Nandrolone Abuse Prior to Head Trauma Mitigates Endoplasmic Reticulum Stress, Mitochondrial Bioenergetic Deficits, and Markers of Neurodegeneration.

The abuse of synthetic steroids, such as nandrolone decanoate (ND), is often associated with violent behavior, increasing the risk of traumatic brain injury (TBI). After a TBI, proteins like APP, ß-amyloid peptide-42 (Aß42), and phosphorylated tau (pTau) accumulate and trigger endoplasmic reticulum (ER) stress associated with an unfolded protein response (UPR). The involvement of mitochondrial bioenergetics in this context remains unexplored. We interrogate whether the abuse of ND before TBI alters the responses of ER stress and mitochondrial bioenergetics in connection with neurodegeneration and memory processing in mice. Male CF1 adult mice were administered ND (15 mg/kg) or vehicle (VEH) s.c. for 19 days, coinciding with the peak day of aggressive behavior, and then underwent cortical controlled impact (CCI) or sham surgery. Spatial memory was assessed through the Morris water maze task (MWM) post-TBI. In synaptosome preparations, i) we challenged mitochondrial complexes (I, II, and V) in a respirometry assay, employing metabolic substrates, an uncoupler, and inhibitors; and ii) assessed molecular biomarkers through Western blot. TBI significantly increased APP, Aß42, and pTauSer396 levels, along with ER-stress proteins, GRP78, ATF6, and CHOP, implying it primed apoptotic signaling. Concurrently, TBI reduced mitochondrial Ca2+ efflux in exchange with Na+, disturbed the formation/dissipation of membrane potential, increased H2O2 production, decreased biogenesis (PGC-1⍺ and TOM20), and ATP biosynthesis coupled with oxygen consumption. Unexpectedly, ND abuse before TBI attenuated the elevations in APP, Aß42, and pTauSer396, accompanied by a decrease in GRP78, ATF6, and CHOP levels, and partial normalization of mitochondrial-related endpoints. A principal component analysis revealed a key hierarchical signature featuring mitochondrial Ca2+ efflux, CHOP, GRP78, TOM20, H2O2, and bioenergetic efficiency as a unique variable (PC1) able to explain the memory deficits caused by TBI, as well as the preservation of memory fitness induced by prior ND abuse.

Development and evaluation of the active learning game "Who Am I?-Cellular Signal Transduction Edition": the positive impact on undergraduate education.

The teaching of physiology plays a crucial role in the education of health care professionals. However, traditional approaches to physiology classes in undergraduate health courses in Brazil often result in passive student participation. Research has shown that active methodologies are more effective in the learning process. In this study, we introduce the game "Who Am I?-Cellular Signal Transduction Edition" as an educational tool. This game follows a popular format with well-known rules and aims to enhance understanding of basic concepts related to hormones, cell signaling, and the functioning of the endocrine system. Our findings demonstrate that the game improves student knowledge and fosters enthusiasm and active engagement among participants. Additionally, student feedback has indicated a high level of appreciation for the game. By incorporating active learning strategies and a gamified approach, "Who Am I?-Cellular Signal Transduction Edition" provides a practical and enjoyable way of teaching physiology. This innovative educational tool has the potential to revolutionize physiology instruction. Demonstrating significant improvement in students' understanding, the game underscores its efficacy in enhancing knowledge acquisition and comprehension of cellular signaling and endocrine physiology topics.NEW & NOTEWORTHY We developed "Who Am I?-Cellular Signal Transduction Edition" to assist students in comprehending concepts of cellular signal transduction. This simple and cost-effective tool is perfect for educational settings with limited resources, and it encourages active learning for both small and large groups. Pre- and posttests have shown that it effectively enhances knowledge of hormonal actions and cellular signaling. Positive feedback from students emphasizes its value in reinforcing understanding and improving classroom engagement, making it a promising educational tool.

Nurses' workload during the COVID-19 pandemic: potential for experiences of moral distress.

OBJECTIVES: to understand nurses' experiences of moral distress related to work overload during the COVID-19 pandemic in Brazil. METHODS: qualitative research, whose data collection occurred through individual interviews with 19 nurses who worked on the front line of COVID-19 in health services in southeastern Brazil. Data were analyzed using thematic content analysis. RESULTS: work overload proved to be a powerful source of experiences of moral distress due to excessive working hours during vaccination, double working hours, a troubled relationship due to pressure from managers and the population and physical and mental exhaustion, which prevented nurses from act according to their judgment. FINAL CONSIDERATIONS: nurses' work overload reflects on quality patient care and prevents nurses from acting in accordance with their moral principles, generating moral distress in nurses.

First report of coexistence of blaKPC-2 and blaNDM-1 in carbapenem-resistant clinical isolates of Klebsiella aerogenes in Brazil.

Klebsiella aerogenes is an important opportunistic pathogen with the potential to develop resistance against last-line antibiotics, such as carbapenems, limiting the treatment options. Here, we investigated the antibiotic resistance profiles of 10 K. aerogenes strains isolated from patient samples in the intensive-care unit of a Brazilian tertiary hospital using conventional PCR and a comprehensive genomic characterization of a specific K. aerogenes strain (CRK317) carrying both the blaKPC-2 and blaNDM-1 genes simultaneously. All isolates were completely resistant to ß-lactam antibiotics, including ertapenem, imipenem, and meropenem with differencing levels of resistance to aminoglycosides, quinolones, and tigecycline also observed. Half of the strains studied were classified as multidrug-resistant. The carbapenemase-producing isolates carried many genes of interest including: ß-lactams (blaNDM-1, blaKPC-2, blaTEM-1, blaCTX-M-1 group, blaOXA-1 group and blaSHVvariants in 20-80% of the strains), aminoglycoside resistance genes [aac(6')-Ib and aph(3')-VI, 70 and 80%], a fluoroquinolone resistance gene (qnrS, 80%), a sulfonamide resistance gene (sul-2, 80%) and a multidrug efflux system transporter (mdtK, 70%) while all strains carried the efflux pumps Acr (subunit A) and tolC. Moreover, we performed a comprehensive genomic characterization of a specific K. aerogenes strain (CRK317) carrying both the blaKPC-2 and blaNDM-1 genes simultaneously. The draft genome assembly of the CRK317 had a total length of 5,462,831 bp and a GC content of 54.8%. The chromosome was found to contain many essential genes. In silico analysis identified many genes associated with resistance phenotypes, including ß-lactamases (blaOXA-9, blaTEM-1, blaNDM-1, blaCTX-M-15, blaAmpC-1, blaAmpC-2), the bleomycin resistance gene (bleMBL), an erythromycin resistance methylase (ermC), aminoglycoside-modifying enzymes [aac(6')-Ib, aadA/ant(3")-Ia, aph(3')-VI], a sulfonamide resistance enzyme (sul-2), a chloramphenicol acetyltransferase (catA-like), a plasmid-mediated quinolone resistance protein (qnrS1), a glutathione transferase (fosA), PEtN transferases (eptA, eptB) and a glycosyltransferase (arnT). We also detected 22 genomic islands, eight families of insertion sequences, two putative integrative and conjugative elements with a type IV secretion system, and eight prophage regions. This suggests the significant involvement of these genetic structures in the dissemination of antibiotic resistance. The results of our study show that the emergence of carbapenemase-producing K. aerogenes, co-harboring blaKPC-2 and blaNDM-1, is a worrying phenomenon which highlights the importance of developing strategies to detect, prevent, and control the spread of these microorganisms.

KSRP improves pancreatic beta cell function and survival.

Impaired insulin production and/or secretion by pancreatic beta cells can lead to high blood glucose levels and type 2 diabetes (T2D). Therefore, investigating new proteins involved in beta cell response to stress conditions could be useful in finding new targets for therapeutic approaches. KH-type splicing regulatory protein (KSRP) is a protein usually involved in gene expression due to its role in post-transcriptional regulation. Although there are studies describing the important role of KSRP in tissues closely related to glucose homeostasis, its effect on pancreatic beta cells has not been explored so far. Pancreatic islets from diet-induced obese mice (C57BL/6JUnib) were used to determine KSRP expression and we also performed in vitro experiments exposing INS-1E cells (pancreatic beta cell line) to different stressors (palmitate or cyclopiazonic acid-CPA) to induce cellular dysfunction. Here we show that KSRP expression is reduced in all the beta cell dysfunction models tested. In addition, when manipulated to knock down KSRP, beta cells exhibited increased death and impaired insulin secretion, whereas KSRP overexpression prevented cell death and increased insulin secretion. Taken together, our findings suggest that KSRP could be an important target to protect beta cells from impaired functioning and death.

Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing ß-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

Modelos teóricos do suicídio: uma revisão narrativa / Modelos teóricos del suicidio: una revisión narrativa / Theoretical models of suicide: a narrative review

RESUMO O suicídio é considerado um grave problema de saúde pública mundial. Compreender a sua manifestação é necessário para traçar futuras intervenções. O objetivo desta revisão narrativa da literatura foi apresentar alguns dos modelos teóricos mais recentes e citados sobre o suicídio: Modelo Cognitivo do Atos Suicidas, teoria Interpessoal do Suicídio, Modelo Motivacional-volitivo Integrado de Suicídio e teoria das Três Etapas. Além disso, foram analisadas as variáveis explicativas que os modelos têm em comum e as evidências empíricas que os sustentam. Os modelos indicam relações entre aspectos individuais e contextuais, e se complementam para compreensão do suicídio. De forma geral, aspectos associados à ideação suicida são mais bem estabelecidos na literatura. No entanto, a diferenciação e a transição da ideação suicida para a tentativa de suicídio precisam ser melhor esclarecidas para ajudar a identificar pessoas em risco de vida e formular ações efetivas de prevenção e tratamento. Apesar de ser uma premissa de modelos explicativos, observou-se a ausência de pesquisas longitudinais que auxiliam na predição do suicídio. As variáveis explicativas, sustentadas por evidências empíricas, podem contribuir para qualificar políticas públicas em saúde para enfrentamento do fenômeno.

RESUMEN. El suicidio se considera un grave problema de salud pública en todo el mundo. Es necesario comprender su manifestación para delinear futuras intervenciones. El objetivo de esta revisión narrativa de la literatura fue presentar algunos de los modelos teóricos más recientes mencionados en la literatura sobre el suicidio: Modelo Cognitivo de Actos Suicidas, Teoría Interpersonal del Suicidio, Modelo Integrado Motivacional-Volativo del Suicidio y Teoría de Tres Pasos. Asimismo, analizar qué variables explicativas tienen en común, así como la evidencia empírica que las sustenta. Los modelos indican relaciones entre aspectos individuales y contextuales, y se complementan para entender el suicidio. En general, los aspectos asociados a la ideación suicida se encontraron mejor establecidos en la literatura. Sin embargo, es necesario aclarar mejor la diferenciación y la transición de la ideación suicida al intento de suicidio para ayudar a identificar a las personas en riesgo de vida y formular acciones de prevención y tratamiento eficaces. A pesar de ser una premisa de los modelos explicativos, faltaron investigaciones longitudinales que ayuden a predecir el suicidio. Las variables explicativas, sustentadas en evidencia empírica, pueden contribuir a calificar las políticas de salud pública para enfrentar el fenómeno.

ABSTRACT. Suicide is a serious public health problem worldwide. Understanding its manifestation is important to outline future interventions. This narrative review of the literature aimed to discuss some of the most recent and prominently referenced theoretical models in the literature about suicide: Cognitive Model of Suicidal Acts, Interpersonal Theory of Suicide, Integrated Motivational-Volitional Model of Suicidal Behavior, and Three-Step Theory. Also, we analyzed the explanatory variables the models have in common and the empirical evidence that supports them. The models indicate relationships between individual and contextual aspects and complement each other to understand suicide. While the literature extensively elucidates factors associated with suicidal ideation, the differentiation and transition from ideation to suicide attempts demand further elucidation to help identify people at risk of death and develop effective prevention and treatment actions. Despite being a premise of explanatory models, there was a lack of longitudinal studies that help predict suicide. The explanatory variables, supported by empirical evidence, can contribute to qualifying public health policies to combat the phenomenon.

Nurses' workload during the COVID-19 pandemic: potential for experiences of moral distress / Carga de trabajo de las enfermeras durante la pandemia de COVID-19: potencial para experiencias de sufrimiento moral / Sobrecarga de trabalho de enfermeiros na pandemia de COVID-19: potência para vivências de sofrimento moral

ABSTRACT Objectives: to understand nurses' experiences of moral distress related to work overload during the COVID-19 pandemic in Brazil. Methods: qualitative research, whose data collection occurred through individual interviews with 19 nurses who worked on the front line of COVID-19 in health services in southeastern Brazil. Data were analyzed using thematic content analysis. Results: work overload proved to be a powerful source of experiences of moral distress due to excessive working hours during vaccination, double working hours, a troubled relationship due to pressure from managers and the population and physical and mental exhaustion, which prevented nurses from act according to their judgment. Final Considerations: nurses' work overload reflects on quality patient care and prevents nurses from acting in accordance with their moral principles, generating moral distress in nurses.

RESUMEN Objetivos: comprender las experiencias de angustia moral de los enfermeros relacionadas con la sobrecarga de trabajo durante la pandemia de COVID-19 en Brasil. Métodos: investigación cualitativa, cuya recolección de datos ocurrió a través de entrevistas individuales con 19 enfermeros que actuaron en la primera línea de COVID-19 en servicios de salud de la región Sudeste de Brasil. Los datos fueron analizados mediante análisis de contenido temático. Resultados: la sobrecarga de trabajo resultó ser una poderosa fuente de experiencias de sufrimiento moral por exceso de jornada durante la vacunación, doble jornada laboral, relaciones conflictivas por presiones de los directivos y la población y agotamiento físico y mental, lo que impidió al enfermero actuar según su criterio. Consideraciones Finales: la sobrecarga de trabajo de las enfermeras se refleja en la calidad de la atención al paciente e impide que las enfermeras actúen de acuerdo con sus principios morales, generando sufrimiento moral en las enfermeras.

RESUMO Objetivos: compreender vivências de sofrimento moral de enfermeiros relacionadas à sobrecarga de trabalho durante a pandemia de COVID-19 no Brasil. Métodos: pesquisa qualitativa, cuja coleta de dados ocorreu através de entrevistas individuais com 19 enfermeiros que atuaram na linha de frente da COVID-19 em serviços de saúde da região Sudeste do Brasil. Os dados foram analisados mediante análise temática de conteúdo. Resultados: a sobrecarga de trabalho mostrou-se potente fonte para vivências de sofrimento moral devido à jornada de trabalho excessiva na vacinação, à dupla jornada de trabalho, à relação conturbada por pressão de gestores e população e ao esgotamento físico e mental, os quais impediam o enfermeiro de agir conforme o seu julgamento. Considerações Finais: a sobrecarga de trabalho dos enfermeiros reflete na assistência de qualidade ao paciente, e impede que os enfermeiros atuem conforme os seus princípios morais, gerando sofrimento moral nos enfermeiros.

Perfil medicamentoso e frequência de polifarmácia em idosos de uma Unidade Básica de Saúde / Drug profile and frequency of polypharmacy in elderly people in a Primary Care Unit / Perfil farmacológico y frecuencia de polifarmacia en ancianos en una Unidad Básica de Salud

Objetivo: identificar o perfil medicamentoso e a frequência de polifarmácia em idosos cadastrados e que fazem acompanhamento em uma unidade básica de saúde. Método: estudo observacional e retrospectivo, realizado em uma unidade básica de saúde de um município do Triângulo Mineiro, Minas Gerais. Foi realizada amostragem aleatória e estratificada para coleta de dados de prontuários físicos e eletrônicos de idosos atendidos nos anos de 2019 e 2020, analisados por meio de estatística descritiva. Resultados: entre 448 prontuários foram analisados, porém somente 208 (46,4%) foram válidos. Os medicamentos mais prescritos foram losartana (n=72; 34,6%), sinvastatina (n=60; 28,8%) e metformina (n=51; 24,5%). Observou-se 24,0% de frequência de polifarmácia (n=51), maior frequência de mulheres (n=42; 30,2%) e com significativa associação com diabetes mellitus (p=0,034). Conclusão: a polifarmárcia foi detectada, mais presente nas mulheres, sendo que medicamentos mais utilizados foram relacionados à hipertensão arterial, dislipidemias e diabetes mellitus. Destaca-se a incompletude de informações nos prontuários analisados(AU)

Objective: to identify the medication profile and frequency of polypharmacy in registered elderly people who are followed up at a primary care unit. Method: observational and retrospective study, carried out in a primary care unit in a municipality in Triângulo Mineiro, Minas Gerais. Random and stratified sampling was carried out to collect data from the physical and electronic medical records of the elderly assisted in the years 2019 and 2020, analyzed using descriptive statistics. Results: among 448 medical records analyzed, 208 (46.4%) were considered valid for inclusion in the study. The most prescribed drugs were losartan (n=72; 34.6%), simvastatin (n=60; 28.8%) and metformin (n=51; 24.5%). There was a 24.0% frequency of polypharmacy (n=51), a higher frequency of wome (n=42; 30.2%) and with a significant association with diabetes mellitus (p=0.034). Conclusion: polypharmacy was detected, more present in women, and the most used drugs were related to arterial hypertension, dyslipidemia and diabetes mellitus. The incompleteness of information in the analyzed medical records stands out. Descriptors: Health of the Elderly; Aged; Primary Health Care; Polypharmacy(AU)

Objetivo: identificar el perfil farmacológico y frecuencia de polifarmacia en ancianos registrados en seguimiento en una unidad básica de salud. Método: estudio observacional y retrospectivo, realizado en una unidad básica de salud de un municipio del Triângulo Mineiro, Minas Gerais. Se realizó un muestreo aleatorio y estratificado para recolectar datos de las historias clínicas físicas y electrónicas de los ancianos atendidos en los años 2019 y 2020, analizados mediante estadística descriptiva. Resultados: de 448 historias clínicas analizadas, 208 (46,4%) fueron consideradas válidas para su inclusión en el estudio. Los fármacos más prescritos fueron Losartán (n=72; 34,6%), Simvastatina (n=60; 28,8%) y Metformina (n=51; 24,5%). La frecuencia de polifarmacia estuvo en el 24,0% (n=51), mayor frecuencia de mujeres (n=42; 30,2%) y con asociación significativa con diabetes mellitus (p=0,034). Conclusión: se detectó la polifarmacia, más presente en las mujeres; los fármacos más utilizados estuvieron relacionados con hipertensión arterial, dislipidemia y diabetes mellitus. Se destaca la incompletitud de la información en las historias clínicas analizadas(AU)

Contributory Factors to Caregiver Burden in Parkinson's Disease.

Background: Although there is growing recognition of the relevancy of informal caregivers there is scarce information on the contributory factors of caregiver burden in Parkinson's Disease (PD). Objective: To identify the main associated factors to caregivers' burden in people caring for a person with PD. Methods: We analyzed the data set from a multinational online survey the Parkinson's real-world impact assesSMent (PRISM) focusing on medication use, comorbidities, health-related quality of life, relationship changes and the use of healthcare and supportive care resources by people with PD and their carers. Structured questionnaires including the Parkinson's disease quality of life questionnaire (PDQ-39), non-motor symptoms questionnaire (NMSQuest) and the Questionnaire for impulsive-compulsive disorder in Parkinson's disease (QUIP) were applied. Caregiver burden was assessed by the Zarit Burden Interview (ZBI). Results: In a cohort of 245 dyads (patient and respective caregiver), caregivers reported a mild to moderate burden. Carers' perception of PD impact in partnership, financial burden, hours of care, patient's age, hypersexuality and health-related quality of life (HRQoL) were found to be significant contributory factors to caregiver burden. Taken together these variables explained 66.8% of the variance in the Interpretation of the ZBI total score. Conclusions: Caring for a person with PD entails substantial burden, particularly when the caregiver perceives greater changes in partnership dynamics, dedicates more time to caregiving tasks, has financial burden, and when the patient is older, reports worst HRQoL and has sexual compulsive urges.

Multigenerational effects of co-exposure to dimethylarsinic acid and polystyrene microplastics on the nematode Caenorhabditis elegans.

In the current study, we assessed the impact of DMA (dimethylarsinic acid) and MPs (microplastics) interactions in C. elegans over the course of five generations. We found that the redox state of the organisms changed over generations as a result of exposure to both pollutants. From the third generation onward, exposure to MPs reduced GST activity, indicating reduced detoxifying abilities of these organisms. Additionally, dimethylarsinic exposure decreased the growth of organisms in the second, fourth, and fifth generations. In comparison to isolated pollutants, the cumulative effects of co-exposure to DMA and MPs seem to have been more harmful to the organisms, as demonstrated by correlation analysis. These findings demonstrate that DMA, despite being considered less hazardous than its inorganic equivalents, can still have toxic effects on species at low concentrations and the presence of MPs, can worsen these effects.

Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study.

Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years' worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness.

Butyrate restores the fat/lean mass ratio balance and energy metabolism and reinforces the tight junction-mediated intestinal epithelial barrier in prediabetic mice independently of its anti-inflammatory and epigenetic actions.

Tissue/cellular actions of butyrate on energy metabolism and intestinal barrier in normal metabolic conditions or prediabetes are still unclear. In this work, we investigated the beneficial effect of dietary supplementation with sodium butyrate on energy metabolism, body mass composition, and intestinal epithelial barrier mediated by tight junction (TJ) in chow diet-fed normal and high-fat diet (HF)-fed prediabetic mice, considering the well-known butyrate action as an epigenetic and inflammatory regulator. Butyrate significantly reduced the fat/lean mass ratio, slightly ameliorated dyslipidemia, restored oral glucose tolerance, and increased basal energy expenditure in prediabetic HF-fed mice but had no effect on control animals. Such effects were observed in the absence of significant alterations in the hypothalamic expression of orexigenic and anorexigenic genes and motor activity. Also, butyrate suppressed the whitening effect of HF on brown adipose tissue but did not affect cell bioenergetics in immortalized UCP1-positive adipocytes in vitro. Butyrate reinforced the intestinal epithelial barrier in HF-fed mice and in Caco-2 monolayers, which involved higher trafficking of TJ proteins to the cell-cell contact region of the intestinal epithelia, without affecting TJ gene expression or the acetylation level of histones H3 and H4 in vivo. All metabolic and intestinal effects of butyrate in prediabetic mice occurred in the absence of detectable changes in systemic or local inflammation, or alterations in endotoxemia markers. Butyrate has no effect on chow diet-fed mice but, in the context of HF-induced prediabetes, it prevents metabolic and intestinal dysfunctions independently of its anti-inflammatory and epigenetic actions.

Biochemical and physiological effects of multigenerational exposure to spheric polystyrene microplastics in Caenorhabditis elegans.

Although studies have already shown the effects of exposure to microplastics (MP) in different species, the effects over generations in these individuals remain poorly understood. Therefore, the present study aimed to evaluate the effect of polystyrene MP (spherical, 1 µm) on the responses of the free-living nematode Caenorhabditis elegans in a multigenerational approach over five subsequent generations. MP concentrations of both 5 and 50 µg/L induced a detoxification response, increasing glutathione S-transferase (GST) activity and inducing the generation of reactive oxygen species (ROS) and lipid peroxidation (TBARS). MP also demonstrated the ability to accumulate in the animal's body during the 96 h of each generational exposure, and possibly, this constant interaction was the main reason for the decreased response in physiological parameters as in the exploratory behavior (body bending) of nematodes, and in the reproduction, being this last parameter most negatively affected during the five exposed generations, with a reduction of almost 50% in the last generation. These results emphasize the importance of multigenerational approaches, highlighting their advantage in the assessment of environmental contaminants.

Optical switching a photon-avalanche-like mechanism in NdAl3(BO3)4 particles excited at 1064 nm by an auxiliary beam at 808 nm.

In recent years, an unconventional excitation of trivalent neodymium ions (N d 3+) at 1064 nm, not resonant with ground-state transitions, has been investigated with the unprecedented demonstration of a photon-avalanche-like (PA-like) mechanism, in which the temperature increase plays a fundamental role. As a proof-of-concept, N d A l 3(B O 3)4 particles were used. A consequence of the PA-like mechanism is the absorption enhancement of excitation photons providing light emission at a broad range covering the visible and near-infrared spectra. In the first study, the temperature increase was due to intrinsic nonradiative relaxations from the N d 3+ and the PA-like mechanism ensued at a given excitation power threshold (P t h ). Subsequently, an external heating source was used to trigger the PA-like mechanism while keeping the excitation power below P t h at room temperature. Here, we demonstrate the switching on of the PA-like mechanism by an auxiliary beam at 808 nm, which is in resonance with the N d 3+ ground-state transition 4 I 9/2→{4 F 5/2,2 H 9/2}. It comprises the first, to the best of our knowledge, demonstration of an optical switched PA, and the underlying physical mechanism is the additional heating of the particles due to the phonon emissions from the N d 3+ relaxation pathways when exciting at 808 nm. The present results have potential applications in controlled heating and remote temperature sensing.

Brevundimonas brasiliensis sp. nov.: a New Multidrug-Resistant Species Isolated from a Patient in Brazil.

To increase knowledge on Brevundimonas pathogens, we conducted in-depth genomic and phenotypic characterization of a Brevundimonas strain isolated from the cerebrospinal fluid of a patient admitted in a neonatal intensive care unit. The strain was identified as a member of the genus Brevundimonas based on Vitek 2 system results and 16S rRNA gene sequencing and presented a multidrug resistance profile (MDR). Several molecular and biochemical tests were used to characterize and identify the species for in-depth results. The draft genome assembly of the isolate has a total length of 3,261,074 bp and a G+C of 66.86%, similar to other species of the genus. Multilocus sequence analysis, Type (Strain) Genome Server, digital DNA-DNA hybridization, and average nucleotide identity confirmed that the Brevundimonas sp. studied represents a distinct species, for which we propose the name Brevundimonas brasiliensis sp. nov. In silico analysis detected antimicrobial resistance genes (AMRGs) mediating resistance to ß-lactams (penP, blaTEM-16, and blaBKC-1) and aminoglycosides [strA, strB, aac(6')-Ib, and aac(6')-Il]. We also found AMRGs encoding the AcrAB efflux pump that confers resistance to a broad spectrum of antibiotics. Colistin and quinolone resistance can be attributed to mutation in qseC and/or phoP and GyrA/GyrB, respectively. The Brevundimonas brasiliensis sp. nov. genome contained copies of type IV secretion system (T4SS)-type integrative and conjugative elements (ICEs); integrative mobilizable elements (IME); and Tn3-type and IS3, IS6, IS5, and IS1380 families, suggesting an important role in the development and dissemination of antibiotic resistance. The isolate presented a range of virulence-associated genes related to biofilm formation, adhesion, and invasion that can be relevant for its pathogenicity. Our findings provide a wealth of data to hinder the transmission of MDR Brevundimonas and highlight the need for monitoring and identifying new bacterial species in hospital environments. IMPORTANCE Brevundimonas species is considered an opportunistic human pathogen that can cause multiple types of invasive and severe infections in patients with underlying pathologies. Treatment of these pathogens has become a major challenge because many isolates are resistant to most antibiotics used in clinical practice. Furthermore, there are no consistent therapeutic results demonstrating the efficacy of antibacterial agents. Although considered a rare pathogen, recent studies have provided evidence of the emergence of Brevundimonas in clinical settings. Hence, we identified a novel pathogenic bacterium, Brevundimonas brasiliensis sp. nov., that presented a multidrug resistance (MDR) profile and carried diverse genes related to drug resistance, virulence, and mobile genetic elements. Such data can serve as a baseline for understanding the genomic diversity, adaptation, evolution, and pathogenicity of MDR Brevundimonas.

Predicting factors of neurodevelopmental performance in children with phenylketonuria.

In phenylketonuria (PKU), high phenylalanine (Phe) levels hamper neurodevelopment impairing executive function later in life. While the second has been more studied, fewer data exist on predictors of PKU patients' development in specific populations. To contribute to the field, we performed a retrospective analysis of predictors of neurodevelopment in PKU patients in a Portuguese cohort. We analyzed the retrospective data on the metabolic control of 89 patients, as their health and familial features. Griffith's Mental Development Scale performance at age 6 (GMDS6) was used to assess neurodevelopment. Our cohort included 14 GMDS6low and 75 GMDS6high patients. In a multivariate analysis, the better predictors of neurodevelopment were the metabolic control at age 3 and year of birth (n = 87, ß0  = -121, ß1  = -1.77, ß2  = 0.06, LRchi2(2) = 13.61, Prob > chi2 = 0.001, Pseudo R2 = 0.1773). With this model, it was possible to define a safety cut-off of 7.8 mg/dL for the Phe level at age 3 (sensitivity = 72.6%, specificity = 78.6%), confirming the safety of the cut-off of 6 mg/dL already used in the clinical practice. Our study supports the relevance of metabolic control to predict the neurodevelopment of PKU patients, in the historical context of the disease management.

An Early and Sustained Inflammatory State Induces Muscle Changes and Establishes Obesogenic Characteristics in Wistar Rats Exposed to the MSG-Induced Obesity Model.

The model of obesity induced by monosodium glutamate cytotoxicity on the hypothalamic nuclei is widely used in the literature. However, MSG promotes persistent muscle changes and there is a significant lack of studies that seek to elucidate the mechanisms by which damage refractory to reversal is established. This study aimed to investigate the early and chronic effects of MSG induction of obesity upon systemic and muscular parameters of Wistar rats. The animals were exposed to MSG subcutaneously (4 mg·g-1 b.w.) or saline (1.25 mg·g-1 b.w.) daily from PND01 to PND05 (n = 24). Afterwards, in PND15, 12 animals were euthanized to determine the plasma and inflammatory profile and to assess muscle damage. In PND142, the remaining animals were euthanized, and samples for histological and biochemical analyses were obtained. Our results suggest that early exposure to MSG reduced growth, increased adiposity, and inducted hyperinsulinemia and a pro-inflammatory scenario. In adulthood, the following were observed: peripheral insulin resistance, increased fibrosis, oxidative distress, and a reduction in muscle mass, oxidative capacity, and neuromuscular junctions, increased fibrosis, and oxidative distress. Thus, we can conclude that the condition found in adult life and the difficulty restoring in the muscle profile is related to the metabolic damage established early on.

Sleeve Gastrectomy-Induced Weight Loss Increases Insulin Clearance in Obese Mice.

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose-insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.

Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes.

We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well-known syndromes: Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.993, χ2 test), but mostly outside the functional domains (p = 0.004; χ2 test). Statistical analyses did not show a correlation between the MED12-related phenotypes and the locations of the variants (p = 0.295; Pearson correlation), nor the protein domain involved (p = 0.422; Pearson correlation). In conclusion, establishing a genotype-phenotype correlation in MED12-related diseases remains challenging. Therefore, we think that patients with a causative MED12 variant are currently underdiagnosed due to the broad patients' clinical presentations.