The role of keratins in modulating carcinogenesis via communication with cells of the immune system

Keratins are intermediate filament proteins expressed by epithelial cells and provide mechanical support for diverse epithelia. In our recent study (Sequeira et al., Nat Comm 9(1):3437), we analysed the role of keratin 76 (Krt76) in inflammation and cancer. Krt76 is expressed throughout embryonic development in the differentiated epithelial layers of a subset of stratified epithelia including tongue, palate and stomach. It is significantly downregulated in human oral squamous cell carcinoma (OSCC), correlating strongly with poor prognosis. We have shown that Krt76-/- mice exhibit systemic inflammation with increased levels of circulating B cells, regulatory T cells and effector T cells. When mice are given a chemical carcinogen in the drinking water, tongue and gastric cancer formation is accelerated in Krt76-/- mutant mice. Our data suggest that the increased tumour susceptibility of Krt76-/- mice is in part due to the enhanced accumulation of regulatory T cells in the tumour microenvironment. Our results support the notion that keratins, in addition to their function as cytoskeletal components, regulate immunity and affect tumour susceptibility of epithelial cells

Kounis Syndrome Associated With Selective Anaphylaxis to Cefazolin.

info:eu-repo/semantics/publishedVersio

A Roadmap for the Human Oral and Craniofacial Cell Atlas

Oral and craniofacial tissues are uniquely adapted for continuous and intricate functioning, including breathing, feeding, and communication. To achieve these vital processes, this complex is supported by incredible tissue diversity, variously composed of epithelia, vessels, cartilage, bone, teeth, ligaments, and muscles, as well as mesenchymal, adipose, and peripheral nervous tissue. Recent single cell and spatial multiomics assays—specifically, genomics, epigenomics, transcriptomics, proteomics, and metabolomics—have annotated known and new cell types and cell states in human tissues and animal models, but these concepts remain limitedly explored in the human postnatal oral and craniofacial complex. Here, we highlight the collaborative and coordinated efforts of the newly established Oral and Craniofacial Bionetwork as part of the Human Cell Atlas, which aims to leverage single cell and spatial multiomics approaches to first understand the cellular and molecular makeup of human oral and craniofacial tissues in health and to then address common and rare diseases. These powerful assays have already revealed the cell types that support oral tissues, and they will unravel cell types and molecular networks utilized across development, maintenance, and aging as well as those affected in diseases of the craniofacial complex. This level of integration and cell annotation with partner laboratories across the globe will be critical for understanding how multiple variables, such as age, sex, race, and ancestry, influence these oral and craniofacial niches. Here, we 1) highlight these recent collaborative efforts to employ new single cell and spatial approaches to resolve our collective biology at a higher resolution in health and disease, 2) discuss the vision behind the Oral and Craniofacial Bionetwork, 3) outline the stakeholders who contribute to and will benefit from this network, and 4) outline directions for creating the first Human Oral and Craniofacial Cell Atlas

Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family

Background: Different mutations in the 1A-subunit of the brain P/Q-type calcium channel gene (CACNA1A) are responsible for familial hemiplegic migraine (FHM), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). Missense and splice site mutations have been found in FHM and episodic ataxia type 2, respectively, whereas a CAG repeat in the CACNA1A gene was found expanded in patients with SCA6. Objective: To identify the disease causing mutation in a large family of patients with phenotypes of hemiplegic migraine with or without cerebellar signs or permanent cerebellar ataxia without migraine inherited in a dominant manner. Patients and Methods: We examined 15 patients from a large family identified through a systematic survey of hereditary ataxias being conducted in Portugal. Linkage analysis was performed with CACNA1A gene markers, and mutation analysis was performed by single strand conformational polymorphism analysis and sequencing. Results: Genetic linkage analysis with CACNA1A intragenic markers showed positive LOD scores. The maximal LOD score was obtained with the polymorphic CAG repeat (Zmax=4.47, =0). By single-strand conformational polymorphism analysis, a shift in exon 13 of the CACNA1A gene was detected in all patients.AG-to-A substitution was then identified, resulting in an arginine-to-glutamine change at codon 583 of this calcium channel 1A-subunit. Conclusions: The disease-causing mutation in this family was identified, showing that a unique mutation in the CACNA1A gene causes several phenotypes, including those of SCA6 and FHM, thus suggesting that SCA6 and FHM are not only allelic diseases but are the same disorder with a large phenotypic variability.Fundação para a Ciência e Tecnologi

Assessing the Role of Carbonyl Adducts, Particularly Malondialdehyde Adducts, in the Development of Dermis Yellowing Occurring during Skin Photoaging

Solar elastosis is associated with a diffuse yellow hue of the skin. Photoaging is related to lipid peroxidation leading to the formation of carbonyl groups. Protein carbonylation can occur by addition of reactive aldehydes, such as malondialdehyde (MDA), 4-hydroxy-nonenal (4-HNE), and acrolein. All the proteins concerned with this modification, and the biological consequences of adduct formation, are not completely identified. The link between yellowish skin and dermal carbonylated proteins induced by aldehyde adducts was investigated. The study was carried out on ex vivo skin samples from sun-exposed or sun-protected areas and on in vitro dermal equivalent models incubated with 5 mM MDA, 4-HNE, or acrolein. The yellow color and the level of MDA, 4-HNE, and acrolein adducts were evaluated. Yellowish color differences were detected in the dermis of sun-exposed skin compared to sun-protected skin and in in vitro models following addition of MDA, 4-HNE, or acrolein. The yellowing was correlated with the carbonyl adducts increasing in the dermis and in in vitro models incubated with aldehydes. The stronger yellowing seemed to be mediated more by MDA than 4-HNE and acrolein. These observations suggest that dermal carbonylation especially induced by MDA result in the yellow hue of dermis and is involved, in part, in the yellowing observed during skin photoaging

Understanding Preclerkship Medical Students’ Poor Performance in Prescription Writing

Objectives: This study aimed to explore reasons for poor performance in prescription writing stations of the objective structured practical examination (OSPE) and absenteeism in prescription writing sessions among preclerkship medical students at the Arabian Gulf University (AGU) in Manama, Bahrain. Methods: This descriptive study was carried out between September 2014 and June 2015 among 157 preclerkship medical students at AGU. Data were collected using focus group discussions and a questionnaire with closed- and open-ended items. Results: All 157 students participated in the study (response rate: 100.0%). The most frequently cited reasons for poor performance in OSPE stations were an inability to select the correct drugs (79.6%), treatment duration (69.4%), drug quantity (69.4%) and drug formulation (68.2%). Additionally, students reported inadequate time for completing the stations (68.8%). During focus group discussions, students reported other reasons for poor performance, including examination stress and the difficulty of the stations. Absenteeism was attributed to the length of each session (55.4%), lack of interest (50.3%), reliance on peers for information (48.4%) and optional attendance policies (47.1%). Repetitive material, large group sessions, unmet student expectations and the proximity of the sessions to summative examinations were also indicated to contribute to absenteeism according to open-ended responses or focus group discussions. Conclusion:This study suggests that AGU medical students perform poorly in prescription writing OSPE stations because of inadequate clinical pharmacology knowledge. Participation in prescription writing sessions needs to be enhanced by addressing the concerns identified in this study. Strategies to improve attendance and performance should take into account the learner-teacher relationship

Medical Students’ Perceptions of Peer Assessment in a Problem-based Learning Curriculum

Objectives: Peer assessment (PA) is believed to support learning and help students develop both professionally and personally. The aim of this study was to examine medical students’ perceptions of intragroup PA in a problem-based learning (PBL) setting. Methods: This study was carried out between September and November 2014 and involved six random groups of fourth-year undergraduate medical students (n = 60) enrolled at the Arabian Gulf University in Manama, Bahrain. While working on set tasks within a curriculum unit, each student evaluated a randomly selected peer using an English language adapted assessment tool to measure responsibility and respect, information processing, critical analysis, interaction and collaborative skills. At the end of the unit, students’ perceptions of PA were identified using a specifically-designed voluntary and anonymous selfadministered questionnaire in English. Results: A total of 55 students participated in the study (response rate: 92%). The majority of students reported that their learning (60%), attendance (67%), respect towards group members (70%) and participation in group discussions (71%) improved as a result of PA. Regarding problem analysis skills, most participants believed that PA improved their ability to analyse problems (65%), identify learning needs (64%), fulfil tasks related to the analysis of learning needs (72%) and share knowledge within their group (74%). Lastly, a large proportion of students reported that this form of assessment helped them develop their communication (71%) and self-assessment skills (73%), as well as collaborative abilities (75%). Conclusion: PA was well accepted by the students in this cohort and led to self-reported improvements in learning, skills, attitudes, engagement and other indicators of personal and professional development. PA was also perceived to have a positive impact on intragroup attitudes

Aluminum alloy production for the reinforcement of the CMS conductor

The Compact Muon Solenoid (CMS) is one of the general-purpose detectors to be provided for the Large Hadron Collider (LHC) project at CERN. The design field of the CMS superconducting magnet is 4 T, the magnetic length is 12.5 m and the free bore is 6 m. To reinforce the high-purity (99.998%) Al-stabilized conductor of the magnet against the magnetic loadings experienced during operation at 4.2 K, two continuous sections of Al-alloy (AA) reinforcement are Electron Beam (EB) welded to it. The reinforcements have a section of 24*18 mm and are produced in continuous 2.55 km lengths. The alloy EN AW-6082 has been selected for the reinforcement due to its excellent extrudability, high strength in the precipitation hardened states, high toughness and strength at cryogenic temperature and good EB weldability. Each of the continuous lengths of the reinforcement is extruded billet on billet and press quenched on-line from the extrusion temperature in an industrial extrusion plant. In order to insure the ready EB weldability of the reinforcement onto the pure aluminum of the insert, tight dimensional tolerances and proper surface finish of the reinforcement are required in the as-extruded state. As well, in order to facilitate the winding operation of the conductor, the uniformity of the mechanical properties of the extruded reinforcement, especially at the billet on billet joints, is critical. To achieve these requirements in an industrial environment, substantial effort was made to refine existing production techniques and to monitor critical extrusion parameters during production. This paper summarizes the main results obtained during the establishment of the extrusion line and of the production phase of the reinforcement. (10 refs)

Retrotransposons are specified as DNA replication origins in the gene-poor regions of Arabidopsis heterochromatin

Genomic stability depends on faithful genome replication. This is achieved by the concerted activity of thousands of DNA replication origins (ORIs) scattered throughout the genome. The DNA and chromatin features determining ORI specification are not presently known. We have generated a high-resolution genome-wide map of 3230 ORIs in cultured Arabidopsis thaliana cells. Here, we focused on defining the features associated with ORIs in heterochromatin. In pericentromeric gene-poor domains ORIs associate almost exclusively with the retrotransposon class of transposable elements (TEs), in particular of the Gypsy family. ORI activity in retrotransposons occurs independently of TE expression and while maintaining high levels of H3K9me2 and H3K27me1, typical marks of repressed heterochromatin. ORI-TEs largely colocalize with chromatin signatures defining GC-rich heterochromatin. Importantly, TEs with active ORIs contain a local GC content higher than the TEs lacking them. Our results lead us to conclude that ORI colocalization with retrotransposons is determined by their transposition mechanism based on transcription, and a specific chromatin landscape. Our detailed analysis of ORIs responsible for heterochromatin replication has implications on the mechanisms of ORI specification in other multicellular organisms in which retrotransposons are major components of heterochromatin and of the entire genome

Evaluation of positive mental health and sense of coherence in mental health professionals

Background: the Sense of Coherence (SOC) of Antonowsky (1996) which is based on salutogenic theory and the multifactor Positive Mental Health (PMH) model of Lluch (1999) provide two constructs for comprehending, evaluating, and intervening in the promotion and maintenance of a good state of mental health. Aim: were assessed self-rated mental health of health professionals working in mental health services and relations between both constructs and sociodemographic, work, and health variables. Methods: the sample was made up of n=102 attending professionals at the mental health units of the Parc Hospitalari Martí i Julià, in Salt, Girona. The variables studied were sociodemographic work-related, health-related, and self-perception of mental health, evaluated by means of the Sense of Coherence questionnaire and the Positive Mental Health questionnaire. The questionnaires were self-administered. Results: overall, the sample studied scored high in the Sense of Coherence and the Positive Mental Health questionnaires. In terms of the relation between the overall scores of the SOC questionnaire and the PMH, analysis revealed a positive relation between the two. Conclusions: this positive relation between the two questionnaires may be of particular interest in future studies of the multifactor model of Positive Mental Health and the salutogenic model that underlies the Sense of Coherence, by generating a global conceptual framework for the study of mental health from a positive perspective