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Music is ubiquitous, both in its instrumental and vocal forms. While speech perception at birth has been at the core of an extensive corpus of research, the origins of the ability to discriminate instrumental or vocal melodies is still not well investigated. In previous studies comparing vocal and musical perception, the vocal stimuli were mainly related to speaking, including language, and not to the non-language singing voice. In the present study, to better compare a melodic instrumental line with the voice, we used singing as a comparison stimulus, to reduce the dissimilarities between the two stimuli as much as possible, separating language perception from vocal musical perception. In the present study, 45 newborns were scanned, 10 full-term born infants and 35 preterm infants at term-equivalent age (mean gestational age at test = 40.17 weeks, SD = 0.44) using functional magnetic resonance imaging while listening to five melodies played by a musical instrument (flute) or sung by a female voice. To examine the dynamic task-based effective connectivity, we employed a psychophysiological interaction of co-activation patterns (PPI-CAPs) analysis, using the auditory cortices as seed region, to investigate moment-to-moment changes in task-driven modulation of cortical activity during an fMRI task. Our findings reveal condition-specific, dynamically occurring patterns of co-activation (PPI-CAPs). During the vocal condition, the auditory cortex co-activates with the sensorimotor and salience networks, while during the instrumental condition, it co-activates with the visual cortex and the superior frontal cortex. Our results show that the vocal stimulus elicits sensorimotor aspects of the auditory perception and is processed as a more salient stimulus while the instrumental condition activated higher-order cognitive and visuo-spatial networks. Common neural signatures for both auditory stimuli were found in the precuneus and posterior cingulate gyrus. Finally, this study adds knowledge on the dynamic brain connectivity underlying the newborns capability of early and specialized auditory processing, highlighting the relevance of dynamic approaches to study brain function in newborn populations.
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Percepção Auditiva , Imageamento por Ressonância Magnética , Música , Humanos , Feminino , Masculino , Percepção Auditiva/fisiologia , Recém-Nascido , Canto/fisiologia , Recém-Nascido Prematuro/fisiologia , Mapeamento Encefálico , Estimulação Acústica , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Voz/fisiologiaRESUMO
Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans-cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N-cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells.
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Antimaláricos , Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Estrutura Molecular , Aminoacridinas/farmacologia , Aminoacridinas/química , Aminoacridinas/síntese química , Relação Dose-Resposta a Droga , Cinamatos/farmacologia , Cinamatos/química , Cinamatos/síntese químicaRESUMO
Marine biofouling, caused by the deposition and accumulation of marine organisms on submerged surfaces, represents a huge concern for the maritime industries and also contributes to environmental pollution and health concerns. The most effective way to prevent this phenomenon is the use of biocide-based coatings which have proven to cause serious damage to marine ecosystems. Several research groups have focused on the search for new environmentally friendly antifoulants, including marine and terrestrial natural products and synthetic analogues. Some of these compounds have been incorporated into marine coatings and display interesting antifouling activities caused by the interference with the biofilm-forming species as well as by the inhibition of the settlement of macroorganisms. This review highlights the proof-of-concept studies of emerging natural or synthetic antifouling compounds in coatings, from lab-made to commercial ones, performed between 2019 and 2023 and their results in the field or in in vivo laboratorial tests.
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Organismos Aquáticos , Incrustação Biológica , Produtos Biológicos , Incrustação Biológica/prevenção & controle , Produtos Biológicos/farmacologia , Animais , Biofilmes/efeitos dos fármacos , Desinfetantes/farmacologia , HumanosRESUMO
Marine biofouling is a major concern for the maritime industry, environment, and human health. Biocides which are currently used in marine coatings to prevent this phenomenon are toxic to the marine environment, and therefore a search for antifoulants with environmentally safe properties is needed. A large number of scientific papers have been published showing natural and synthetic compounds with potential to prevent the attachment of macro- and microfouling marine organisms on submerged surfaces. Flavonoids are a class of compounds which are highly present in nature, including in marine organisms, and have been found in a wide range of biological activities. Some natural and synthetic flavonoids have been evaluated over the last few years for their potential to prevent the settlement and/or the growth of marine organisms on submerged structures, thereby preventing marine biofouling. This review compiles, for the first-time, natural flavonoids as well as their synthetic analogues with attributed antifouling activity against macrofouling and microfouling marine organisms.
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Incrustação Biológica , Desinfetantes , Humanos , Incrustação Biológica/prevenção & controle , Organismos Aquáticos , Desinfetantes/farmacologiaRESUMO
Marine biofouling remains a huge concern for maritime industries and for environmental health. Although the current biocide-based antifouling coatings can prevent marine biofouling, their use has been associated with toxicity for the marine environment, being urgent to find sustainable alternatives. Previously, our research group has identified a prenylated chalcone (1) with promising antifouling activity against the settlement of larvae of the macrofouling species Mytilus galloprovincialis (EC50 = 16.48⯵M and LC50 > 200⯵M) and lower ecotoxicity when compared to Econea®, a commercial antifouling agent in use. Herein, a series of chalcone 1 analogues were designed and synthesized in order to obtain optimized antifouling compounds with improved potency while maintaining low ecotoxicity. Compounds 8, 15, 24, and 27 showed promising antifouling activity against the settlement of M. galloprovincialis larvae, being dihydrochalcone 27 the most potent. The effect of compound 24 was associated with the inhibition of acetylcholinesterase activity. Among the synthesized compounds, compound 24 also showed potent complementary activity against Navicula sp. (EC50 = 4.86⯵M), similarly to the lead chalcone 1 (EC50 = 6.75⯵M). Regarding the structure-activity relationship, the overall results demonstrate that the substitution of the chalcone of the lead compound 1 by a dihydrochalcone scaffold resulted in an optimized potency against the settlement of mussel larvae. Marine polyurethane (PU)-based coatings containing the best performed compound concerning anti-settlement activity (dihydrochalcone 27) were prepared, and mussel larvae adherence was reduced compared to control PU coatings.
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Incrustação Biológica , Larva , Mytilus , Animais , Incrustação Biológica/prevenção & controle , Larva/efeitos dos fármacos , Mytilus/efeitos dos fármacos , Chalconas/farmacologia , Chalconas/química , Relação Estrutura-Atividade , Chalcona/farmacologia , Chalcona/análogos & derivados , Chalcona/química , Desinfetantes/toxicidade , Desinfetantes/farmacologiaRESUMO
The pursuit of high-power solar laser systems with high efficiency and capacity for large tracking error compensation is determinant for the applicability of this renewable technology. A side-pumped dual-rod Ce:Nd:YAG solar laser was developed and tested at the focus of a 2 m diameter parabolic concentrator. Maximum continuous-wave total solar laser power of 58 W was measured. To the best of our knowledge, this is the highest laser power from a Ce:NdYAG solar laser. Moreover, wide tracking error compensation width of 5.1° in the azimuthal direction was reached, being 4.25 times higher than the previous measurement without solar tracking assistance.
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Solar laser technology typically requires a highly accurate solar tracking system that operates continuously, which increases energy consumption and reduces the system's lifetime. We propose a multi-rod solar laser pumping approach to enhance solar laser stability under non-continuous solar tracking conditions. Using a heliostat, solar radiation is redirected toward a first-stage parabolic concentrator. At its focus, an aspheric lens further concentrates the solar rays onto five Nd:YAG rods positioned within an elliptical-shaped pump cavity. Numerical analysis using Zemax and LASCAD software showed that the tracking error width at 10% laser power loss for the five 6.5 mm diameter and 15 mm length rods was 2.20°, which is 50% higher than that of the solar laser in previous non-continuous solar tracking experiments. 2.0% solar-to-laser conversion efficiency was also attained.
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OBJECTIVES: The impact of Covid-19 infection on pregnancy and perinatal outcomes is not fully known. To describe the risk factors and perinatal outcome of pregnant women with suspected COVID-19 infection. METHODS: We evaluated medical records of women with suspected or confirmed SARS-CoV-2 infection who received health care services at the University Hospital of São Bernardo do Campo from March 1 to July 31, 2020, and personal, clinical, and laboratory data of these women and their newborns. RESULTS: Of the 219 women identified, 29% were asymptomatic. Considering the total population, 26% and 17% had obesity and hypertensive syndrome, respectively. Fever measured in the emergency room was the main reason for hospitalization. The presence or not of flu-like symptoms did not impact on perinatal outcomes. Pregnant women requiring hospitalization had newborns with lower birth weight (p < 0.01), shorter length (p = 0.02), and smaller head circumference (p = 0.03), and, in these cases, a higher number of cesarean section deliveries was observed. CONCLUSION: COVID-19 infection did not affect the prognosis of pregnancy and newborns. However, the worst clinical outcome, requiring hospitalization, had an impact on the anthropometric measurements of newborns.
What is already known on this subject?The SARS-CoV-2 infection is not fully undestood, specially during pregnancy and puerperae. There are conflicted information about this in the literature so far. However, it is known that respiratory infections such as influenza and SARS can develop unfavorably in pregnant women, since pregnancy changes the women's physiological condition, including altered immunity to tolerate placenta and fetus proper development.What this study adds?COVID-19 did not affect the prognosis of pregnancy and newborns in this study, but, the worst clinical outcome (hospitalization), impacted the anthropometric measurements of newborns.
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COVID-19 , Complicações Infecciosas na Gravidez , Gravidez , Feminino , Recém-Nascido , Humanos , SARS-CoV-2 , COVID-19/epidemiologia , Gestantes , Mães , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/epidemiologia , Cesárea , Brasil/epidemiologia , Hospitais Municipais , Transmissão Vertical de Doenças Infecciosas , Resultado da Gravidez/epidemiologiaRESUMO
BACKGROUND: It has become increasingly important to identify molecular markers for accurately diagnosing prostate cancer (PCa) stages between localized PCa (LPC) and locally advanced PCa (LAPC). However, there is a lack of profiling both epigenome-wide DNA methylation and transcriptome for the same patients with PCa at different stages. This study aims to identify epitranscriptomic biomarkers screened in the peri-prostatic (PP) adipose tissue for predicting LPC and LAPC. METHODS: We profiled gene expression and DNA methylation of 10 PCa patients' PP adipose tissue (4 LPC and 6 LAPC). Differential analysis was used to identify differentially methylated CpG sites and expressed genes. An integrative analysis of the microarray gene expression profiles and DNA methylation profiles was conducted using LASSO (least absolute shrinkage and selection operator) between each studied gene and the CpG sites in their promoter region. This epitranscriptomic signature was constructed by combining the association and differential analyses. The signature was then refined using the genetic mutation data of >1500 primary PCa and metastasis PCa samples from 4 different studies. We determined genes that were the most significantly affected by mutations. Machine learning models were built to evaluate the classification ability of the identified signature using the gene expression profiles from three external cohorts. RESULTS: From the LASSO-based association analysis, we identified 56 genes presenting significant anti-correlation between the expression level and the methylation level of at least one CpG site in the promoter region (p-value<5 × 10-8). From the differential analysis, we detected 16,405 downregulated genes and 9485 genes containing at least one hypermethylated CpG site. We identified 30 genes that showed anti-correlation, down-regulation and hyper-methylation simultaneously. Using genetic mutation data, we determined that 6 of the 30 genes showed significant differences (adjusted p-value<0.05) in mutation frequencies between the primary PCa and metastasis PCa samples. The identified 30 genes performed well in distinguishing PCa patients with metastasis from PCa patient without metastasis (area under the receiver operating characteristic curve (AUC) = 0.81). The gene signature also performed well in distinguishing PCa patients with high risk of progression from PCa patients with low risk of progression (AUC = 0.88). CONCLUSIONS: We established an integrative framework to identify differentially expressed genes with an aberrant methylation pattern on PP adipose tissue that may represent novel candidate molecular markers for distinguishing between LPC and LAPC.
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Metilação de DNA , Neoplasias da Próstata , Biomarcadores/metabolismo , Ilhas de CpG , Epigenoma , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Regiões Promotoras Genéticas , Neoplasias da Próstata/metabolismo , TranscriptomaRESUMO
As one of the most metabolically complex systems in the body, the liver ensures multi-organ homeostasis and ultimately sustains life. Nevertheless, during early postnatal development, the liver is highly immature and takes about 2 years to acquire and develop almost all of its functions. Different events occurring at the environmental and cellular levels are thought to mediate hepatic maturation and function postnatally. The crosstalk between the liver, the gut and its microbiome has been well appreciated in the context of liver disease, but recent evidence suggests that the latter could also be critical for hepatic function under physiological conditions. The gut-liver crosstalk is thought to be mediated by a rich repertoire of microbial metabolites that can participate in a myriad of biological processes in hepatic sinusoids, from energy metabolism to tissue regeneration. Studies on germ-free animals have revealed the gut microbiome as a critical contributor in early hepatic programming, and this influence extends throughout life, mediating liver function and body homeostasis. In this seminar, we describe the microbial molecules that have a known effect on the liver and discuss how the gut microbiome and the liver evolve throughout life. We also provide insights on current and future strategies to target the gut microbiome in the context of hepatology research.
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Microbioma Gastrointestinal/fisiologia , Testes de Função Hepática/estatística & dados numéricos , Fígado/crescimento & desenvolvimento , Homeostase/imunologia , Homeostase/fisiologia , Humanos , Fígado/fisiologia , Testes de Função Hepática/métodosRESUMO
Music is known to induce emotions and activate associated memories, including musical memories. In adults, it is well known that music activates both working memory and limbic networks. We have recently discovered that as early as during the newborn period, familiar music is processed differently from unfamiliar music. The present study evaluates music listening effects at the brain level in newborns, by exploring the impact of familiar or first-time music listening on the subsequent resting-state functional connectivity in the brain. Using a connectome-based framework, we describe resting-state functional connectivity (RS-FC) modulation after music listening in three groups of newborn infants, in preterm infants exposed to music during their neonatal-intensive-care-unit (NICU) stay, in control preterm, and full-term infants. We observed modulation of the RS-FC between brain regions known to be implicated in music and emotions processing, immediately following music listening in all newborn infants. In the music exposed group, we found increased RS-FC between brain regions known to be implicated in familiar and emotionally arousing music and multisensory processing, and therefore implying memory retrieval and associative memory. We demonstrate a positive correlation between the occurrence of the prior music exposure and increased RS-FC in brain regions implicated in multisensory and emotional processing, indicating strong engagement of musical memories; and a negative correlation with the Default Mode Network, indicating disengagement due to the aforementioned cognitive processing. Our results describe the modulatory effect of music listening on brain RS-FC that can be linked to brain correlates of musical memory engrams in preterm infants.
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Tonsila do Cerebelo/fisiologia , Percepção Auditiva/fisiologia , Córtex Cerebral/fisiologia , Conectoma , Rede de Modo Padrão/fisiologia , Emoções/fisiologia , Recém-Nascido Prematuro/fisiologia , Música , Reconhecimento Psicológico/fisiologia , Tálamo/fisiologia , Tonsila do Cerebelo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Rede de Modo Padrão/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Tálamo/diagnóstico por imagemRESUMO
The addition of biocides to marine coatings has been the most used solution to avoid marine biofouling, however they are persistent, bioaccumulative, and toxic (PBT) to marine ecosystems. The development of natural products or Nature-inspired synthetic compounds to replace these harmfull biocides has been pursued as one of the most promising antifouling (AF) alternatives. Following a bioprospection strategy, we have previously reported the AF activity of gallic acid persulfate (1) against the settlement of Mytilus galloprovincialis larvae (EC50 = 18 µM and LC50/EC50 = 27) without exhibiting ecotoxicity to Artemia salina. In this work, a lead optimization strategy was applied to compound 1 in order to improve potency while maintaining a low ecotoxicity profile. In this direction, twenty-seven compounds were synthesized, from which eighteen were obtained for the first time. An AF screening was performed against the settlement of mussel M. galloprovincialis larvae and derivative 26, 2-(3,4,5-trihydroxybenzamido)ethan-1-aminium bromide, was found to be more potent (EC50 = 3 µM and LC50/EC50 = 73) than compound 1 and the biocide Econea® (EC50 = 4 µM). The potential impact on neurotransmission, and ecotoxicity against two non-target marine organisms was also evaluated. Marine polyurethane (PU)-based coatings containing compound 26 were prepared and lower adherence of mussel larvae was observed compared to compound 26 free PU-coatings. Studies concerning the leaching of compound 26 from the prepared coating were also conducted, and < 10% of this compound was detected after 45 days of submersion in water. Overall, we have optimized the potency against the settlement of mussels of our initial lead compound, not compromising the toxicity and compatibility with PU-based coatings.
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Incrustação Biológica , Desinfetantes , Mytilus , Animais , Incrustação Biológica/prevenção & controle , Desinfetantes/farmacologia , Ecossistema , Ácido Gálico/farmacologia , LarvaRESUMO
Prematurity disrupts brain development during a critical period of brain growth and organization and is known to be associated with an increased risk of neurodevelopmental impairments. Investigating whole-brain structural connectivity alterations accompanying preterm birth may provide a better comprehension of the neurobiological mechanisms related to the later neurocognitive deficits observed in this population. Using a connectome approach, we aimed to study the impact of prematurity on neonatal whole-brain structural network organization at term-equivalent age. In this cohort study, twenty-four very preterm infants at term-equivalent age (VPT-TEA) and fourteen full-term (FT) newborns underwent a brain MRI exam at term age, comprising T2-weighted imaging and diffusion MRI, used to reconstruct brain connectomes by applying probabilistic constrained spherical deconvolution whole-brain tractography. The topological properties of brain networks were quantified through a graph-theoretical approach. Furthermore, edge-wise connectivity strength was compared between groups. Overall, VPT-TEA infants' brain networks evidenced increased segregation and decreased integration capacity, revealed by an increased clustering coefficient, increased modularity, increased characteristic path length, decreased global efficiency and diminished rich-club coefficient. Furthermore, in comparison to FT, VPT-TEA infants had decreased connectivity strength in various cortico-cortical, cortico-subcortical and intra-subcortical networks, the majority of them being intra-hemispheric fronto-paralimbic and fronto-limbic. Inter-hemispheric connectivity was also decreased in VPT-TEA infants, namely through connections linking to the left precuneus or left dorsal cingulate gyrus - two regions that were found to be hubs in FT but not in VPT-TEA infants. Moreover, posterior regions from Default-Mode-Network (DMN), namely precuneus and posterior cingulate gyrus, had decreased structural connectivity in VPT-TEA group. Our finding that VPT-TEA infants' brain networks displayed increased modularity, weakened rich-club connectivity and diminished global efficiency compared to FT infants suggests a delayed transition from a local architecture, focused on short-range connections, to a more distributed architecture with efficient long-range connections in those infants. The disruption of connectivity in fronto-paralimbic/limbic and posterior DMN regions might underlie the behavioral and social cognition difficulties previously reported in the preterm population.
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Encéfalo/diagnóstico por imagem , Conectoma , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Feminino , Neuroimagem Funcional , Idade Gestacional , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/crescimento & desenvolvimento , Giro do Cíngulo/fisiopatologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/crescimento & desenvolvimento , Lobo Parietal/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/crescimento & desenvolvimento , Tálamo/fisiopatologiaRESUMO
Hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSC-HLC) are expected to have important applications in drug screening and regenerative medicine. However, hiPSC-HLC are difficult to produce on a large-scale to obtain relevant numbers for such applications. The aim of this study was to implement a novel integrated strategy for scalable production of hiPSC-HLC and demonstrate the applicability of dielectric spectroscopy to monitor hiPSC expansion/differentiation processes. We cultured hiPSC as three-dimensional (3D) aggregates in stirred-tank bioreactors (STB) operated in perfusion with an in situ capacitance probe. Dissolved oxygen concentration and dilution rate were controlled along the process and after 5 days of cell expansion, the hepatic differentiation was integrated in sequential steps for 28 days. The hiPSC were able to grow as 3D aggregates and the expression of hepatic markers and albumin production after differentiation confirmed that hepatocyte differentiation improved when compared to 2D culture. These hiPSC-HLC exhibited functional characteristics of hepatocytes including glycogen storage and drug metabolization capacity. Our results also show a good correlation between the cell permittivity measured online and the aggregate biovolume measured by standard offline methods, demonstrating for the first time the potential of dielectric spectroscopy to monitor hiPSC expansion and differentiation in STB.
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Técnicas de Cultura de Células , Diferenciação Celular , Espectroscopia Dielétrica , Hepatócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Hepatócitos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologiaRESUMO
INTRODUCTION: The cesarean section rate around the world, currently estimated at 21.1%, continues to increase. Women who undergo a cesarean section sustain a seven- to ten-fold greater risk of infective morbidity compared with those who deliver vaginally. MATERIAL AND METHODS: We aimed to assess the impact of changing gloves intraoperatively on post-cesarean section infective morbidity (PROSPERO CRD42018110529). MEDLINE, Scopus, Web of Science, CINAHL, WHO Global Index Medicus, and Cochrane Central were searched for randomized controlled trials until June 2020. Published randomized controlled trials that evaluated the effects of glove changing during cesarean section on infective complications were considered eligible for the review. Two reviewers independently selected studies, assessed the risk of bias, and extracted data about interventions and adverse maternal outcomes. Dichotomous variables were presented and included in the meta-analyses as risk ratios (RR) with 95% confidence intervals (CI). The quality of evidence was assessed using the GRADE approach in alignment with the recommendations from the Cochrane Review Group. RESULTS: We identified seven randomized controlled trials reporting data over 1948 women. Changing gloves during a cesarean section was associated with a statistically significantly lower incidence of wound infective complications (RR 0.41, 95% CI 0.26-0.65, p < 0.0001; GRADE moderate quality evidence). This intervention seemed to be effective only if performed after delivery of the placenta. No significant difference was seen in the incidence of endometritis (RR 0.96, 95% CI 0.78-1.20, p = 0.74; GRADE moderate quality evidence) and/or febrile morbidity (RR 0.73, 95% CI 0.30-1.81, p = 0.50; GRADE moderate quality evidence), regardless of the timing of the intervention. CONCLUSIONS: Changing gloves after delivery of the placenta during a cesarean section is associated with a significant reduction in the incidence of post-surgical wound complications compared with keeping the same gloves throughout the whole surgery. However, an adequately powered study to assess the limitations and cost-effectiveness of the intervention is needed before this recommendation can be translated into current clinical practice.
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Cesárea/normas , Luvas Cirúrgicas , Infecção da Ferida Cirúrgica/prevenção & controle , Feminino , Humanos , Complicações Pós-Operatórias/prevenção & controle , GravidezRESUMO
Marine biofouling is a natural process that represents major economic, environmental, and health concerns. Some booster biocides have been used in biofouling control, however, they were found to accumulate in environmental compartments, showing negative effects on marine organisms. Therefore, it is urgent to develop new eco-friendly alternatives. Phenyl ketones, such as benzophenones and acetophenones, have been described as modulators of several biological activities, including antifouling activity (AF). In this work, acetophenones were combined with other chemical substrates through a 1,2,3-triazole ring, a strategy commonly used in Medicinal Chemistry. In our approach, a library of 14 new acetophenone-triazole hybrids was obtained through the copper(I)-catalyzed alkyne-azide cycloaddition "click" reaction. All of the synthesized compounds were evaluated against the settlement of a representative macrofouling species, Mytilus galloprovincialis, as well as on biofilm-forming marine microorganisms, including bacteria and fungi. The growth of the microalgae Navicula sp. was also evaluated after exposure to the most promising compounds. While compounds 6a, 7a, and 9a caused significant inhibition of the settlement of mussel larvae, compounds 3b, 4b, and 7b were able to inhibit Roseobacter litoralis bacterial biofilm growth. Interestingly, acetophenone 7a displayed activity against both mussel larvae and the microalgae Navicula sp., suggesting a complementary action of this compound against macro- and microfouling species. The most potent compounds (6a, 7a, and 9a) also showed to be less toxic to the non-target species Artemia salina than the biocide Econea®. Regarding both AF potency and ecotoxicity activity evaluation, acetophenones 7a and 9a were put forward in this work as promising eco-friendly AF agents.
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Acetofenonas/farmacologia , Incrustação Biológica/prevenção & controle , Desinfetantes/farmacologia , Triazóis/farmacologia , Acetofenonas/química , Animais , Organismos Aquáticos , Biofilmes/efeitos dos fármacos , Bivalves/efeitos dos fármacos , Desinfetantes/química , Larva/efeitos dos fármacos , Microalgas/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
Biofouling, which occurs when certain marine species attach and accumulate in artificial submerged structures, represents a serious economic and environmental issue worldwide. The discovery of new non-toxic and eco-friendly antifouling systems to control or prevent biofouling is, therefore, a practical and urgent need. In this work, the antifouling activity of a series of 24 xanthones, with chemical similarities to natural products, was exploited. Nine (1, 2, 4, 6, 8, 16, 19, 21, and 23) of the tested xanthones presented highly significant anti-settlement responses at 50 µM against the settlement of mussel Mytilus galloprovincialis larvae and low toxicity to this macrofouling species. Xanthones 21 and 23 emerged as the most effective larval settlement inhibitors (EC50 = 7.28 and 3.57 µM, respectively). Additionally, xanthone 23 exhibited a therapeutic ratio (LC50/EC50) > 15, as required by the US Navy program attesting its suitability as natural antifouling agents. From the nine tested xanthones, none of the compounds were found to significantly inhibit the growth of the marine biofilm-forming bacterial strains tested. Xanthones 4, 6, 8, 16, 19, 21, and 23 were found to be non-toxic to the marine non-target species Artemia salina (<10% mortality at 50 µM). Insights on the antifouling mode of action of the hit xanthones 21 and 23 suggest that these two compounds affected similar molecular targets and cellular processes in mussel larvae, including that related to mussel adhesion capacity. This work exposes for the first time the relevance of C-1 aminated xanthones with a 3,4-dioxygenated pattern of substitution as new non-toxic products to prevent marine biofouling.
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Incrustação Biológica/prevenção & controle , Xantonas/farmacologia , Animais , Organismos Aquáticos , Biofilmes/efeitos dos fármacos , Bivalves/efeitos dos fármacos , Larva/efeitos dos fármacos , Xantonas/químicaRESUMO
The accumulation of marine biofouling on ship hulls causes material damage, the spread of invasive species, and, indirectly, an increase in full consumption and subsequent pollutant gas emissions. Most efficient antifouling (AF) strategies rely on the conventional release of persistent, bioaccumulative, and toxic biocides incorporated in marine coatings. A simple oxygenated xanthone, 3,4-dihydroxyxanthone (1), was previously reported as a promising AF agent toward the settlement of Mytilus galloprovincialis larvae, with a therapeutic ratio higher than the commercial biocide Econea®. In this work, a structure-AF activity relationship study, an evaluation of environmental fate, and an AF efficiency in marine coatings were performed with compound 1. Hydroxy or methoxy groups at 3 and 4 positions in compound 1 favored AF activity, and groups with higher steric hindrances were detrimental. Compound 1 demonstrated low water-solubility and a short half-life in natural seawater, contrary to Econea®. In silico environmental fate predictions showed that compound 1 does not bioaccumulate in organism tissues, in contrast to other current emerging biocides, has a moderate affinity for sediments and slow migrates to ground water. No toxicity was observed against Vibrio fischeri and Phaeodactylum tricornutum. Polyurethane-based marine coatings containing compound 1 prepared through an innovative non-release-strategy were as efficient as those containing Econea® with low releases to water after 45 days. This proof-of-concept helped to establish compound 1 as a promising eco-friendly AF agent.
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The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53-MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53-MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Chalconas/farmacologia , Chalconas/uso terapêutico , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Humanos , Neoplasias/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismoRESUMO
Prematurity disrupts brain maturation by exposing the developing brain to different noxious stimuli present in the neonatal intensive care unit (NICU) and depriving it from meaningful sensory inputs during a critical period of brain development, leading to later neurodevelopmental impairments. Musicotherapy in the NICU environment has been proposed to promote sensory stimulation, relevant for activity-dependent brain plasticity, but its impact on brain structural maturation is unknown. Neuroimaging studies have demonstrated that music listening triggers neural substrates implied in socio-emotional processing and, thus, it might influence networks formed early in development and known to be affected by prematurity. Using multi-modal MRI, we aimed to evaluate the impact of a specially composed music intervention during NICU stay on preterm infant's brain structure maturation. 30 preterm newborns (out of which 15 were exposed to music during NICU stay and 15 without music intervention) and 15 full-term newborns underwent an MRI examination at term-equivalent age, comprising diffusion tensor imaging (DTI), used to evaluate white matter maturation using both region-of-interest and seed-based tractography approaches, as well as a T2-weighted image, used to perform amygdala volumetric analysis. Overall, WM microstructural maturity measured through DTI metrics was reduced in preterm infants receiving the standard-of-care in comparison to full-term newborns, whereas preterm infants exposed to the music intervention demonstrated significantly improved white matter maturation in acoustic radiations, external capsule/claustrum/extreme capsule and uncinate fasciculus, as well as larger amygdala volumes, in comparison to preterm infants with standard-of-care. These results suggest a structural maturational effect of the proposed music intervention on premature infants' auditory and emotional processing neural pathways during a key period of brain development.