Electrospun Polycaprolactone Membranes Expanded with Chitosan Granules for Cell Infiltration.

The small pore size of electrospun membranes prevents their use as three-dimensional scaffolds. In this work, we produced polycaprolactone (PCL) electrospun fibrous membranes with expanded pores by incorporating chitosan (CS) granules into the PCL solution. Scanning electron microscopy images confirmed the presence of the CS granules embedded in the PCL fibers, creating an open structure. Tensile testing results showed that the addition of CS decreased both Young's modulus and the yield stress, but co-electrospun membranes (PCL fibers blended with CS-containing PCL fibers) exhibited higher values compared to single electrospun membranes (CS-containing PCL fibers). Human fibroblasts adhered to and proliferated on all scaffolds. Nuclear staining revealed that cells populated the entire scaffold when CS granules were present, while in PCL membranes, cells were mostly limited to the surface due to the small pore size. Overall, our findings demonstrate that electrospun membranes containing CS granules have sufficiently large pores to facilitate fibroblast infiltration without compromising the mechanical stability of the structure.

Therapeutic Polymer-Based Cannabidiol Formulation: Tackling Neuroinflammation Associated with Ischemic Events in the Brain.

Cannabidiol (CBD) is the most relevant nonpsychostimulant phytocompound found in Cannabis sativa. CBD has been extensively studied and has been proposed as a therapeutic candidate for neuroinflammation-related conditions. However, being a highly lipophilic drug, it has several drawbacks for pharmaceutical use, including low solubility and high permeability. Synthetic polymers can be used as drug delivery systems to improve CBD's stability, half-life, and biodistribution. Here, we propose using a synthetic polymer as a nanoparticulate vehicle for CBD (NPCBD) to overcome the pharmacological drawbacks of free drugs. We tested the NPCBD-engineered system in the context of ischemic events in a relevant oxygen and glucose deprivation (OGD) model in primary cortical cells (PCC). Moreover, we have characterized the inflammatory response of relevant cell types, such as THP-1 (human monocytes), HMC3 (human microglia), and PCC, to NPCBD and observed a shift in the inflammatory state of the treated cells after the ischemic event. In addition, NPCBD exhibited a promising ability to restore mitochondrial function after OGD insult in both HMC3 and PCC cells at low doses of 1 and 0.2 µM CBD. Taken together, these results suggest the potential for preclinical use.

Adipose tissue derived stem cell secretome induces motor and histological gains after complete spinal cord injury in Xenopus laevis and mice.

Mesenchymal stem cell-based therapies have been studied for spinal cord injury (SCI) treatment due to their paracrine action upon damaged tissues. MSCs neuroregenerative role may relate to the contents of their secretome in anti-inflammatory cytokines and growth-permissive factors. We propose using the secretome of MSCs isolated from the adipose tissue-adipose tissue-derived stem cells (ASCs) as a cell-free based therapy for SCI. In vivo studies were conducted in two SCI models, Xenopus laevis and mice, after complete spinal cord transection. Our results on both models demonstrated positive impacts of ASC secretome on their functional recovery which were correlated with histopathological markers of regeneration. Furthermore, in our mice study, secretome induced white matter preservation together with modulation of the local and peripheral inflammatory response. Altogether, these results demonstrate the neuroregenerative and potential for inflammatory modulation of ASC secretome suggesting it as a good candidate for cell-free therapeutic strategies for SCI.

Database of all currently known mobile colistin resistance genes.

We created a database of all currently known mobile colistin resistance genes and variants (n = 115). It contains accession numbers of the gene and protein sequences, mutations between the protein variants and the main proteins, and additional metadata. It is accompanied by all genetic and protein sequences as two aggregated FASTA files.

Changes in tissue protein N-glycosylation and associated molecular signature occur in the human Parkinsonian brain in a region-specific manner.

Parkinson's disease (PD) associated state of neuroinflammation due to the aggregation of aberrant proteins is widely reported. One type of post-translational modification involved in protein stability is glycosylation. Here, we aimed to characterize the human Parkinsonian nigro-striatal N-glycome, and related transcriptome/proteome, and its correlation with endoplasmic reticulum (ER) stress and unfolded protein response (UPR), providing a comprehensive characterization of the PD molecular signature. Significant changes were seen upon a PD: a 3% increase in sialylation and 5% increase in fucosylation in both regions, and a 2% increase in oligomannosylated N-glycans in the substantia nigra. In the latter, a decrease in the mRNA expression of sialidases and an upregulation in the UPR pathway were also seen. To show the correlation between these, we also describe a small in vitro study where changes in specific glycosylation trait enzymes (inhibition of sialyltransferases) led to impairments in cell mitochondrial activity, changes in glyco-profile, and upregulation in UPR pathways. This complete characterization of the human nigro-striatal N-glycome provides an insight into the glycomic profile of PD through a transversal approach while combining the other PD "omics" pieces, which can potentially assist in the development of glyco-focused therapeutics.

Investigating academic performance and perceptions of human physiology and exercise physiology courses among undergraduate students of physical education at a Brazilian public university.

PURPOSE: To compare the academic performance of undergraduate students in physical education who studied exercise physiology before and after studying human physiology and investigate students' perceptions of human physiology and exercise physiology courses. METHODS: This study included 311 undergraduate students pursuing a bachelor's degree in physical education. Participants were divided into two groups: those who had previously attended and completed the human physiology course (group 1, n = 212, 68.2%) and those who had not previously attended or had attended but failed the human physiology course (group 2, n = 99, 31.8%). The prevalence ratio (PR) and 95% confidence interval (95% CI) were calculated using a Poisson regression model with a robust variance estimator. The second aim comprised 67 students with bachelor's degrees in physical education who completed an electronic questionnaire about their perceptions of human physiology and exercise physiology curriculum. RESULTS: Compared with those who attended human physiology and passed, those who had not previously attended or had attended but failed the human physiology course have a higher PR of 2.37 (95% CI, 1.68-3.34) for failing exercise physiology. Regarding the students' perceptions of human physiology and exercise physiology courses, most students reported that they were challenging (58.2% and 64.2%, respectively), but they also recognized the importance of these courses for professional practice (59.7% and 85.1%, respectively). CONCLUSION: Human physiology should be considered a prerequisite for an undergraduate course leading to a bachelor's degree in physical education. Furthermore, students considered human physiology and exercise physiology courses important yet challenging. Therefore, continuous student assessment is vital for improving the teaching-learning process.

A rare endoscopic pattern in a patient with gastroesophageal reflux disease

A 21-year-old man, with personal history of asthma and no usual medication, was referred to gastroenterology appointment due to dysphagia for solids and previous episodes of food impaction in the last 5 months. He also reported nocturnal heartburn without any other warning signs. Upper gastroscopy revealed a peptic stenosis in the distal esophagus. Histopathologic examination showed hyperplasia and numerous intraepithelial eosinophils, without dysplasia or malignancy. Therapy with a double-dose proton pump inhibitor (PPI) was started. (AU)

Combinatorial analysis of ACE and ACE2 polymorphisms reveals protection against COVID-19 worsening: A genetic association study in Brazilian patients.

Since angiotensin-converting enzyme 2, ACE2, was identified as the receptor for SARS-CoV-2 and considering the intense physiological interplay between the two angitensinases isoforms, ACE and ACE2, as counter-regulatory axis of the renin-angiotensin system, we proposed the evaluation of polymorphisms in these two key regulators in relation to COVID-19 severity. A genetic association study involving 621 COVID-19 hospitalized patients from Brazil was performed. All subjects had a confirmed diagnosis of COVID-19 via RT-PCR. Patients were categorized into two groups: the "mild" group (N = 296), composed of individuals hospitalized in ward beds who progressed to cure, and the "severe" group (N = 325), composed of individuals who required hospitalization in an intensive care unit (ICU), or who died. Blood samples were genotyped for ACE I/D polymorphism and ACE2 G8790A polymorphism by real-time PCR via TaqMan assay. The analysis of combined polymorphisms revealed a protective role for genotypic profile II/A_ (ORA = 0,26; p = 0,037) against the worsening of COVID-19 in women. The results indicate a protection profile to COVID-19 progression, in which the II/A_ carriers have almost four times less chance of a severe outcome. It is proposed that a decreased activity of ACE (deleterious effects) in conjunction with an increased ACE2 activity (protective effects), should be the underlying mechanism. The findings are unprecedented once other studies have not explored the genotypic combination analysis for ACE and ACE2 polymorphisms and bring perspectives and expectations for dealing with the COVID-19 pandemic based on definitions of genetically-based risk groups within the context of personalized medicine.

Safety of Endoscopy Units during the COVID-19 Pandemic.

Introduction: The COVID-19 pandemic drastically changed the daily routine of all healthcare systems worldwide, and endoscopy units were no exception. Endoscopic exams were considered to have a high risk of transmission, and therefore, the safety of endoscopy units and the consequent need for pre-endoscopy SARS-CoV-2 screening were questioned early on. The aim of our study was to assess the safety of endoscopy units during the COVID-19 pandemic, as well as the effectiveness/necessity for SARS-CoV-2 screening prior to endoscopies. Material and Methods: This is a retrospective and single-center study carried out in a Portuguese tertiary hospital. All patients who underwent endoscopic procedures between September 1, 2020 and February 28, 2021 were included. The pre-endoscopy screening consisted of a specific questionnaire or a RT-PCR test for SARS-CoV-2 (nasal and oropharyngeal swab). Data were obtained through patient's clinical records and the Trace COVID platform. Results: A total of 2,166 patients were included. Patients had a mean age of 61.8 years and were predominantly male (56.2%, n = 1,218). Eighty-one (3.7%) patients had previous SARS-CoV-2 infection, with a median difference of 74 days (IQ 40.5:160.5) between infection and endoscopy. Most patients (70.2%, n = 1,521) underwent PCR screening for SARS-CoV-2 up to 72 h before the procedure, with the remaining patients (29.8%, n = 645) answering a questionnaire of symptoms and risk contacts up to 3 days before endoscopy. Of the patients who underwent RT-PCR screening for SARS-CoV-2, 21 (1.4%) tested positive, and all were asymptomatic at the time of the screening. The evaluation for SARS-CoV-2 infection up to 14 days after the endoscopic exams identified 9 positive patients (0.42%) for SARS-CoV-2. The median difference in days between endoscopy and the diagnosis of infection was 10 days. Discussion/Conclusion: Pre-endoscopy screening with RT-PCR test for SARS-CoV-2 identified a very small number of patients with COVID-19 infection as well as patients with COVID-19 infection in the following 14 days. Therefore, the risk of infection in endoscopy units is negligible if screening of symptoms and risk contacts is applied and individual protective equipment is used.

Introdução: A pandemia COVID-19 mudou drasticamente o dia-a-dia de todos os sistemas de saúde a nível mundial e as unidades de endoscopia não foram exceção. Os exames endoscópicos foram considerados exames com alto risco de transmissão pelo que desde cedo se questionou a segurança das unidades de endoscopia e a consequente necessidade de rastreio SARS-CoV-2 pré-endoscopia. O objetivo do estudo foi avaliar a segurança das unidades de endoscopia durante a pandemia por COVID-19 bem como a eficácia/necessidade de rastreio SARS-CoV-2 prévio aos exames endoscópicos. Material e métodos: Foi desenvolvido um estudo retrospetivo e unicêntrico, no qual todos os doentes submetidos a exames endoscópicos entre 1 de setembro de 2020 e 28 de fevereiro de 2021 foram incluídos. Como estratégia de rastreio pré endoscopia foram aplicados questionários específicos de sintomas e contactos de risco, ou teste PCR de SARS-CoV-2 (zaragatoa nasal e orofaríngea). Os dados clínicos foram obtidos através do processo clínico do doente e da plataforma Trace COVID-19. Resultados: Foram incluídos um total de 2,166 doentes submetidos a exames endoscópicos durante o período de estudo. Os doentes incluídos apresentaram uma média de idades de 61.8 anos e eram maioritariamente do sexo masculino (56.2%, n = 1,218). 3.7% (n = 81) dos doentes já tinha tido infeção por COVID-19 no passado, sendo a mediana da diferença de dias entre a infeção e a data do exame de 74 dias. A maioria dos doentes (70.2%, n = 1,521) foi submetido a rastreio por PCR de SARS-CoV-2 até 72 horas antes do procedimento, sendo os restantes doentes (29.8%, n = 645) submetidos a um questionário de sintomas e contactos de risco realizado até 3 dias antes do procedimento. Dos doentes que realizaram rastreio por PCR de SARS-CoV-2, 21 (1.4%) apresentaram teste positivo, estando todos assintomáticos à data do teste. Aquando da verificação de infeção por SARS-CoV-2 até 14 dias após a realização dos exames endoscópicos apurou-se que apenas 9 doentes (0.42%) testaram positivo para SARS-CoV-2, sendo a mediana da diferença de dias entre a data do exame e o diagnóstico de infeção de 10 dias. Discussão/Conclusão: O rastreio pré-endoscopia com teste PCR de SARS-CoV-2 identificou um número reduzido de doentes infetados com COVID-19 e o número de doentes com infeção por COVID-19, nos 14 dias seguintes aos exames endoscópicos, foi muito baixo. Assim, se aplicado o rastreio de sintomas e contactos de risco, usados os equipamentos de proteção individual adequados, o risco de infeção nas unidades de endoscopia torna-se negligenciável.

Transglutaminase Type 2-MITF axis regulates phenotype switching in skin cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer due to its high heterogeneity that drives tumor aggressiveness. Melanoma plasticity consists of two distinct phenotypic states that co-exist in the tumor niche, the proliferative and the invasive, respectively associated with a high and low expression of MITF, the master regulator of melanocyte lineage. However, despite efforts, melanoma research is still far from exhaustively dissecting this phenomenon. Here, we discovered a key function of Transglutaminase Type-2 (TG2) in regulating melanogenesis by modulating MITF transcription factor expression and its transcriptional activity. Importantly, we demonstrated that TG2 expression affects melanoma invasiveness, highlighting its positive value in SKCM. These results suggest that TG2 may have implications in the regulation of the phenotype switching by promoting melanoma differentiation and impairing its metastatic potential. Our findings offer potential perspectives to unravel melanoma vulnerabilities via tuning intra-tumor heterogeneity.

Postcolonoscopy Colorectal Cancer in a Referral Center for Colorectal Cancer: Prevalence and Risk Factors.

Background and Aims: Colonoscopy is effective to detect and remove colorectal lesions. However, after a negative colonoscopy, cancers could be detected during the interval follow-up. This study was designed to identify characteristics and risk factors for postcolonoscopy colorectal cancer - interval type. Methods: Medical records of individuals who were newly diagnosed with colorectal cancer between January 2018 and December 2019 were reviewed. Clinical, demographic, and endoscopic variables were analyzed. Those with the diagnosis of colorectal cancer between two consecutive colonoscopies performed within the appropriated surveillance range were considered to have postcolonoscopy colorectal cancer - interval type. A comparison between the group of patients with non-postcolonoscopy colorectal cancer - interval type and the group of patients with postcolonoscopy colorectal cancer - interval type was then performed. Results: During the study period, 491 patients were newly diagnosed with colorectal cancer. Among them, 61 (12.4%) had postcolonoscopy colorectal cancer - interval subtype. Postcolonoscopy colorectal cancer - interval type was three times more prevalent on the proximal colon (p = 0.014) and was associated with the presence of two or more cardiovascular risk factors (aOR = 4.25; p = 0.016), cholecystectomy in the past (aOR = 10.09; p = 0.019), and family history of colorectal cancer on a first-degree relative (aOR = 4.25; p = 0.006). Moreover, isolated cardiovascular risk factors revealed a protective effect for the absence of all cardiovascular risk factors (aOR = 20; p = 0.034). The ROC curve associated with the multivariate model revealed a predictive power of 77.8% (p < 0.001). Conclusions: Postcolonoscopy colorectal cancer - interval type is more common in the proximal colon and in patients with a family history (first-degree relative) of colorectal cancer, two or more cardiovascular risk factors, and a history of cholecystectomy. All of these are easily detectable in clinical practice and may be of extreme importance in the control of postcolonoscopy colorectal cancer in the near future.

Introdução: A colonoscopia é eficaz a detetar e remover lesões do colon e reto. Contudo, após uma colonoscopia normal, podem ser detetadas neoplasias durante o intervalo de vigilância recomendado entre colonoscopias. O objetivo do estudo foi identificar características e fatores de risco para o desenvolvimento de cancro colorretal póscolonoscopia ­ subtipo de intervalo. Material e Métodos: Estudo retrospetivo e unicêntrico realizado entre janeiro de 2018 e dezembro de 2019 que incluiu todos os doentes diagnosticados de novo com cancro colorretal. Variáveis clínicas, demográficas e endoscópicas foram obtidas após consulta do processo clínico. Doentes com diagnóstico de cancro colorretal entre duas colonoscopias consecutivas, realizadas no intervalo de vigilância recomendado, foram considerados como tendo cancro colorretal pós-colonoscopia ­ subtipo de intervalo. Foi, então, realizada a comparação entre o grupo de doentes com cancro colorretal não pós colonoscopia ­ subtipo de intervalo e o grupo de doentes com cancro colorretal pós colonoscopia ­ subtipo de intervalo. Resultados: Durante o período de estudo, 491 doentes foram diagnosticados de novo com cancro colorretal. Destes, 61 (12.4%) foram considerados como tendo cancro colorretal pós-colonoscopia ­ subtipo de intervalo. O cancro colorretal pós-colonoscopia ­ subtipo de intervalo foi três vezes mais prevalente no colon proximal (p = 0.014) e associou-se a presença de dois ou mais fatores de risco cardiovasculares (aOR = 0.45; p = 0.016), colecistectomia no passado (aOR = 10.09; p = 0.0.19) e história familiar de cancro colorretal num familiar de primeiro grau (aOR = 4.25; p = 0.006). Aquando da análise dos fatores de risco cardiovasculares isolados, observou- se um fator protetor aquando da ausência de todos os fatores de risco cardiovasculares (aOR = 20; p = 0.034). A curva ROC associada ao modelo multivariado revelou um poder preditivo de 77.8% (p < 0.001). Conclusão: O cancro colorretal pós-colonoscopia ­ subtipo de intervalo é mais comum no colon proximal e em doentes com história familiar (em familiares de primeiro grau) de cancro colorretal, dois ou mais fatores de risco cardio-vasculares e história de colecistectomia. Todos estes fatores de risco são facilmente detetáveis na prática clínica e podem ser de extrema importância no controlo, a curto e longo prazo, do cancro colorretal pós-colonoscopia.

PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.

Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of PITRM1) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists. Methods: We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients' fibroblasts, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis. Results: We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Discussion: Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.

Levelling-up rhodolith-bed science to address global-scale conservation challenges.

Global marine conservation remains fractured by an imbalance in research efforts and policy actions, limiting progression towards sustainability. Rhodolith beds represent a prime example, as they have ecological importance on a global scale, provide a wealth of ecosystem functions and services, including biodiversity provision and potential climate change mitigation, but remain disproportionately understudied, compared to other coastal ecosystems (tropical coral reefs, kelp forests, mangroves, seagrasses). Although rhodolith beds have gained some recognition, as important and sensitive habitats at national/regional levels during the last decade, there is still a notable lack of information and, consequently, specific conservation efforts. We argue that the lack of information about these habitats, and the significant ecosystem services they provide, is hindering the development of effective conservation measures and limiting wider marine conservation success. This is becoming a pressing issue, considering the multiple severe pressures and threats these habitats are exposed to (e.g., pollution, fishing activities, climate change), which may lead to an erosion of their ecological function and ecosystem services. By synthesizing the current knowledge, we provide arguments to highlight the importance and urgency of levelling-up research efforts focused on rhodolith beds, combating rhodolith bed degradation and avoiding the loss of associated biodiversity, thus ensuring the sustainability of future conservation programs.

High-Throughput Microscopy Analysis of Mitochondrial Membrane Potential in 2D and 3D Models.

Recent proteomic, metabolomic, and transcriptomic studies have highlighted a connection between changes in mitochondria physiology and cellular pathophysiological mechanisms. Secondary assays to assess the function of these organelles appear fundamental to validate these -omics findings. Although mitochondrial membrane potential is widely recognized as an indicator of mitochondrial activity, high-content imaging-based approaches coupled to multiparametric to measure it have not been established yet. In this paper, we describe a methodology for the unbiased high-throughput quantification of mitochondrial membrane potential in vitro, which is suitable for 2D to 3D models. We successfully used our method to analyze mitochondrial membrane potential in monolayers of human fibroblasts, neural stem cells, spheroids, and isolated muscle fibers. Moreover, by combining automated image analysis and machine learning, we were able to discriminate melanoma cells from macrophages in co-culture and to analyze the subpopulations separately. Our data demonstrated that our method is a widely applicable strategy for large-scale profiling of mitochondrial activity.

Predicting ß-lactam susceptibility from the genome of Streptococcus pneumoniae and other mitis group streptococci.

Introduction: For Streptococcus pneumoniae, ß-lactam susceptibility can be predicted from the amino acid sequence of the penicillin-binding proteins PBP1a, PBP2b, and PBP2x. The combination of PBP-subtypes provides a PBP-profile, which correlates to a phenotypic minimal inhibitory concentration (MIC). The non-S. pneumoniae Mitis-group streptococci (MGS) have similar PBPs and exchange pbp-alleles with S. pneumoniae. We studied whether a simple BLAST analysis could be used to predict phenotypic susceptibility in Danish S. pneumoniae isolates and in internationally collected MGS. Method: Isolates with available WGS and phenotypic susceptibility data were included. For each isolate, the best matching PBP-profile was identified by BLAST analysis. The corresponding MICs for penicillin and ceftriaxone was retrieved. Category agreement (CA), minor-, major-, and very major discrepancy was calculated. Genotypic-phenotypic accuracy was examined with Deming regression. Results: Among 88 S. pneumoniae isolates, 55 isolates had a recognized PBP-profile, and CA was 100% for penicillin and 98.2% for ceftriaxone. In 33 S. pneumoniae isolates with a new PBP-profile, CA was 90.9% (penicillin) and 93.8% (ceftriaxone) using the nearest recognized PBP-profile. Applying the S. pneumoniae database to non-S. pneumoniae MGS revealed that none had a recognized PBP-profile. For Streptococcus pseudopneumoniae, CA was 100% for penicillin and ceftriaxone in 19 susceptible isolates. In 33 Streptococcus mitis isolates, CA was 75.8% (penicillin) and 86.2% (ceftriaxone) and in 25 Streptococcus oralis isolates CA was 8% (penicillin) and 100% (ceftriaxone). Conclusion: Using a simple BLAST analysis, genotypic susceptibility prediction was accurate in Danish S. pneumoniae isolates, particularly in isolates with recognized PBP-profiles. Susceptibility was poorly predicted in other MGS using the current database.

Comparison among Neuroblastoma Stages Suggests the Involvement of Mitochondria in Tumor Progression.

Neuroblastoma (NB) is the most common extracranial tumor of early childhood and accounts for 15% of all pediatric cancer mortalities. However, the precise pathways and genes underlying its progression are unknown. Therefore, we performed a differential gene expression analysis of neuroblastoma stage 1 and stage 4 + 4S to discover biological processes associated with NB progression. From this preliminary analysis, we found that NB samples (stage 4 + 4S) are characterized by altered expression of some proteins involved in mitochondria function and mitochondria-ER contact sites (MERCS). Although further analyses remain necessary, this review may provide new hints to better understand NB molecular etiopathogenesis, by suggesting that MERCS alterations could be involved in the progression of NB.

The effects of three different low-volume aerobic training protocols on cardiometabolic parameters of type 2 diabetes patients: A randomized clinical trial.

Objective: To compare the effects of different aerobic training protocols on cardiometabolic variables in patients with type 2 diabetes mellitus (T2DM). Methods: This study was a parallel clinical trial. Fifty-two men and women with T2DM (>40 years) were randomly allocated into three groups, and 44 (22 males/22 females) were included in the final analysis. Exercise intensity was based on the speed corresponding to the maximum oxygen consumption (v V ˙ O2max). Moderate intensity continuous training (MICT) involved 14 minutes at 70% of v V ˙ O2max; short interval high-intensity interval training (S-HIIT) consisted of 20 bouts of 30 seconds at 100% of V˙O2max with 30 seconds passive recovery; long interval high-intensity training (L-HIIT) consisted of 5 bouts of 2 minutes at 100% of v V ˙ O2max with 2 minutes passive recovery. Training protocols were performed on a motorized treadmill two times per week for eight weeks. Glycated hemoglobin (Hb1Ac), total cholesterol, triglycerides, resting systolic blood pressure (SBP), resting diastolic blood pressure (DBP), resting heart rate (resting HR) and maximum oxygen consumption (V˙O2max) were measured before and after the exercise intervention. The study was registered on the Brazilian clinical trial records (ID: RBR45 4RJGC3). Results: There was a significant difference between groups for changes on V ˙ O2max. Greater increases on V ˙ O2max were achieved for L-HIIT (p = 0.04) and S-HIIT (p = 0.01) in comparison to MICT group, with no significant difference between L-HIIT and S-HIIT (p = 0.9). Regarding comparison within groups, there were significant reductions on HbA1c and triglycerides levels only for L-HIIT (p< 0.05). V ˙ O2max significantly increased for both L-HIIT (MD = 3.2 ± 1.7 ml/kg/min, p< 0.001) and S-HIIT (MD = 3.4 ± 1.7, p< 0.001). There was a significant reduction on resting SBP for L-HIIT group (MD = -12.07 ± 15.3 mmHg, p< 0.01), but not for S-HIIT and MICT. There were no significant changes from pre- to post-training on fasting glycemia, total cholesterol, HDL, LDL, resting HR and resting DBP for any group (p > 0.05). Conclusion: Low-volume HIIT promoted greater improvements in cardiorespiratory capacity in comparison with low-volume MICT, independent of the protocols used. There were no other differences between groups. All protocols improved at least one of the variables analyzed; however, the most evident benefits were after the high-intensity protocols, especially L-HIIT.

dMyc-dependent upregulation of CD98 amino acid transporters is required for Drosophila brain tumor growth.

Tumor cells have an increased demand for nutrients to sustain their growth, but how these increased metabolic needs are ensured or how this influences tumor formation and progression remains unclear. To unravel tumor metabolic dependencies, particularly from extracellular metabolites, we have analyzed the role of plasma membrane metabolic transporters in Drosophila brain tumors. Using a well-established neural stem cell-derived tumor model, caused by brat knockdown, we have found that 13 plasma membrane metabolic transporters, including amino acid, carbohydrate and monocarboxylate transporters, are upregulated in tumors and are required for tumor growth. We identified CD98hc and several of the light chains with which it can form heterodimeric amino acid transporters, as crucial players in brat RNAi (brat IR) tumor progression. Knockdown of these components of CD98 heterodimers caused a dramatic reduction in tumor growth. Our data also reveal that the oncogene dMyc is required and sufficient for the upregulation of CD98 transporter subunits in these tumors. Furthermore, tumor-upregulated dmyc and CD98 transporters orchestrate the overactivation of the growth-promoting signaling pathway TOR, forming a core growth regulatory network to support brat IR tumor progression. Our findings highlight the important link between oncogenes, metabolism, and signaling pathways in the regulation of tumor growth and allow for a better understanding of the mechanisms necessary for tumor progression.