K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.

Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.

Mutation of p53 increases the competitive ability of pluripotent stem cells.

During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality-control mechanism that contributes to this balance by eliminating viable cells that are less fit than their neighbours. The mutations that confer cells with a competitive advantage and the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are 'super-competitors' that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependent, as it does not occur when cells are pluripotent and it is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through competition for space or nutrients, but instead is mediated by short-range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.

Expression of a novel mycobacterial phosphodiesterase successfully lowers cAMP levels resulting in reduced tolerance to cell wall-targeting antimicrobials.

cAMP and antimicrobial susceptibility in mycobacteriaAntimicrobial tolerance, the ability to survive exposure to antimicrobials via transient nonspecific means, promotes the development of antimicrobial resistance (AMR). The study of the molecular mechanisms that result in antimicrobial tolerance is therefore essential for the understanding of AMR. In gram-negative bacteria, the second messenger molecule 3'',5''-cAMP has been previously shown to be involved in AMR. In mycobacteria, however, the role of cAMP in antimicrobial tolerance has been difficult to probe due to its particular complexity. In order to address this difficulty, here, through unbiased biochemical approaches consisting in the fractionation of clear protein lysate from a mycobacterial strain deleted for the known cAMP phosphodiesterase (Rv0805c) combined with mass spectrometry techniques, we identified a novel cyclic nucleotide-degrading phosphodiesterase enzyme (Rv1339) and developed a system to significantly decrease intracellular cAMP levels through plasmid expression of Rv1339 using the constitutive expression system, pVV16. In Mycobacterium smegmatis mc2155, we demonstrate that recombinant expression of Rv1339 reduced cAMP levels threefold and resulted in altered gene expression, impaired bioenergetics, and a disruption in peptidoglycan biosynthesis leading to decreased tolerance to antimicrobials that target cell wall synthesis such as ethambutol, D-cycloserine, and vancomycin. This work increases our understanding of the role of cAMP in mycobacterial antimicrobial tolerance, and our observations suggest that nucleotide signaling may represent a new target for the development of antimicrobial therapies.

Niobium Oxides as Heterogeneous Catalysts for Biginelli Multicomponent Reaction.

This study reports a simple, reusable, and recoverable niobium-based heterogeneous catalysts for Biginelli multicomponent reactions. Different methods of catalysts preparation were investigated. For this purpose, HY-340 (Nb2O5·nH2O) and Nb2O5 were chemically and/or thermally treated and investigated as catalysts for dihydropyrimidinones (DHPMs) production. The catalysts were characterized by scanning electron microscopy, high-resolution transmission electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, temperature-programmed desorption of NH3, adsorption/desorption of N2 at -196 °C, and thermogravimetric and differential thermal analysis. The characterization results showed that niobium oxides have the potential to be used as catalysts because of high crystallinity and large surface area. Among the tested catalysts, Nb2O5 chemically treated (Nb2O5/T) showed the best catalytic performance. In the absence of solvents, 94% yield of DHPMs was achieved. Also, Nb2O5/T can be reused three times without a significant yield decrease. Additionally, a feasible reaction pathway was suggested based on the Knoevenagel mechanism for DHPM synthesis using niobium-based catalysts.

Surgical Anatomy in Orbital Fractures: A Surgeons Perspective.

Fractures of the orbit are frequently noted in craniomaxillofacial trauma. The complexity of the anatomy and the proximity to various vital structures often complicates the surgical management of these fractures. The authors have thus attempted to review the literature on anatomy of the bony orbit and its soft tissue envelope in a simplified manner with due emphasis on surgical anatomy and exploration of the orbit with a surgical perspective. The contents of this narrative literature review may be useful for young maxillofacial surgeons and will aid in the process of management of orbital fractures.

Awareness of ovarian cancer symptoms and risk factors in a young ethnically diverse British population.

BACKGROUND: Ovarian cancer does not cause many symptoms in the early stages, which is why the majority of cases are of advanced disease. Increasing awareness of ovarian cancer symptoms may lead to earlier diagnosis and improved outcomes. METHODS: Participants in Britain completed the Ovarian Cancer Awareness Measure by online survey (n = 459). RESULTS: Our participants were 75% female, 25% male and a young (27.89 ± 11.44 years) ethnically diverse population (40.3% White, 29.3% Asian and 18.0% Black). Individuals recalled 1.24 ± 1.30 symptoms, and recognised 5.96 ± 2.4 symptoms. We found higher levels of recall and recognition compared to previous research possibly due to using an online survey. Recognition was lowest for difficulty eating (39.4%) and persistently feeling full (38.7%). Males had slightly lower symptom recall and recognition than females. Participants incorrectly recalled an irregular menstrual cycle (22.4%) as an ovarian cancer symptom and 67% answered the age of incidence question incorrectly. Suggesting that participants incorrectly associate ovarian cancer as a disease of pre-menopausal women. Individuals recalled 1.47 ± 1.20 risk factors, and recognised 6.1 ± 2.4 risk factors. Family history of ovarian cancer was recalled by 59% of participants. Recognition was lowest for in vitro fertilisation treatment (23.0%) and talcum powder in the genital area (23.0%). The generic cancer risk factors of alcohol (9.3%) and poor diet (8.8%) were recalled as specific ovarian cancer risk factors. 57.9% of participants incorrectly answered that there is an ovarian cancer screening programme. Suggesting confusion between ovarian and cervical cancer as participants also recalled cervical cancer risk factors of sexually transmitted diseases (6.3%) and human papillomavirus (1.5%). 29.7% of female participants would seek help for an ovarian cancer symptom within 1-2 days. Help seeking was higher in the Black and Asian ethnicities (44.4% and 45.0%; p = 0.018). CONCLUSION: Awareness of ovarian cancer symptoms is low. Ovarian cancer awareness campaigns should include common misconceptions identified in this research.

Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

Global spatial dynamics and vaccine-induced fitness changes of Bordetella pertussis.

As with other pathogens, competitive interactions between Bordetella pertussis strains drive infection risk. Vaccines are thought to perturb strain diversity through shifts in immune pressures; however, this has rarely been measured because of inadequate data and analytical tools. We used 3344 sequences from 23 countries to show that, on average, there are 28.1 transmission chains circulating within a subnational region, with the number of chains strongly associated with host population size. It took 5 to 10 years for B. pertussis to be homogeneously distributed throughout Europe, with the same time frame required for the United States. Increased fitness of pertactin-deficient strains after implementation of acellular vaccines, but reduced fitness otherwise, can explain long-term genotype dynamics. These findings highlight the role of vaccine policy in shifting local diversity of a pathogen that is responsible for 160,000 deaths annually.

Vehiculation of Methyl Salicylate from Microcapsules Supported on Textile Matrix.

In recent years, textile industries have focused their attention on the development of functional finishing that presents durability and, consequently, controlled release. However, in the case of methyl salicylate microcapsules supported on a textile matrix, studies indicate only the interactions between substrate and microcapsules and the drug delivery system, not applying the release equations. This study reports the mechanism and kinetics of controlled release of microcapsules of gelatin and gum Arabic containing methyl salicylate as active ingredient incorporated into textile matrices. According to the results presented, it was possible to verify that the wall materials participated in the coacervation process, resulting in microcapsules with well-defined geometry, besides promoting the increase of the thermal stability of the active principle. The samples (100% cotton, CO, and 100% polyamide, PA) functionalized with microcapsules released methyl salicylate in a controlled manner, based on the adjustment made by the Korsmeyer-Peppas model, indicating a Fickian mechanism. The influence of temperature was noticeable when the samples were subjected to washing, since with higher temperature (50 °C), the release was more pronounced than when subjected to lower temperature (37 °C). The results presented in this study indicate that the mechanism of backbone release is influenced by the textile matrix and by the durability of the microcapsule during the wash cycles.

Kinetic spectrophotometric method for real-time monitoring of ultraviolet photoreactions: A mini-photoreactor.

It is proposed a new approach to evaluate the performance of ultraviolet photoreactions by integrating UV-LED and a UV-Vis cuvette as a mini-reactor for kinetic monitoring in a spectrophotometer not influenced by external light. This system uses only 3.0 mL of solutions in a rectangular quartz cuvette with a mini-bar magnetic stirrer in a cell holder and a UV-LED of 5 W with λmax at 370 nm was positioned on the top of the cuvette and maintained at 25.0 oC. The effectiveness of this photoreactor was demonstrated by measuring the real-time degradation of two model compounds, salicylic acid and methylene blue, in homogeneous and heterogenous systems. Photolysis of MB with H2O2 results in increasing of rate constants as [H2O2] increased. Heterogeneous photocatalysis of MB and SA was fastest achieved in ZnO dosage of 0,20 g.L-1. This mini-photoreactor allows monitoring the real-time kinetic performance collecting almost a thousand points in each experiment, leading to accurate rate constants. Moreover, this system presented positive environmental aspects such as: lower reactants and catalyst amounts, lower cost and waste amounts, use of the UV-LED radiation and labor time saving. This is a novel approach to determine the photoreaction effectiveness and it can be applied to systematic studies especially for the kinetic parameter determinations.

DATASUS: sua importância na divulgação das informações e dados em saúde

A importância do DATASUS na divulgação das informações e dados em saúde se dá mediante a criação de programas que visam melhorar a saúde da população de diversas formas. Para a criação destes programas é necessário a colaboração das Secretarias de Saúde Municipais e Estaduais através da transcrição/transmissão destes dados para os sistemas e aplicativos do DATASUS. Até o momento vem desempenhando seu papel no processo de informatização destes dados de saúde, com foco nas ações de saúde coletiva, fazendo com que a informação e a informática andem juntas, fornecendo subsídios para que os gestores de todas as esferas de governo possam elaborar políticas de saúde pública em benefício de todos. O compartilhamento de dados de interesse para diversos públicos é o ponto principal. O acesso a informações de saúde de forma ágil e rápida, a gratuidade na distribuição de aplicativos e sistemas são pontos que merecem destaque, assim como o constante treinamento / capacitação de usuários dos seus sistemas e aplicativos. O DATASUS ao longo dos anos vem fazendo esforços para a qualificação e disseminação da informação através da informatização, contribuindo assim com o contínuo aperfeiçoamento da política de saúde do país.

Melhoria do cuidado ao paciente queimado: elaboração de um instrumento de avaliação / Improvement of burn paciente care: elaboration of an evaluation instrument

Este estudo possui o propósito de orientar a elaboração de um instrumento de avaliação para contribuir com a melhoria do cuidado ao paciente queimado. Atualmente, os pacientes queimados são atendidos, em sua maioria, por hospitais gerais, por profissionais não especializados nessa patologia, devido aos poucos Centros de Referência em Assistência a Queimados distribuídos pelo país. Os instrumentos de avaliação existentes são mais voltados para a estrutura de uma unidade de queimados e não dão ênfase aos processos de cuidado. Dessa forma, buscou-se adaptar os aspectos gerais dos padrões contidos do Manual Internacional de Padrões de Acreditação Hospitalar do Consórcio Brasileiro de Sistemas e Serviços de Saúde e Joint Commission International à abordagem do paciente queimado. Para tanto, foram utilizados protocolos vigentes no Brasil e nos Estados Unidos, que são os parâmetros existentes, para nortear o atendimento de pacientes queimados. O trabalho foi desenvolvido em 3 momentos: 1. realização, pela autora, de cruzamento dos padrões referentes a processos de cuidado com os protocolos (Brasil e Estados Unidos); 2. avaliação dos consultores quanto à importância de se incluir, nas orientações para a elaboração do instrumento de avaliação, aspectos do tratamento de pacientes queimados, que tradicionalmente não são abordados pelos protocolos e que compõem os padrões de acreditação, bem como acrescentar outras considerações sobre os padrões atendidos ou parcialmente atendidos pelos protocolos; 3. síntese do material pela autora. Como resultado final deste estudo, pretende-se favorecer a melhora da qualidade do cuidado prestado ao paciente queimado, a partir de orientações para a elaboração de Instrumento de Avaliação, que tanto beneficiará o Ministério da Saúde, na avaliação de sua Rede Estadual de Assistência aos Pacientes Queimados, quanto os hospitais, como guia para os profissionais que atuam nessa área.