Fabrication of CNT-N@Manganese Oxide Hybrid Nanomaterials through a Versatile One-Pot Eco-Friendly Route toward Engineered Textile Supercapacitors.

The expansion of the Internet of Things market and the proliferation of wearable technologies have generated a significant demand for textile-based energy storage systems. This work reports the engineered design of hybrid electrode nanomaterials of N-doped carbon nanotubes (CNT-N) functionalized with two types of manganese oxides (MOs)-birnessite (MnO2) and hausmannite (Mn3O4)-and their application in solid-state textile-based hybrid supercapacitors (SCs). A versatile citric acid-mediated eco-friendly one-pot aqueous precipitation process is proposed for the fabrication of the hybrids. Remarkably, different types of MOs were obtained by simply changing the reaction temperature from room temperature to 100 °C, without any post-thermal treatment. Asymmetric textile SCs were developed using cotton fabrics coated with CNT-N and the hybrids as textile electrodes, and poly(vinyl) alcohol/orthophosphoric acid as the solid-gel electrolyte. The asymmetric devices presented enhanced energy storage performance relative to the symmetric device based on CNT-N and excellent cycling stability (>96%) after 8000 charge/discharge cycles owing to synergistic effects between CNT-N and the MOs, which endowed nonfaradaic and pseudocapacitive features to the SCs. The asymmetric SC based on CNT-N@MnO2 featured 47% higher energy density and comparable power density to the symmetric CNT-N-based device (8.70 W h cm-2 at 309.01 µW cm-2 vs. 5.93 W h cm-2 at 346.58 µW cm-2). The engineered hybrid CNT-N@MO nanomaterials and the eco-friendly citric acid-assisted one-pot precipitation route open promising prospects not only for energy storage, but also for (photo)(electro)catalysis, wastewater treatment, and (bio)sensing.

Sit4 Genetically Interacts with Vps27 to Regulate Mitochondrial Function and Lifespan in Saccharomyces cerevisiae.

The Sit4 protein phosphatase plays a key role in orchestrating various cellular processes essential for maintaining cell viability during aging. We have previously shown that SIT4 deletion promotes vacuolar acidification, mitochondrial derepression, and oxidative stress resistance, increasing yeast chronological lifespan. In this study, we performed a proteomic analysis of isolated vacuoles and yeast genetic interaction analysis to unravel how Sit4 influences vacuolar and mitochondrial function. By employing high-resolution mass spectrometry, we show that sit4Δ vacuolar membranes were enriched in Vps27 and Hse1, two proteins that are part of the endosomal sorting complex required for transport-0. In addition, SIT4 exhibited a negative genetic interaction with VPS27, as sit4∆vps27∆ double mutants had a shortened lifespan compared to sit4∆ and vps27∆ single mutants. Our results also show that Vps27 did not increase sit4∆ lifespan by improving protein trafficking or vacuolar sorting pathways. However, Vps27 was critical for iron homeostasis and mitochondrial function in sit4∆ cells, as sit4∆vps27∆ double mutants exhibited high iron levels and impaired mitochondrial respiration. These findings show, for the first time, cross-talk between Sit4 and Vps27, providing new insights into the mechanisms governing chronological lifespan.

Flexible Magnetocaloric Fiber Mats for Room-Temperature Energy Applications.

Currently, magnetocaloric refrigeration technologies are emerging as ecofriendly and more energy-efficient alternatives to conventional expansion-compression systems. However, major challenges remain. A particular concern is the mechanical properties of magnetocaloric materials, namely, their fatigue under cycling and difficulty in processing and shaping. Nevertheless, in the past few years, using multistimuli thermodynamic cycles with multicaloric refrigerants has led to higher heat-pumping efficiencies. To address simultaneously the challenges and develop a multicaloric material, in this work, we have prepared magnetocaloric-based flexible composite mats composed of micrometric electroactive (EA) polyvinylidene fluoride (PVDF) fibers with embedded magnetocaloric/strictive La(Fe,Si)13 particles by the simple and cost-effective electrospinning technique. The composite's structural characterization, using X-ray diffraction (XRD) analysis, Fourier transform infrared (FTIR) spectroscopy, and measurements of the local-scale piezoresponse, revealed a cubic NaZn13-type structure of the La(Fe,Si)13 phase and the formation of the dominant polar ß-phase of the PVDF polymer. The PVDF-La(Fe,Si)13 composite showed an enhancement of the longitudinal piezoelectric coefficient (effective d33) (-11.01 pm/V) compared with the single PVDF fiber matrix (-9.36 pm/V). The main magnetic properties of La(Fe,Si)13 powder were retained in the PVDF-La(Fe,Si)13 composite, including its giant magnetocaloric effect. By retaining the unique magnetic properties of La(Fe,Si)13 embedded in the electroactive piezoelectric polymer fiber mats, we have designed a flexible, easily shapeable, and multifunctional composite enabling its potential application in multicaloric heat-pumping devices and other sensing and actuating devices.

Prediction and biological analysis of yeast VDAC1 phosphorylation.

The mitochondrial outer membrane protein porin 1 (Por1), the yeast orthologue of mammalian voltage-dependent anion channel (VDAC), is the major permeability pathway for the flux of metabolites and ions between cytosol and mitochondria. In yeast, several Por1 phosphorylation sites have been identified. Protein phosphorylation is a major modification regulating a variety of biological activities, but the potential biological roles of Por1 phosphorylation remains unaddressed. In this work, we analysed 10 experimentally observed phosphorylation sites in yeast Por1 using bioinformatics tools. Two of the residues, T100 and S133, predicted to reduce and increase pore permeability, respectively, were validated using biological assays. In accordance, Por1T100D reduced mitochondrial respiration, while Por1S133E phosphomimetic mutant increased it. Por1T100A expression also improved respiratory growth, while Por1S133A caused defects in all growth conditions tested, notably in fermenting media. In conclusion, we found phosphorylation has the potential to modulate Por1, causing a marked effect on mitochondrial function. It can also impact on cell morphology and growth both in respiratory and, unpredictably, also in fermenting conditions, expanding our knowledge on the role of Por1 in cell physiology.

Multifunctional Nanoparticles with Superparamagnetic Mn(II) Ferrite and Luminescent Gold Nanoclusters for Multimodal Imaging.

Gold nanoclusters (AuNCs) with fluorescence in the Near Infrared (NIR) by both one- and two-photon electronic excitation were incorporated in mesoporous silica nanoparticles (MSNs) using a novel one-pot synthesis procedure where the condensation polymerization of alkoxysilane monomers in the presence of the AuNCs and a surfactant produced hybrid MSNs of 49 nm diameter. This method was further developed to prepare 30 nm diameter nanocomposite particles with simultaneous NIR fluorescence and superparamagnetic properties, with a core composed of superparamagnetic manganese (II) ferrite nanoparticles (MnFe2O4) coated with a thin silica layer, and a shell of mesoporous silica decorated with AuNCs. The nanocomposite particles feature NIR-photoluminescence with 0.6% quantum yield and large Stokes shift (290 nm), and superparamagnetic response at 300 K, with a saturation magnetization of 13.4 emu g-1. The conjugation of NIR photoluminescence and superparamagnetic properties in the biocompatible nanocomposite has high potential for application in multimodal bioimaging.

Mitochondria and the cell cycle in budding yeast.

As centers for energy production and essential biosynthetic activities, mitochondria are vital for cell growth and proliferation. Accumulating evidence suggests an integrated regulation of these organelles and the nuclear cell cycle in distinct organisms. In budding yeast, a well-established example of this coregulation is the coordinated movement and positional control of mitochondria during the different phases of the cell cycle. The molecular determinants involved in the inheritance of the fittest mitochondria by the bud also seem to be cell cycle-regulated. In turn, loss of mtDNA or defects in mitochondrial structure or inheritance often lead to a cell cycle delay or arrest, indicating that mitochondrial function can also regulate cell cycle progression, possibly through the activation of cell cycle checkpoints. The up-regulation of mitochondrial respiration at G2/M, presumably to fulfil energetic requirements for progression at this phase, also supports a mitochondria-cell cycle interplay. Cell cycle-linked mitochondrial regulation is accomplished at the transcription level and through post-translational modifications, predominantly protein phosphorylation. Here, we address mitochondria-cell cycle interactions in the yeast Saccharomyces cerevisiae and discuss future challenges in the field.

Fe3O4@Au Core-Shell Magnetic Nanoparticles for the Rapid Analysis of E. coli O157:H7 in an Electrochemical Immunoassay.

Escherichia coli (E. coli) O157:H7 is a pathogenic bacterium that causes serious toxic effects in the human gastrointestinal tract. In this paper, a method for its effective analytical control in a milk sample was developed. To perform rapid (1 h) and accurate analysis, monodisperse Fe3O4@Au magnetic nanoparticles were synthesized and used in an electrochemical sandwich-type magnetic immunoassay. Screen-printed carbon electrodes (SPCE) were used as transducers, and electrochemical detection was performed by chronoamperometry using a secondary horseradish peroxidase-labeled antibody and 3,3',5,5'-tetramethylbenzidine. This magnetic assay was used to determine the E. coli O157:H7 strain in the linear range from 20 to 2 × 106 CFU/mL, with a limit of detection of 20 CFU/mL. The selectivity of the assay was tested using Listeria monocytogenes p60 protein, and the applicability of the assay was assessed by analyzing a commercial milk sample, demonstrating the usefulness of the synthesized nanoparticles in the developed magnetic immunoassay.

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann-Pick Type C1.

Niemann-Pick type C1 (NPC1) is an endolysosomal transmembrane protein involved in the export of cholesterol and sphingolipids to other cellular compartments such as the endoplasmic reticulum and plasma membrane. NPC1 loss of function is the major cause of NPC disease, a rare lysosomal storage disorder characterized by an abnormal accumulation of lipids in the late endosomal/lysosomal network, mitochondrial dysfunction, and impaired autophagy. NPC phenotypes are conserved in yeast lacking Ncr1, an orthologue of human NPC1, leading to premature aging. Herein, we performed a phosphoproteomic analysis to investigate the effect of Ncr1 loss on cellular functions mediated by the yeast lysosome-like vacuoles. Our results revealed changes in vacuolar membrane proteins that are associated mostly with vesicle biology (fusion, transport, organization), autophagy, and ion homeostasis, including iron, manganese, and calcium. Consistently, the cytoplasm to vacuole targeting (Cvt) pathway was increased in ncr1∆ cells and autophagy was compromised despite TORC1 inhibition. Moreover, ncr1∆ cells exhibited iron overload mediated by the low-iron sensing transcription factor Aft1. Iron deprivation restored the autophagic flux of ncr1∆ cells and increased its chronological lifespan and oxidative stress resistance. These results implicate iron overload on autophagy impairment, oxidative stress sensitivity, and cell death in the yeast model of NPC1.

The APC/C Activator Cdh1p Plays a Role in Mitochondrial Metabolic Remodelling in Yeast.

Cdh1p is one of the two substrate adaptor proteins of the anaphase promoting complex/cyclosome (APC/C), a ubiquitin ligase that regulates proteolysis during cell cycle. In this work, using a proteomic approach, we found 135 mitochondrial proteins whose abundance was significantly altered in the cdh1Δ mutant, with 43 up-regulated proteins and 92 down-regulated proteins. The group of significantly up-regulated proteins included subunits of the mitochondrial respiratory chain, enzymes from the tricarboxylic acid cycle and regulators of mitochondrial organization, suggesting a metabolic remodelling towards an increase in mitochondrial respiration. In accordance, mitochondrial oxygen consumption and Cytochrome c oxidase activity increased in Cdh1p-deficient cells. These effects seem to be mediated by the transcriptional activator Yap1p, a major regulator of the yeast oxidative stress response. YAP1 deletion suppressed the increased Cyc1p levels and mitochondrial respiration in cdh1Δ cells. In agreement, Yap1p is transcriptionally more active in cdh1Δ cells and responsible for the higher oxidative stress tolerance of cdh1Δ mutant cells. Overall, our results unveil a new role for APC/C-Cdh1p in the regulation of the mitochondrial metabolic remodelling through Yap1p activity.

Mitochondrial respiration promotes Cdc37-dependent stability of the Cdk1 homolog Cdc28.

Cdc28, the homolog of mammalian Cdk1, is a conserved key regulatory kinase for all major cell cycle transitions in yeast. We have found that defects in mitochondrial respiration (including deletion of ATP2, an ATP synthase subunit) inhibit growth of cells carrying a degron allele of Cdc28 (cdc28td) or Cdc28 temperature-sensitive mutations (cdc28-1 and cdc28-1N) at semi-permissive temperatures. Loss of cell proliferation in the atp2Δcdc28td double mutant is associated with aggravated cell cycle arrest and mitochondrial dysfunction, including mitochondrial hyperpolarization and fragmentation. Unexpectedly, in mutants defective in mitochondrial respiration, steady-state protein levels of mutant cdc28 are strongly reduced, accounting for the aggravated growth defects. Stability of Cdc28 is promoted by the Hsp90-Cdc37 chaperone complex. Our results show that atp2Δcdc28td double-mutant cells, but not single mutants, are sensitive to chemical inhibition of the Hsp90-Cdc37 complex, and exhibit reduced levels of additional Hsp90-Cdc37 client kinases, suggesting an inhibition of this complex. In agreement, overexpression of CDC37 improved atp2Δcdc28td cell growth and Cdc28 levels. Overall, our study shows that simultaneous disturbance of mitochondrial respiration and Cdc28 activity reduces the capacity of Cdc37 to chaperone client kinases, leading to growth arrest.

Impactos Psicossociais e na Qualidade de Vida do Tratamento Oncológico em Crianças e Adolescentes / Psychosocial and Quality-of-Life Impacts of Cancer Treatment in Children and Adolescents / Impactos Psicosociales y en la Calidad de Vida del Tratamiento del Cáncer en Niños y Adolescentes

Introdução: Tão importante quanto o diagnóstico e o tratamento do câncer pediátrico são os cuidados relacionados ao impacto psicossocial, educacional e emocional. Objetivo: Avaliar em crianças e adolescentes com diagnóstico de câncer os impactos psicossociais, de qualidade de vida e da presença de acompanhante durante os procedimentos. Método: Estudo transversal, descritivo, com pacientes de 8 a 18 anos e diagnóstico de neoplasia maligna. Os pacientes responderam aos questionários: PedsQL 4.0 Qualidade de Vida (8 a 12 anos), PedsQL 3.0 Módulo de Câncer (8 a 12 anos), PedsQL 4.0 Qualidade de Vida (13 a 18 anos), PedsQL 3.0 Módulo de Câncer (13 a 18 anos) e outro sobre acompanhantes elaborado pelos autores. Resultados: Foram incluídos 25 pacientes pediátricos oncológicos que se sentiam mais felizes na presença de um acompanhante e menos ansiosos durante os procedimentos. Foi percebido grande impacto na qualidade de vida. No questionário Qualidade de Vida, não houve diferença significativa (p=0,627) entre os grupos de pacientes com 8 a 12 anos e 13 a 18 anos, porém o grupo com 8 a 12 anos teve impacto significativamente maior no questionário Módulo de Câncer (p=0,0094). Conclusão: O impacto psicossocial e na qualidade de vida é razoavelmente grande em pacientes pediátricos oncológicos. Além disso, os mais jovens parecem sofrer um impacto psicossocial maior. Os pacientes se dizem mais felizes com a presença de acompanhante, e mais ansiosos na sua ausência.

Introduction: As important as the diagnosis and treatment of pediatric cancer are the care related to psychosocial, educational, and emotional impact. Objective: To evaluate in children and adolescents diagnosed with cancer the psychosocial and quality-of-life impacts and the presence of a companion during the procedures. Method: Cross-sectional descriptive study of patients aged 8 to 18 years of age diagnosed with malignant neoplasms. Patients responded the questionnaires PedsQL 4.0 Quality of Life (8 to 12 years), PedsQL 3.0 Cancer Module (8 to 12 years), PedsQL 4.0 Quality of Life (13 to 18 years), PedsQL 3.0 Cancer Module (13 to 18 years) and another about companions created by the authors. Results: There were 25 pediatric oncology patients included who felt happier in the presence of a companion, and less anxious during the procedures. A great impact on quality of life was perceived. In the Quality-of-Life questionnaire, no significant difference (p=0.627) between the groups of patients aged 8 to 12 years and 13 to 18 years were found, but the group aged 8 to 12 years had a significantly higher impact on the Cancer Module questionnaire (p= 0.0094). Conclusion: The impact on quality of life and psychosocial is fairly large in pediatric oncology patients. The youngest appear to suffer great psychosocial impact. Patients claim they are happier in the presence of a companion, and more anxious in its absence

Introducción: Tan importante como el diagnóstico y tratamiento del cáncer pediátrico, son los cuidados sobre el impacto psicosocial, educativo y emocional. Objetivo: Evaluar en niños y adolescentes diagnosticados de cáncer el impacto psicosocial y en la calidad de vida y la presencia de un acompañante durante los procedimientos. Método: Estudio transversal descriptivo de pacientes de 8 a 18 años con diagnóstico de neoplasia maligna. Los pacientes respondieron a los cuestionarios: PedsQL 4.0 Calidad de Vida (8 a 12 años), PedsQL 3.0 Módulo de Cáncer (8 a 12 años), PedsQL 4.0 Calidad de Vida (13 a 18 años), PedsQL 3.0 Módulo de Cáncer (13 a 18 años) y otro sobre cuidadores elaborado por los autores. Resultados: Se incluyeron 25 pacientes de oncología pediátrica que se sentían más felices con la presencia de un acompañante y menos ansiosos al realizar procedimientos. Se percibió un gran impacto en la calidad de vida. En el cuestionario de Calidad de Vida, no hubo diferencia significativa (p=0,627) entre los grupos de pacientes de 8 a 12 años y de 13 a 18 años, pero el grupo de 8 a 12 años tuvo un impacto significativamente mayor en el cuestionario del Módulo de Cáncer (p=0,0094). Conclusión: El impacto en la calidad de vida y psicosocial es razonablemente grande en los pacientes oncológicos pediátricos. Los de menor edad parecen sufrir un mayor impacto psicosocial. Los pacientes dicen sentirse más felices con la presencia de un acompañante, y más ansiosos en su ausencia.

A battery of tandem mass spectrometry assays with stable isotope-dilution for the quantification of 15 anti-tuberculosis drugs and two metabolites in patients with susceptible-, multidrug-resistant- and extensively drug-resistant tuberculosis.

OBJECTIVE: Anti-tuberculosis (antiTB) drugs are characterized by an important inter-interindividual pharmacokinetic variability poorly predictable from individual patients' characteristics. Therapeutic drug monitoring (TDM) may therefore be beneficial for patients with Mycobacterium tuberculosis infection, especially for the management of multidrug/extensively drug resistant- (MDR/XDR)-TB. Our objective was to develop robust HPLC-MS/MS methods for plasma quantification of 15 antiTB drugs and 2 metabolites, namely rifampicin, isoniazid plus N-acetyl-isoniazid, pyrazinamide, ethambutol (the conventional quadritherapy for susceptible TB) as well as combination of agents against MDR/XDR-TB: bedaquiline, clofazimine, delamanid and its metabolite M1, levofloxacin, linezolid, moxifloxacin, pretomanid, rifabutin, rifapentine, sutezolid, and cycloserine. METHODS: Plasma protein precipitation was used for all analytes except cycloserine, which was analyzed separately after derivatization with benzoyl chloride. AntiTB quadritherapy drugs (Pool1) were separated by Hydrophilic Interaction Liquid Chromatography (column Xbridge BEH Amide, 2.1 × 150 mm, 2.5 µm, Waters®) while MDR/XDR-TB agents (Pool 2) and cycloserine (as benzoyl derivative) were analyzed by reverse phase chromatography on a column XSelect HSS T3, 2.1 × 75 mm, 3.5 µm (Waters®). All runs last <7 min. Quantification was performed by selected reaction monitoring electrospray tandem mass spectrometry, using stable isotopically labelled internal standards. RESULTS: The method covers the clinically relevant plasma levels and was extensively validated based on FDA recommendations, with intra- and inter-assay precision (CV) < 15% over the validated ranges. Application of the method is illustrated by examples of TDM for two patients treated for drug-susceptible- and MDR-TB. CONCLUSION: Such convenient extraction methods and the use of stable isotope-labelled drugs as internal standards provide an accurate and precise quantification of plasma concentrations of all major clinically-used antiTB drugs regimens and is optimally suited for clinically efficient TDM against tuberculosis.

Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy.

Seipin is encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and FLD1/SEI1 in yeast. The gain-of-function N88S mutation in the BSCL2 gene was identified in a cohort of autosomal dominant motor neuron diseases (MNDs) collectively known as seipinopathies. Previous work has shown that this mutation disrupts N-glycosylation, leading to the formation of inclusion bodies (IBs) and contributing to severe Endoplasmic Reticulum (ER) stress and cell death. In this work, we established a humanized yeast model of N88S seipinopathy that recapitulated the formation of IBs and activation of the unfolded protein response (UPR) observed in mammalian systems. Autophagy and the Hrd1-mediated endoplasmic reticulum-associated degradation (ERAD) were fully functional in cells expressing mutant homomers and WT-mutant heteromers of seipin, discarding the possibility that mutant seipin accumulate due to impaired protein quality control systems. Importantly, the N88S seipin form IBs that appear to induce changes in ER morphology, in association with Kar2 chaperone and the Hsp104 disaggregase. For the first time, we have determined that N88S homo-oligomers expressing cells present reduced viability, decreased antioxidant activity and increased oxidative damage associated with loss of mitochondrial membrane potential, higher reactive oxygen species (ROS) levels and lipid peroxidation. This was correlated with the activation of oxidative stress sensor Yap1. Moreover, activation of ERAD and UPR quality control mechanisms were essential for proper cell growth, and crucial to prevent excessive accumulation of ROS in cells expressing N88S homomers solely. Overall, this study provides new insights into the molecular underpinnings of these rare diseases and offers novel targets for potential pharmacological intervention.

In Vivo Clonal Analysis Reveals Random Monoallelic Expression in Lymphocytes That Traces Back to Hematopoietic Stem Cells.

Evaluating the epigenetic landscape in the stem cell compartment at the single-cell level is essential to assess the cells' heterogeneity and predict their fate. Here, using a genome-wide transcriptomics approach in vivo, we evaluated the allelic expression imbalance in the progeny of single hematopoietic cells (HSCs) as a read-out of epigenetic marking. After 4 months of extensive proliferation and differentiation, we found that X-chromosome inactivation (XCI) is tightly maintained in all single-HSC derived hematopoietic cells. In contrast, the vast majority of the autosomal genes did not show clonal patterns of random monoallelic expression (RME). However, a persistent allele-specific autosomal transcription in HSCs and their progeny was found in a rare number of cases, none of which has been previously reported. These data show that: 1) XCI and RME in the autosomal chromosomes are driven by different mechanisms; 2) the previously reported high frequency of genes under RME in clones expanded in vitro (up to 15%) is not found in clones undergoing multiple differentiation steps in vivo; 3) prior to differentiation, HSCs have stable patterns of autosomal RME. We propose that most RME patterns in autosomal chromosomes are erased and established de novo during cell lineage differentiation.

Phosphoregulation of the ATP synthase beta subunit stimulates mitochondrial activity for G2/M progression.

Mitochondrial ATP synthase is a multifunctional enzyme complex involved in ATP production. We previously reported that the ATP synthase catalytic beta subunit (Atp2p in yeast) is regulated by the 2A-like protein phosphatase Sit4p, which targets Atp2p at T124/T317 impacting on ATP synthase levels and mitochondrial respiration. Here we report that Atp2-T124/T317 is also potentially regulated by Cdc5p, a polo-like mitotic kinase. Since both Cdc5p and Sit4p have established roles in cell cycle regulation, we investigated whether Atp2-T124/T317 phosphorylation was cell cycle-related. We present evidence that Atp2p levels and phosphorylation vary during cell cycle progression, with an increase at G2/M phase. Atp2-T124/T317 phosphorylation stimulates mitochondrial membrane potential, respiration and ATP levels at G2/M phase, indicating that dynamic Atp2p phosphorylation contributes to mitochondrial activity at this specific cell cycle phase. Preventing Atp2p phosphorylation delays G2/M to G1 transition, suggesting that enhanced bioenergetics at G2/M may help meet the energetic demands of cell cycle progression. However, mimicking constitutive T124/T317 phosphorylation or overexpressing Atp2p leads to mitochondrial DNA instability, indicating that reversible Atp2p phosphorylation is critical for homeostasis. These results indicate that transient phosphorylation of Atp2p, a protein at the core of the ATP production machinery, impacts on mitochondrial bioenergetics and supports cell cycle progression at G2/M.

Saúde LGBTQIA+: análise na educação médica / LGBTQIA+ health: analysis in medical education

O trabalho insere-se nas áreas temáticas da atenção à saúde da população LGBTQIA+ e da formação dos profissionais de saúde focada nesta área. Tem por objetivo analisar o conhecimento específico dos estudantes de medicina do Paraná, Brasil, no atendimento à saúde da população LGBTQIA+ e realizar levantamento do nível de conhecimento referido pelos estudantes acerca da atenção à saúde da população LGBTQIA+. Foram entrevistados 240 acadêmicos de medicina de 11 instituições de ensino médico do Estado do Paraná, por intermédio de questionário eletrônico disponibilizado via redes sociais, e analisadas as porcentagens das respostas. A maior parte (68,4%) "discordam totalmente" ou "discordam" que receberam formação específica na área de atendimento à saúde da população LGBTQIA+. Há pouca familiaridade dos estudantes com a terminologia existente dentro desse universo. Em conclusão, percebe-se a necessidade de adequação da educação médica no que concerne às especificidades da saúde da população LGBTQIA+

The work is part of the thematic areas of health care for the LGBTQIA+ population and the training of health professionals focused on this area. It aims to analyze the specific knowledge of medical students in Paraná, Brazil, in the health care of the LGBTQIA+ population and to carry out a survey of the level of knowledge reported by the students about the health care of the LGBTQIA+ population. A total of 240 medical students from 11 medical education institutions in the State of Paraná were interviewed, using an electronic questionnaire made available via social networks, and the percentages of responses were analyzed. Most (68.4%) "strongly disagree" or "disagree" that they received specific training in the area of health care for the LGBTQIA+ population. There is little familiarity of students with the terminology existing within this universe. In conclusion, there is a need to adapt medical education with regard to the health specifics of the LGBTQIA+ population

Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with IL7R to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant IL7R alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with MYC transcriptional activation. Additionally, we find that mutant IL7R collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant IL7R and Myc activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.

RNA sequencing-based screen for reactivation of silenced alleles of autosomal genes.

In mammalian cells, maternal and paternal alleles usually have similar transcriptional activity. Epigenetic mechanisms such as X-chromosome inactivation (XCI) and imprinting were historically viewed as rare exceptions to this rule. Discovery of autosomal monoallelic autosomal expression (MAE) a decade ago revealed an additional allele-specific mode regulating thousands of mammalian genes. Despite MAE prevalence, its mechanistic basis remains unknown. Using an RNA sequencing-based screen for reactivation of silenced alleles, we identified DNA methylation as key mechanism of MAE mitotic maintenance. In contrast with the all-or-nothing allelic choice in XCI, allele-specific expression in MAE loci is tunable, with exact allelic imbalance dependent on the extent of DNA methylation. In a subset of MAE genes, allelic imbalance was insensitive to DNA demethylation, implicating additional mechanisms in MAE maintenance in these loci. Our findings identify a key mechanism of MAE maintenance and provide basis for understanding the biological role of MAE.

Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia.

Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

Solar Light-Induced Methylene Blue Removal over TiO2/AC Composites and Photocatalytic Regeneration.

TiO2-containing photocatalysts, which combine TiO2 with carbon-based materials, are promising materials for wastewater treatment due to synergistic photodegradation and adsorption phenomena. In this work, TiO2/AC composites were produced by the in situ immobilization of TiO2 nanoparticles over activated carbon (AC) derived from spent coffee grains, using different TiO2/AC proportions. The TiO2/AC composites were tested as adsorbents (dark) and as photocatalysts in a combined adsorption+photocatalytic process (solar irradiation) for methylene blue (MB) removal from ultrapure water, and from a secondary effluent (SecEf) of an urban wastewater treatment plant. All the materials were characterized by XRD (X-ray powder diffraction), N2 adsorption-desorption isotherms at -196 °C, SEM (scanning electron microscopy), UV-Vis diffuse reflectance, FTIR (Fourier-transform infrared spectroscopy), TPD (temperature programmed desorption), XPS (X-ray photoelectron spectroscopy) and TGA (thermogravimetric analysis). The TiAC60 (60% C) composite presented the lowest band gap (1.84 eV), while, for TiAC29 (29% C), the value was close to that of bare TiO2 (3.18 vs. 3.17 eV). Regardless of the material, the solar irradiation improved the percentage of MB discolouration when compared to adsorption in dark conditions. In the case of simultaneous adsorption+photocatalytic assays performed in ultrapure water, TiAC29 presented the fastest MB removal. Nevertheless, both TiAC29 and TiAC60 led to excellent MB removal percentages (96.1-98.1%). UV-induced photoregeneration was a promising strategy to recover the adsorption capacity of the materials, especially for TiAC60 and AC (>95%). When the assays were performed in SecEf, all the materials promoted discolouration percentages close to those obtained in ultrapure water. The bulk water parameters revealed that TiAC60 allowed the removal of a higher amount of MB, associated with the overall improvement of the SecEf quality.