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The centrosome is the primary microtubule organizing center of the cells and templates the formation of cilia, thereby operating at a nexus of critical cellular functions. Here, we use proximity-dependent biotinylation (BioID) to map the centrosome-cilium interface; with 58 bait proteins we generate a protein topology network comprising >7,000 interactions. Analysis of interaction profiles coupled with high resolution phenotypic profiling implicates a number of protein modules in centriole duplication, ciliogenesis, and centriolar satellite biogenesis and highlights extensive interplay between these processes. By monitoring dynamic changes in the centrosome-cilium protein interaction landscape during ciliogenesis, we also identify satellite proteins that support cilia formation. Systematic profiling of proximity interactions combined with functional analysis thus provides a rich resource for better understanding human centrosome and cilia biology. Similar strategies may be applied to other complex biological structures or pathways.
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Centrossomo/metabolismo , Cílios/metabolismo , Mapas de Interação de Proteínas , Biotinilação , Ciclo Celular , Humanos , Centro Organizador dos Microtúbulos/metabolismoRESUMO
Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial. Upon consumption, nitrate can undergo sequential reduction reactions in vivo to produce nitric oxide (â¢NO), a ubiquitous paracrine messenger that supports multiple physiological events such as vasodilation and neuromodulation. In the brain, â¢NO plays a key role in neurovascular coupling, a fine process associated with the dynamic regulation of cerebral blood flow matching the metabolic needs of neurons and crucial for sustaining brain function. Neurovascular coupling dysregulation has been associated with neurodegeneration and cognitive dysfunction during different pathological conditions and aging. We discuss the potential biological action of nitrate on brain health, concerning the molecular mechanisms underpinning this association, particularly via modulation of â¢NO-dependent neurovascular coupling. The impact of nitrate supplementation on cognitive performance was scrutinized through preclinical and clinical data, suggesting that intervention length and the health condition of the participants are determinants of the outcome. Also, it stresses the need for multimodal quantitative studies relating cellular and mechanistic approaches to function coupled with behavior clinical outputs to understand whether a mechanistic relationship between dietary nitrate and cognitive health is operative in the brain. If proven, it supports the exciting hypothesis of cognitive enhancement via diet.
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Acoplamento Neurovascular , Humanos , Acoplamento Neurovascular/fisiologia , Nitratos/farmacologia , Óxido Nítrico/metabolismo , Suplementos Nutricionais , CogniçãoRESUMO
After the Zika virus (ZIKV) epidemic in Brazil, ZIKV infections were linked to damage to the central nervous system (CNS) and congenital anomalies. Due to the virus's ability to cross the placenta and reach brain tissue, its effects become severe, leading to Congenital Zika Syndrome (CZS) and resulting in neuroinflammation, microglial activation, and secretion of neurotoxic factors. The presence of ZIKV triggers an inadequate fetal immune response, as the fetus only has the protection of maternal antibodies of the Immunoglobulin G (IgG) class, which are the only antibodies capable of crossing the placenta. Because of limited understanding regarding the long term consequences of ZIKV infection and the involvement of maternal antibodies, this study sought to assess the impact of the ZIKV + IgGâºcomplex on murine microglial cells. The cells were exposed to ZIKV, IgG antibodies, and the ZIKV + IgGâºcomplex for 24 and 72 h. Treatment-induced cytotoxic effects were evaluated using the cell viability assay, oxidative stress, and mitochondrial membrane potential. The findings indicated that IgG antibodies exhibit cytotoxic effects on microglia, whether alone or in the presence of ZIKV, leading to compromised cell viability, disrupted mitochondrial membrane potential, and heightened oxidative damage. Our conclusion is that IgG antibodies exert detrimental effects on microglia, triggering their activation and potentially disrupting the creation of a neurotoxic environment. Moreover, the presence of antibodies may correlate with an elevated risk of ZIKV-induced neuroinflammation, contributing to long-term CNS damage.
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STUDY QUESTION: Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations? SUMMARY ANSWER: Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades. WHAT IS KNOWN ALREADY: The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci. However, little is known about the specific role of non-genetic factors and their influence on the genetic determinants in this type of conditions. STUDY DESIGN, SIZE, DURATION: Case-control genetic association analyses were performed including a total of 912 SPGF cases and 1360 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants had European ancestry (Iberian and German). SPGF cases were diagnosed during the last decade either with idiopathic non-obstructive azoospermia (n = 547) or with idiopathic non-obstructive oligozoospermia (n = 365). Case-control genetic association analyses were performed by logistic regression models considering the generation as a covariate and by in silico functional characterization of the susceptibility genomic regions. MAIN RESULTS AND THE ROLE OF CHANCE: This analysis revealed 13 novel genetic association signals with SPGF, with eight of them being independent. The observed associations were mostly explained by the interaction between each lead variant and the age-group. Additionally, we established links between these loci and diverse non-genetic factors, such as toxic or dietary habits, respiratory disorders, and autoimmune diseases, which might potentially influence the genetic architecture of idiopathic SPGF. LARGE SCALE DATA: GWAS data are available from the authors upon reasonable request. LIMITATIONS, REASONS FOR CAUTION: Additional independent studies involving large cohorts in ethnically diverse populations are warranted to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Overall, this study proposes an innovative strategy to achieve a more precise understanding of conditions such as SPGF by considering the interactions between a variable exposome through different generations and genetic predisposition to complex diseases. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the "Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)" (ref. PY20_00212, P20_00583), the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. PID2020-120157RB-I00 funded by MCIN/ AEI/10.13039/501100011033), and the 'Proyectos I+D+i del Programa Operativo FEDER 2020' (ref. B-CTS-584-UGR20). ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, is also partially supported by the Portuguese Foundation for Science and Technology (Projects: UIDB/00009/2020; UIDP/00009/2020). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
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Azoospermia , Oligospermia , Masculino , Humanos , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Azoospermia/genética , Oligospermia/genética , Exposição AmbientalRESUMO
Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine derivatives able to discriminate between live and dead cells. To our knowledge, these compounds are the first fluorescent nucleobase analogues (FNAs) with cell viability monitoring potential. These new fluorescent molecules are synthesized using highly efficient and cost-effective methods and feature unprecedented photophysical properties (longer absorption and emission wavelengths, environment-sensitive emission, and unprecedented brightness within FNAs). Using a live-dead Saccharomyces cerevisiae cell and theoretical assays, the fluorescent 2,4,5-triaminopyrimidine derivatives were found to specifically accumulate inside dead cells by interacting with dsDNA grooves, thus paving the way for the emergence of novel and safe fluorescent cell viability markers emitting in the blue region. As the majority of commercially available viability dyes emit in the green to red region of the visible spectrum, these novel markers might be useful to meet the needs of blue markers for co-staining combinations.
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Corantes Fluorescentes , Microscopia , Sobrevivência CelularRESUMO
INTRODUCTION: An ideal orthodontic treatment involves qualitative and quantitative measurements of dental and skeletal components to evaluate patients' discrepancies, such as facial, occlusal, and functional characteristics. Deciding between orthodontics and orthognathic surgery remains challenging, especially in borderline patients. Advances in technology are aiding clinical decisions in orthodontics. The increasing availability of data and the era of big data enable the use of artificial intelligence to guide clinicians' diagnoses. This study aims to test the capacity of different machine learning (ML) models to predict whether orthognathic surgery or orthodontics treatment is required, using soft and hard tissue cephalometric values. METHODS: A total of 920 lateral radiographs from patients previously treated with either conventional orthodontics or in combination with orthognathic surgery were used, comprising n = 558 Class II and n = 362 Class III patients, respectively. Thirty-two measures were obtained from each cephalogram at the initial appointment. The subjects were randomly divided into training (n = 552), validation (n = 183), and test (n = 185) datasets, both as an entire sample and divided into Class II and Class III sub-groups. The extracted data were evaluated using 10 machine learning models and by a four-expert panel consisting of orthodontists (n = 2) and surgeons (n = 2). RESULTS: The combined prediction of 10 models showed top-ranked performance in the testing dataset for accuracy, F1-score, and AUC (entire sample: 0.707, 0.706, 0.791; Class II: 0.759, 0.758, 0.824; Class III: 0.822, 0.807, 0.89). CONCLUSIONS: The proposed combined 10 ML approach model accurately predicted the need for orthognathic surgery, showing better performance in Class III patients.
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In March 2024, the first ever human case of rabies, following a dog bite, was detected in Timor-Leste. This paper briefly discusses the circumstances of transmission, clinical presentation, palliative care of the case and public health measures taken. Timor-Leste was previously considered rabies-free. Any person who is bitten or scratched by an animal that could potentially transmit rabies virus (especially dogs, bats, monkeys or cats) in Timor-Leste should be assessed for consideration of provision of rabies post-exposure prophylaxis.
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Mordeduras e Picadas , Profilaxia Pós-Exposição , Vírus da Raiva , Raiva , Animais , Gatos , Cães , Feminino , Humanos , Mordeduras e Picadas/virologia , Quirópteros/virologia , Raiva/diagnóstico , Raiva/veterinária , Raiva/transmissão , Vacina Antirrábica/administração & dosagem , Vírus da Raiva/isolamento & purificação , Timor-Leste/epidemiologia , AdolescenteRESUMO
Rasmussen's encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.
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Encefalite , Humanos , Encefalite/genética , Encefalite/patologia , Encefalite/metabolismo , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/metabolismo , Feminino , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Ciclo Celular/genéticaRESUMO
It has been widely established that the characterization of extracellular vesicles (EVs), particularly small EVs (sEVs), shed by different cell types into biofluids, helps to identify biomarkers and therapeutic targets in neurological and neurodegenerative diseases. Recent studies are also exploring the efficacy of mesenchymal stem cell-derived extracellular vesicles naturally enriched with therapeutic microRNAs and proteins for treating various diseases. In addition, EVs released by various neural cells play a crucial function in the modulation of signal transmission in the brain in physiological conditions. However, in pathological conditions, such EVs can facilitate the spread of pathological proteins from one brain region to the other. On the other hand, the analysis of EVs in biofluids can identify sensitive biomarkers for diagnosis, prognosis, and disease progression. This review discusses the potential therapeutic use of stem cell-derived EVs in several central nervous system diseases. It lists their differences and similarities and confers various studies exploring EVs as biomarkers. Further advances in EV research in the coming years will likely lead to the routine use of EVs in therapeutic settings.
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Biomarcadores , Doenças do Sistema Nervoso Central , Vesículas Extracelulares , Humanos , Vesículas Extracelulares/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/terapia , Doenças do Sistema Nervoso Central/diagnóstico , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Mesenquimais/metabolismo , Doenças Neurodegenerativas/terapia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/diagnósticoRESUMO
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has posed unprecedented challenges to global health systems, particularly among vulnerable populations such as the elderly. Understanding the interplay between anthropometric markers, molecular profiles, and disease severity is crucial for effective clinical management and intervention strategies. We conducted a cohort study comprising 43 elderly COVID-19 patients admitted to São Lucas Hospital, PUCRS, Brazil. Anthropometric measurements, including calf circumference (CC) and abdominal circumference (AC), were assessed alongside molecular analyses of peripheral blood samples obtained within 48 h of hospital admission. Sociodemographic data were collected from electronic medical records for comprehensive analysis. Our findings revealed a possible relationship between overweight status, increased abdominal adiposity, and prolonged hospitalization duration, alongside heightened disease severity. We also found no significant correlations between BMI, vitamin D levels, and clinical outcomes. Elevated oxygen requirements were observed in both normal and overweight individuals, with the latter necessitating prolonged oxygen therapy. Molecular analyses revealed changes in the inflammatory profile regarding the outcome of the patients. Our study highlights the critical importance of both anthropometric and molecular markers in predicting disease severity and clinical outcomes in elderly individuals with COVID-19.
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Biomarcadores , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/sangue , Idoso , Masculino , Feminino , Biomarcadores/sangue , Idoso de 80 Anos ou mais , Índice de Gravidade de Doença , Inflamação/sangue , Estado Nutricional , Brasil/epidemiologia , Estudos de Coortes , Índice de Massa Corporal , Sobrepeso/sangueRESUMO
INTRODUCTION: Skeletal stability after bimaxillary surgical correction of Class III malocclusion was investigated through a qualitative and quantitative analysis of the maxilla and the distal and proximal mandibular segments using a 3-dimensional voxel-based superimposition among virtual surgical predictions performed by the orthodontist in close communication with the maxillofacial surgeon and 12-18 months postoperative outcomes. METHODS: A comprehensive secondary data analysis was conducted on deidentified preoperative (1 month before surgery [T1]) and 12-18 months postoperative (midterm [T2]) cone-beam computed tomography scans, along with virtual surgical planning (VSP) data obtained by Dolphin Imaging software. The sample for the study consisted of 17 patients (mean age, 24.8 ± 3.5 years). Using 3D Slicer software, automated tools based on deep-learning approaches were used for cone-beam computed tomography orientation, registration, bone segmentation, and landmark identification. Colormaps were generated for qualitative analysis, whereas linear and angular differences between the planned (T1-VSP) and observed (T1-T2) outcomes were calculated for quantitative assessments. Statistical analysis was conducted with a significance level of α = 0.05. RESULTS: The midterm surgical outcomes revealed a slight but significantly less maxillary advancement compared with the planned position (mean difference, 1.84 ± 1.50 mm; P = 0.004). The repositioning of the mandibular distal segment was stable, with insignificant differences in linear (T1-VSP, 1.01 ± 3.66 mm; T1-T2, 0.32 ± 4.17 mm) and angular (T1-VSP, 1.53° ± 1.60°; T1-T2, 1.54° ± 1.50°) displacements (P >0.05). The proximal segments exhibited lateral displacement within 1.5° for both the mandibular right and left ramus at T1-VSP and T1-T2 (P >0.05). CONCLUSIONS: The analysis of fully digital planned and surgically repositioned maxilla and mandible revealed excellent precision. In the midterm surgical outcomes of maxillary advancement, a minor deviation from the planned anterior movement was observed.
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Má Oclusão Classe III de Angle , Procedimentos Cirúrgicos Ortognáticos , Humanos , Adulto Jovem , Adulto , Procedimentos Cirúrgicos Ortognáticos/métodos , Má Oclusão Classe III de Angle/diagnóstico por imagem , Má Oclusão Classe III de Angle/cirurgia , Ortodontistas , Imageamento Tridimensional , Mandíbula/diagnóstico por imagem , Mandíbula/cirurgia , Tomografia Computadorizada de Feixe Cônico , Maxila/diagnóstico por imagem , Maxila/cirurgia , CefalometriaRESUMO
OBJECTIVE: Crohn's disease (CD) is heterogeneous, and proximal involvement in the small bowel (SB) is associated with worse outcomes. Nonetheless, studies on the impact of duodenal and jejunal lesions in SB CD are limited. This study aimed to investigate the clinical characteristics and outcomes of individuals diagnosed with SB CD, comparing those with and without proximal inflammation. METHODS: A cohort of 53 treatment-naive SB CD patients that underwent Capsule Endoscopy at diagnosis were retrospectively selected. The inflammatory activity was quantified using the Lewis Score for each SB tertile. RESULTS: Thirty-seven (69.8%) patients displayed inflammatory activity in the first and/or second tertile together with third tertile involvement (Proximal+T3 group). Sixteen (30.2%) had inflammation in the third tertile only (T3 group). Individuals in the Proximal+T3 group had a higher risk for moderate-to-severe inflammation (OR 4.93, 95% CI: 1.3-18.3, p=0.013). A subgroup analysis for those with mild inflammatory activity showed that individuals in the Proximal+T3 group initiated biologic drugs more often (OR 11, 95% CI: 1.1-109.7, p=0.036). CONCLUSION: Proximal SB lesions are associated with increased inflammatory activity, necessitating more frequent use of biologics in patients with mild disease. Early detection of proximal SB CD with Capsule Endoscopy may contribute to timely treatment.
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Centriolar satellites are small electron-dense granules that cluster in the vicinity of centrosomes. Satellites have been implicated in multiple critical cellular functions including centriole duplication, centrosome maturation, and ciliogenesis, but their precise composition and assembly properties have remained poorly explored. Here, we perform in vivo proximity-dependent biotin identification (BioID) on 22 human satellite proteins, to identify 2,113 high-confidence interactions among 660 unique polypeptides. Mining this network, we validate six additional satellite components. Analysis of the satellite interactome, combined with subdiffraction imaging, reveals the existence of multiple unique microscopically resolvable satellite populations that display distinct protein interaction profiles. We further show that loss of satellites in PCM1-depleted cells results in a dramatic change in the satellite interaction landscape. Finally, we demonstrate that satellite composition is largely unaffected by centriole depletion or disruption of microtubules, indicating that satellite assembly is centrosome-independent. Together, our work offers the first systematic spatial and proteomic profiling of human centriolar satellites and paves the way for future studies aimed at better understanding the biogenesis and function(s) of these enigmatic structures.
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Autoantígenos/genética , Proteínas de Ciclo Celular/genética , Centríolos/metabolismo , Proteômica/métodos , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Deleção de Genes , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Mapas de Interação de Proteínas , Espectrometria de Massas em TandemRESUMO
Male infertility affects â¼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.
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Pontos de Checagem do Ciclo Celular/genética , Infertilidade Masculina/genética , Meiose/genética , Mutação/genética , Proteínas/genética , Espermatogênese/genética , Adulto , Alelos , Animais , Azoospermia/genética , Homozigoto , Humanos , Masculino , Camundongos , Fenótipo , Espermatozoides/anormalidades , Testículo/anormalidades , Turquia , Sequenciamento do Exoma/métodosRESUMO
In maritime settings, effective communication between vessels and land infrastructure is crucial, but existing technologies often prove impractical for energy-sensitive IoT applications, like deploying sensors at sea. In this study, we explore the viability of a low-power, cost-effective wireless communication solution for maritime sensing data. Specifically, we conduct an experimental assessment of the Azorean Long Range Wide Area Network (LoRaWAN) coverage. Our tests involve positioning the gateway at the island's highest point and installing end nodes on medium-sized fishing vessels. Through measurements of received signal strength indicator (RSSI), signal-to-noise ratio (SNR), and lines of sight (LOS), we showcase the potential of LoRaWAN transmissions to achieve communication distances exceeding 130 km in a LOS-free scenario over the ocean. These findings highlight the promising capabilities of LoRaWAN for reliable and long-range maritime communication of sensing data.
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This paper demonstrates the generation of broadband emission in the visible and infrared ranges induced by a concentrated beam of infrared radiation from CsPbBr3 ceramics doped with Yb3+ ions. The sample was obtained by the conventional solid-state reaction method, and XRD measurements confirmed the phase purity of the material crystallizing in the orthorhombic system. Spectroscopic measurements required further sample preparation in the form of ceramics using a high-pressure press. The research showed that as the excitation power increases, the emission intensity does not increase linearly from the beginning of the experiment. Irradiation of the material results in the accumulation of the delivered energy. Absorption of a sufficient number of photons triggers avalanche emission. It was found that the most intense luminescence is produced in a vacuum. Changes in conductivity were also observed, where the excitation was able to lower the resistivity of the material and it was highly dependent on the excitation power. The mechanism responsible for the generation of the observed phenomenon involving intervalence charge transfer (IVCT) transitions has been postulated.
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BACKGROUND: Grape agri-food wastes, such as skin, seeds, and other discarded by-products, contain phytochemical compounds that offer potential health benefits. METHODS: This study aimed to investigate the polyphenol composition and bioactivities of different extracts obtained from grape marc and seeds, with the goal of exploring their potential for application as natural food additives. RESULTS: Regardless of the extraction method used (dynamic maceration, ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE)), all extracts exhibited relatively high concentrations of phenolic compounds. The chemical characterization of the extracts revealed the presence of specific compounds and chemical groups associated with each extraction methodology. Moreover, the extracts displayed satisfactory antioxidant activities, especially in inhibiting lipoperoxidation as assessed by the TBARS assay. Additionally, the extracts demonstrated effective inhibition against different strains of bacteria and fungi known as food contaminants. Taken together, these findings indicate that those extracts have the potential to be tested as natural antioxidants and preservatives with sustainable origins in food and beverage systems. Among the extraction methods evaluated, traditional maceration and UAE provided extracts with the highest antioxidant and antimicrobial activities. CONCLUSIONS: Our results suggest the opportunity to explore grape marc and seeds discarded by the winery industry in Portugal as natural sources of bioactive compounds, which could be employed as functional food ingredients or technological additives. The valorization of grape biowastes offers a promising strategy to reduce waste and harness their potential health benefits.
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Eliminação de Resíduos , Vitis , Polifenóis/química , Vitis/química , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem , Extratos Vegetais/química , Sementes/químicaRESUMO
BACKGROUND: The efficacy of mandibular advancement devices (MAD) and maxillomandibular advancement (MMA) in improving upper airway (UA) patency has been described as being comparable to continuous positive airway pressure (CPAP) outcomes. However, no previous study has compared MAD and MMA treatment outcomes for the upper airway enlargement. This study aimed to evaluate three-dimensionally the UA changes and mandibular rotation in patients after MAD compared to MMA. METHODS: The sample consisted of 17 patients with treated with MAD and 17 patients treated with MMA matched by weight, height, body mass index. Cone-beam computed tomography from before and after both treatments were used to measure total UA, superior/inferior oropharynx volume and surface area; and mandibular rotation. RESULTS: Both groups showed a significant increase in the superior oropharynx volume after the treatments (p = 0.003) and the MMA group showed greater increase (p = 0.010). No statistical difference was identified in the MAD group considering the inferior volume, while the MMA group showed a significantly gain (p = 0.010) and greater volume (p = 0.024). Both groups showed anterior mandibular displacement. However, the mandibular rotation were statistically different between the groups (p < 0.001). While the MAD group showed a clockwise rotation pattern (-3.97 ± 1.07 and - 4.08 ± 1.30), the MMA group demonstrated a counterclockwise (2.40 ± 3.43 and 3.41 ± 2.79). In the MAD group, the mandibular linear anterior displacement was correlated with superior [p = 0.002 (r=-0.697)] and inferior [p = 0.004 (r = 0.658)] oropharynx volume, suggesting that greater amounts of mandibular advancement are correlated to a decrease in the superior oropharynx and an increase in the inferior oropharynx. In the MMA group, the superior oropharynx volume was correlated to mandibular anteroposterior [p = 0.029 (r=-0.530)] and vertical displacement [p = 0.047 (r = 0.488)], indicating greater amounts of mandibular advancement may lead to a lowest gain in the superior oropharynx volume, while a great mandibular superior displacement is correlated with improvements in this region. CONCLUSIONS: The MAD therapy led to a clockwise mandibular rotation, increasing the dimensions of the superior oropharynx; while a counterclockwise rotation with greater increases in all UA regions were showed in the MMA treatment.
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Nariz , Placas Oclusais , Humanos , Índice de Massa Corporal , Tomografia Computadorizada de Feixe Cônico , Mandíbula/diagnóstico por imagem , Mandíbula/cirurgiaRESUMO
Vif is a lentiviral accessory protein that counteracts the antiviral activity of cellular APOBEC3 (A3) cytidine deaminases in infected cells. The exact contribution of each member of the A3 family for the restriction of HIV-2 is still unclear. Thus, the aim of this work was to identify the A3s with anti-HIV-2 activity and compare their restriction potential for HIV-2 and HIV-1. We found that A3G is a strong restriction factor of both types of viruses and A3C restricts neither HIV-1 nor HIV-2. Importantly, A3B exhibited potent antiviral activity against HIV-2, but its effect was negligible against HIV-1. Whereas A3B is packaged with similar efficiency into both viruses in the absence of Vif, HIV-2 and HIV-1 differ in their sensitivity to A3B. HIV-2 Vif targets A3B by reducing its cellular levels and inhibiting its packaging into virions, whereas HIV-1 Vif did not evolve to antagonize A3B. Our observations support the hypothesis that during wild-type HIV-1 and HIV-2 infections, both viruses are able to replicate in host cells expressing A3B but using different mechanisms, probably resulting from a Vif functional adaptation over evolutionary time. Our findings provide new insights into the differences between Vif protein and their cellular partners in the two human viruses. Of note, A3B is highly expressed in some cancer cells and may cause deamination-induced mutations in these cancers. Thus, A3B may represent an important therapeutic target. As such, the ability of HIV-2 Vif to induce A3B degradation could be an effective tool for cancer therapy. IMPORTANCE Primate lentiviruses encode a series of accessory genes that facilitate virus adaptation to its host. Among those, the vif-encoded protein functions primarily by targeting the APOBEC3 (A3) family of cytidine deaminases. All lentiviral Vif proteins have the ability to antagonize A3G; however, antagonizing other members of the A3 family is variable. Here, we report that HIV-2 Vif, unlike HIV-1 Vif, can induce degradation of A3B. Consequently, HIV-2 Vif but not HIV-1 Vif can inhibit the packaging of A3B. Interestingly, while A3B is packaged efficiently into the core of both HIV-1 and HIV-2 virions in the absence of Vif, it only affects the infectivity of HIV-2 particles. Thus, HIV-1 and HIV-2 have evolved two distinct mechanisms to antagonize the antiviral activity of A3B. Aside from its antiviral activity, A3B has been associated with mutations in some cancers. Degradation of A3B by HIV-2 Vif may be useful for cancer therapies.
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Citidina Desaminase/metabolismo , Produtos do Gene vif/metabolismo , HIV-1/metabolismo , HIV-2/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Animais , Citidina Desaminase/genética , Células HEK293 , Infecções por HIV , Humanos , Antígenos de Histocompatibilidade Menor/genética , Receptor EphB2RESUMO
OBJECTIVE: Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). METHODS: We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. RESULTS: Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). INTERPRETATION: These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239-252.