-based decision-making exercise was developed in each criterion; weights and scores were combined to obtain the value of intervention relative to each criterion/subcriterion, that were further combined into the Modulated Relative Benefit-Risk Balance (MRBRB). RESULTS: The most important criterion favouring FCM was Compared Efficacy/Effectiveness (0.183 ± 0.07), followed by Patient Preferences (0.059 ± 0.10). Only Direct medical costs criterion favoured FS (-0.003 ± 0.03). MRBRB favoured FCM; 0.45 ± 0.19; in a scale from -1 to + 1. CONCLUSIONS: In conclusion, considering the several criteria involved in the decision-making process, participants agreed with the use of FCM according to its MRBRB.

Volatile Compounds in Tofu Obtained by Soy Milk Fermentation with Lactobacillus plantarum BAL-03-ITTG and Lactobacillus fermentum BAL-21-ITTG.

Tofu is one of the main foods made with soybeans. The aim of this work was to evaluate the effect of L. plantarum and L. fermentum on the volatile compounds and sensorial profile of fermented tofu during ripening. The soy milk was fermented separately with two native strains (L. plantarum or L. fermentum) until reaching a pH of 5.5, and the fermented tofu was obtained. The tofu obtained by acidification with lactic acid was used as a control and was characterized by microbial survival (L. plantarum, L. fermentum, and P. freudenreichii) for 0, 20, and 40 days of storage at 15 °C. Moreover, the lactic and acetic acid content was determined by high-performance liquid chromatography (HPLC), and the volatile compounds were evaluated by gas. Chromatography-mass spectrometry (GC-MS). The results were analyzed by an ANOVA test (P < 0.05). After storage, the lactic acid bacteria (LAB) survived in the fermented tofu at a concentration higher than 8.0 log CFU/g after 40 days of storage. The shelf life of fermented tofu obtained by acidification was fewer than 20 days because of the presence of fungi and yeasts. The hexanal content was reduced by approximately 96% (P < 0.05) in the tofu obtained by fermentation compared with the control. This process for fermented tofu production employing two native strains could be used for industrial purposes.

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology.

Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.

Changes in the physiological and biochemical state of peanut plants (Arachis hypogaea L.) induced by exposure to green metallic nanoparticles.

Different types of nanoparticles (NPs) are increasingly used in multiple sectors such as industry, medicine and agriculture. This application has increased the possibility of NPs accumulating and contaminating the environment. Plants are one of the essential building blocks of all ecosystems and the interaction between NPs and plants is an indispensable aspect of risk assessment. To understand the effects of NPs in agricultural systems, in the present study we investigated the effects of exposure of Ag, Cu and Cu/Ag phytonanoparticles in Arachis hypogaea L. plants at a physiological and biochemical level, for which NPs solutions were applied foliarly at concentrations of 250, 500, 750 and 1000 ppm for 48 days. Parameters such as leaf length, chlorophyll and concentration of phytohormones showed that phytonanoparticles could cause serious damage to plant growth and development. Plants exposed to phytonanoparticles showed an increase in total phenols, proline, PAL activity and antioxidant enzymes, this to mitigate the stress caused. The alteration in the composition and content of fatty acids in the peanut kernels after exposure to different NPs indicated that they could affect the yield and quality of crop. Therefore, it is necessary to investigate its potential impact on food quality. Statement of noveltyIn this manuscript, we report for the first time that green nanoparticles induced a lower degree of toxicity in plants compared to commercial nanoparticles.Our results indicate that the mechanisms by which peanut plants respond to the application of nanoparticles were an increase in the activity of phenylalanine ammonia-lyase and antioxidant enzymes. So far there are few studies on the effect of nanoparticles on plant hormones, our results revealed a significant decrease in indole-3 acetic acid and induced the synthesis of gibberellins. The modification in the composition and content of fatty acids in the peanut kernels indicated that the nanoparticles could affect the quality of the crop.

Zinc Oxide Phytonanoparticles' Effects on Yield and Mineral Contents in Fruits of Tomato (Solanum lycopersicum L. cv. Cherry) under Field Conditions.

The use of phytonanoparticles in agriculture could decrease the use of fertilizers and therefore decrease soil contamination, due to their size being better assimilated in plants. It is important to mention that the nanofertilizer is slow-releasing and improves plant physiological properties and various nutritional parameters. The influence of soil and foliar applications of phytonanoparticles of ZnO with the Moringa oleifera extract under three concentrations (25, 50, and 100 ppm) was evaluated on the cherry tomato crop (Solanum lycopersicum L.). Synthesis of the phytonanoparticles was analyzed with ultraviolet-visible spectroscopy (UV-Vis) and infrared transmission spectroscopy with Fourier transform (FT-IR), as well as the analysis with the dynamic light scattering (DLS) technique. The morphometric parameters were evaluated before and after the application of the nanoparticles. The minerals' content of fruits was done 95 days after planting. Results showed that soil application was better at a concentration of 25 ppm of phytonanoparticles since it allowed the greatest number of flowers and fruits on the plant; however, it was demonstrated that when performing a foliar application, the fruit showed the highest concentrations for the elements Mg, Ca, and Na at concentrations of 511, 4589, and 223 mg kg-1, respectively.

Measuring circadian function in bipolar disorders: Empirical and conceptual review of physiological, actigraphic, and self-report approaches.

BACKGROUND: Interest in biological clock pathways in bipolar disorders (BD) continues to grow, but there has yet to be an audit of circadian measurement tools for use in BD research and practice. PROCEDURE: The International Society for Bipolar Disorders Chronobiology Task Force conducted a critical integrative review of circadian methods that have real-world applicability. Consensus discussion led to the selection of three domains to review-melatonin assessment, actigraphy, and self-report. RESULTS: Measurement approaches used to quantify circadian function in BD are described in sufficient detail for researchers and clinicians to make pragmatic decisions about their use. A novel integration of the measurement literature is offered in the form of a provisional taxonomy distinguishing between circadian measures (the instruments and methods used to quantify circadian function, such as dim light melatonin onset) and circadian constructs (the biobehavioral processes to be measured, such as circadian phase). CONCLUSIONS: Circadian variables are an important target of measurement in clinical practice and biomarker research. To improve reproducibility and clinical application of circadian constructs, an informed systematic approach to measurement is required. We trust that this review will decrease ambiguity in the literature and support theory-based consideration of measurement options.

Poor sleep quality associates with self-reported psychiatric and cardiometabolic symptoms independently of sleep timing patterns in a large sample of rural and urban workers.

Poor sleep associates with mental and cardiometabolic pathological outcomes. The participation of sleep timing features in the pathways by which this relationship occurs is not clear. This study aims to evaluate the interrelationship between sleep quality and self-reported psychiatric/cardiometabolic symptoms, considering mediation and moderation effects of sleep timing patterns, and urban versus rural work environment, respectively; and to verify the association between sleep quality and polymorphisms of AANAT, RORA and TIMELESS genes. An epidemiological survey was performed in a rural area in southern Brazil. Eight-hundred and twenty-nine subjects were evaluated for sleep quality using the Pittsburgh Sleep Quality Index, and sleep timing patterns using the Munich Chronotype Questionnaire. Work characteristics and psychiatric/cardiometabolic symptoms were assessed using a structured self-report questionnaire. Three polymorphisms of AANAT, RORA and TIMELESS (rs3760138, rs782931 and rs774045, respectively) were genotyped in blood samples. We found statistically significant associations of poor sleep quality with self-reported psychiatric symptoms (B = 0.382; 95% CI 0.289-0.476; adjusted p-value <.001), and with self-reported cardiometabolic symptoms (B = 0.079; 95% CI 0.013-0.151; adjusted p-value = .048). The genetic analysis showed that RORA GA/AA genotype was associated to poor sleep quality (B = 0.146, 95% CI 0.054-0.239; adjusted p-value = .004). No moderated mediation effects were observed in the conditional analysis. TIMELESS polymorphism was not included in the analysis due to the low frequency of risk genotypes. These results yield new insights regarding the interrelationship between sleep characteristics and psychiatric/cardiometabolic self-reported symptoms, taking into account genes related to the biological clocks and melatonin pathways.

p38ß and Cancer: The Beginning of the Road.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is implicated in cancer biology and has been widely studied over the past two decades as a potential therapeutic target. Most of the biological and pathological implications of p38MAPK signaling are often associated with p38α (MAPK14). Recently, several members of the p38 family, including p38γ and p38δ, have been shown to play a crucial role in several pathologies including cancer. However, the specific role of p38ß (MAPK11) in cancer is still elusive, and further investigation is needed. Here, we summarize what is currently known about the role of p38ß in different types of tumors and its putative implication in cancer therapy. All evidence suggests that p38ß might be a key player in cancer development, and could be an important therapeutic target in several pathologies, including cancer.

Pro-inflammatory mediators and neutrophils are increased in synovial fluid from heifers with acute ruminal acidosis.

BACKGROUND: Acute ruminal acidosis (ARA) is a metabolic disease of cattle characterized by an aseptic synovitis. ARA is the result of an increased intake of highly fermentable carbohydrates that frequently occurs in dairy cattle subjected to high production requirements. In human joint diseases such as rheumatoid arthritis and gout, several pro-inflammatory molecules are increased in the synovial fluid, including cytokines, prostaglandin E2 (PGE2), metalloproteinases, and neutrophil extracellular traps (NETs). The aim of this study was to identify the presence of proinflammatory mediators and neutrophils in the synovial fluid of heifers with ARA, induced by an oligofructose overload. Five heifers were challenged with an oligofructose overload (13 g/kg BW) dissolved in water. As a control, a similar vehicle volume was used in four heifers. Synovial fluid samples were collected from the tarso-crural joint and PGE2, IL-6, IL-1ß, ATP, lactate dehydrogenase (LDH), albumin, glucose, matrix metalloproteinase-9 (MMP-9), cellular free DNA, NETs, and serpin B1 were analyzed at 0, 9, and 24 h post treatment. RESULTS: At 9 h post oligofructose overload, an increase of IL-1ß, IL-6, PGE2, serpin B1 and LDH was detected in the joints when compared to the control group. At 24 h, the synovial fluid was yellowish, viscous, turbid, and contained abundant neutrophils. An increase of DNA-backbone-like traps, histone 3 (H3cit), aggregated neutrophil extracellular traps (aggNETs), and serpin B1 were observed 24 h post treatment. Furthermore, albumins, LDH, ATP, MMP-9, IL-6, and IL-1ß were increased after 24 h. CONCLUSIONS: The overall results indicate that IL-1ß, IL-6 and PGE2, were the earliest proinflammatory parameters that increased in the synovial fluid of animals with ARA. Furthermore, the most sever inflammatory response in the joint was observed after 24 h and could be associated with a massive presence of neutrophils and release of aggNETs.

Evaluation of Breathworks' Mindfulness for Stress 8-week course: Effects on depressive symptoms, psychiatric symptoms, affects, self-compassion, and mindfulness facets in Brazilian health professionals.

OBJECTIVES: This study was aimed to evaluate the effects of the Breathworks' Mindfulness for Stress 8-week course on depressive and psychiatric symptoms, and on positive and negative affects, compared with active control and wait list. METHOD: A total of 84 primary care health professionals enrolled in the study, in quasi-experimental research design. The scales Beck Depression Inventory, Self-Reporting Questionnaire, Positive and Negative Affect Schedule, Self-Compassion Scale, and Five Facets of Mindfulness Questionnaire were applied before and after the interventions. RESULTS: Depressive symptoms, psychiatric symptoms, and negative affects had a statistically significant decrease before postintervention evaluations in Mindfulness for Stress group, and the levels of self-compassion and observe and non-reactivity dimensions of mindfulness improved after the intervention. CONCLUSIONS: The Mindfulness for Stress program can be considered a feasible group intervention to improve the mental health of healthcare professionals.

Mesoscopic study of the ternary phase diagram of the PS-PB-PtBMA triblock copolymer: modification of the phase structure by the composition effect.

We explored in detail the ordered nanostructures and the ternary phase diagram of the polystyrene-polybutadiene-poly(tert-butyl methacrylate) (PS-PB-PtBMA) triblock copolymer via dissipative particle dynamics (DPD) simulations and coarse-grained models. The mesoscopic simulations show that the PS-PB-PtBMA copolymer in the bulk state can generate eight equilibrium phase regions with well-defined morphologies such as core-shell variations of spheres, cylinders, perforated layers, lamellar, gyroid, as well as cylinder-in-lamella, spheres-in-lamella, and cylinders in hexagonal lattice. The ordered phases exhibit high dependence on the chemical nature and volume fraction, thus portraying specific composition regions with high thermodynamic stability over a ternary phase diagram. The ternary phase diagram, including all equilibrium and metastable nanostructures detected, is described, and analysed in this work in detail. Finally, our dynamic simulation outcomes agree with experimental results. Our aim is to contribute to the understanding of the relationship between block volume fractions and bulk morphologies in ternary polymer systems.

The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation through Modulation of NOTCH Signaling.

The involvement of NOTCH signaling in macrophage activation by Toll receptors has been clearly established, but the factors and pathways controlling NOTCH signaling during this process have not been completely delineated yet. We have characterized the role of TSPAN33, a tetraspanin implicated in a disintegrin and metalloproteinase (ADAM) 10 maturation, during macrophage proinflammatory activation. Tspan33 expression increases in response to TLR signaling, including responses triggered by TLR4, TLR3, and TLR2 activation, and it is enhanced by IFN-γ. In this study, we report that induction of Tspan33 expression by TLR and IFN-γ is largely dependent on NOTCH signaling, as its expression is clearly diminished in macrophages lacking Notch1 and Notch2 expression, but it is enhanced after overexpression of a constitutively active intracellular domain of NOTCH1. TSPAN33 is the member of the TspanC8 tetraspanin subgroup more intensely induced during macrophage activation, and its overexpression increases ADAM10, but not ADAM17, maturation. TSPAN33 favors NOTCH processing at the membrane by modulating ADAM10 and/or Presenilin1 activity, thus increasing NOTCH signaling in activated macrophages. Moreover, TSPAN33 modulates TLR-induced proinflammatory gene expression, at least in part, by increasing NF-κB-dependent transcriptional activity. Our results suggest that TSPAN33 represents a new control element in the development of inflammation by macrophages that could constitute a potential therapeutic target.

Interleukin-3 Prevents Cellular Death Induced by Oxidative Stress in HEK293 Cells.

Interleukin-3 (IL-3) is a well-characterized growth factor in hematopoietic cells, but it is also expressed in other cell types with poorly described functions. Many studies have provided evidence that IL-3 plays an important role in cell survival. We have previously shown that IL-3 is able to increase glucose uptake in HEK293 cells, suggesting that this factor requires sustained glucose metabolism to promote cell survival. In this study, we demonstrate that IL-3 contributes to cell survival under oxidative stress, a prominent feature in the pathophysiology of cancer, diabetes, and neurodegenerative diseases, as well as in the aging process. Our results suggest a molecular mechanism that involves signaling pathways mediated by PI-3k/Akt and Erk. Altogether, these findings show an important role for IL-3 in supporting the viability of non-hematopoietic systems. J. Cell. Biochem. 118: 1330-1340, 2017. © 2016 Wiley Periodicals, Inc.