Computational modelling of supramolecular metallopeptide assemblies.

Among the important questions in supramolecular peptide self-assemblies are their interactions with metallic compounds and ions. In the last decade, intensive efforts have been devoted to understanding the structural properties of these interactions including their dynamical and catalytic impact in natural and de novo systems. Since structural insights from experimental approaches could be particularly challenging, computational chemistry methods are interesting complementary tools. Here, we present the general multiscale strategies we developed and applied for the study of metallopeptide assemblies. These strategies include prediction of metal binding site, docking of metallic moieties, classical and accelerated molecular dynamics and finally QM/MM calculations. The systems of choice for this chapter are, on one side, peptides involved in neurodegenerative diseases and, on the other, de novo fibrillar systems with catalytic properties. Both successes and remaining challenges are highlighted so that the protocol could be apply to other system of this kind.

Computational Study of Amyloidß42 Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.

One of the main hallmarks of Alzheimer's Disease is the formation of ß-amyloid plaques, whose formation may be enhanced by metal binding or the appearance of familial mutations. In the present study, the simultaneous effect of familial mutations (E22Q, E22G, E22K, and D23N) and binding to metal ions (Cu(II) or Al(III)) is studied at the Aß42 monomeric and fibrillar levels. With the application of GaMD and MD simulations, it is observed that the effects of metal binding and mutations differ in the monomeric and fibrillar forms. In the monomeric structures, without metal binding, all mutations reduce the amount of α-helix and increase, in some cases, the ß-sheet content. In the presence of Cu(II) and Al(III) metal ions, the peptide becomes less flexible, and the ß-sheet content decreases in favor of forming α-helix motifs that stabilize the system through interhelical contacts. Regarding the fibrillar structures, mutations decrease the opening of the fiber in the vertical axis, thereby stabilizing the S-shaped structure of the fiber. This effect is, in general, enhanced upon metal binding. These results may explain the different Aß42 aggregation patterns observed in familial mutations.

Percepción de calidad de vida asociada a salud bucal y determinantes sociales en inmigrantes haitianos

Introducción: El objetivo de este estudio fue identificar la autopercepción de calidad de vida asociada a salud bucal y los determinantes sociales, con la ayuda de un instrumento adaptado culturalmente en inmigrantes haitianos de la ciudad de Talca. Materiales y Métodos: Este estudio tuvo un diseño transversal, incluyendo adaptación cultural (grupos focales) y traducción al créole de encuestas poblacionales chilenas. Se aplicó el instrumento a una muestra por conveniencia de haitianos/as. Se analizaron descriptivamente los datos demográficos, socio-económicos y de calidad de vida asociada con salud bucal (OHIP-7), seguido por un análisis bivariante (chi-cuadrado). Resultados: Participaron un total de 116 personas, mayoría hombres (60.4%) con edades de 19 a 47 años. Un 33% no entiende español. Un 51,7% considera que su salud oral es regular o mala. Factores demográficos no se asociaron a una peor percepción de salud bucal. Calidad de la vivienda, problemas de comunicación y desconocimiento del sistema de salud afectan negativamente la percepción de calidad de vida asociada con salud bucal. Conclusión: Los migrantes haitianos, en su mayoría, perciben su salud oral como regular o mala. Sobre todo, en grupos más desprotegidos la salud oral es percibida como deteriorada y parece tener un efecto negativo en su calidad de vida.

Introduction: The aim of this study was to explore the oral health-related quality of life and social determinants among Haitian immigrants residing in the city of Talca. A culturally adapted survey instrument was designed and used. Methods: The study had a cross-sectional design, including a cultural adaptation (focus groups) and translation to creole of national health surveys. The survey was applied in a convenience sample of Haitian immigrants. Descriptive analyses of demographic, socio-economic and oral health-related quality of life (OHIP-7) were conducted. Bivariate analyses included chi-squared tests. Results: A total of 116 respondents answered the survey. The majority were males (60.4%) with ages ranging from 19 to 47 years. 33% of the sample did not comprehend Spanish. Most than half of participants (51.7%) perceived their oral health as fair or poor. Demographic factors did not affect the oral health perception. Housing, language and health system ignorance negatively affected the perception of the oral health-related quality of life. Conclusion: The majority of Haitian immigrants perceived their oral health as fair or poor. Among more vulnerable groups, oral health is perceived as deteriorated and with an adverse effect on the quality of life.

Systematic influenza screening in cardiac intensive care units during the influenza season: A prospective study in Spain.

BACKGROUND: Little is known about the incidence of influenza among admissions to the cardiac intensive care unit (C-ICU), accuracy of clinical suspicion, and influenza vaccination uptake. We evaluated the incidence of influenza at C-ICU admission during the influenza season, potential underdiagnosis, and vaccination uptake. METHODS: Prospective study at five C-ICUs during the 2017-2020 influenza seasons. A nasopharyngeal swab was collected at admission from patients who consented (n = 788). Testing was with Xpert®XpressFlu/RSV. RESULTS: Influenza was detected in 43 patients (5.5%) (40 FluA; 3 FluB) and clinically suspected in 27 (62.8%). Compared to patients without influenza, patients with influenza more frequently had heart failure (37.2% vs 22.8%, P = 0.031), previous contact with relatives with influenza-like illnesses (23.3% vs 12.5%, P = 0.042), antimicrobial use (67.4% vs 23.2%, P <0.01), and need for mechanical ventilation (25.6% vs 14.5%, P = 0.048). Patients received oseltamivir promptly. We found no differences in mortality (11.6% vs 5.2%, P = 0.076). Patients with influenza more frequently had myocarditis (9.3% vs 0.9%, P <0.01) and pericarditis (7.0% vs 0.8%, P = 0.01). Overall, 43.0% of patients (339/788) were vaccinated (51.9% of those with a clear indication [303/584]). CONCLUSION: Influenza seems to be a frequently underdiagnosed underlying condition in admissions to the C-ICU. Influenza should be screened for at C-ICU admission during influenza epidemics.

Amyloid Fibrils Formed by Short Prion-Inspired Peptides Are Metalloenzymes.

Enzymes typically fold into defined 3D protein structures exhibiting a high catalytic efficiency and selectivity. It has been proposed that the earliest enzymes may have arisen from the self-assembly of short peptides into supramolecular amyloid-like structures. Several artificial amyloids have been shown to display catalytic activity while offering advantages over natural enzymes in terms of modularity, flexibility, stability, and reusability. Hydrolases, especially esterases, are the most common artificial amyloid-like nanozymes with some reported to act as carbonic anhydrases (CA). Their hydrolytic activity is often dependent on the binding of metallic cofactors through a coordination triad composed of His residues in the ß-strands, which mimic the arrangement found in natural metalloenzymes. Tyr residues contribute to the coordination of metal ions in the active center of metalloproteins; however, their use has been mostly neglected in the design of metal-containing amyloid-based nanozymes. We recently reported that four different polar prion-inspired heptapeptides spontaneously self-assembled into amyloid fibrils. Their sequences lack His but contain three alternate Tyr residues exposed to solvent. We combine experiments and simulations to demonstrate that the amyloid fibrils formed by these peptides can efficiently coordinate and retain different divalent metal cations, functioning as both metal scavengers and nanozymes. The metallized fibrils exhibit esterase and CA activities without the need for a histidine triad. These findings highlight the functional versatility of prion-inspired peptide assemblies and provide a new sequential context for the creation of artificial metalloenzymes. Furthermore, our data support amyloid-like structures acting as ancestral catalysts at the origin of life.

Strong versus weak embodiment: Spatial iconicity in physical, abstract, and social semantic categories.

BACKGROUND: Perceptual and action systems seem to be related to complex cognitive processes, but the scope of grounded or embodied cognition has been questioned. Zwaan and Yaxley (2003) proposed that cognitive processes of making semantic relatedness judgments can be facilitated when word pairs are presented in ways that their referents maintain their iconic configuration rather than their reverse-iconic configuration (the spatial iconicity effect). This effect has been observed in different semantic categories using specific experiments, but it is known that embodiment is highly dependent on task demands. METHOD: The present study analyzed the spatial iconicity effect in three semantic categories (physical, abstract, and social) using the same experimental criteria to determine the scope of embodied cognition. In this reaction-time experiment, 75 participants judged the semantic relatedness of 384 word pairs whose experimental items were presented in their iconic or reverse-iconic configurations. RESULTS: Two mixed-effects models with crossed random effects revealed that the interaction between word meaning and spatial position was present only for physical concepts but neither for abstract nor social concepts. CONCLUSIONS: Within the framework of strong and weak embodiment theories, the data support weak embodiment theory as the most explicative one.

Computational assessment of the impact of Cu(II) and Al(III) on ß-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications.

One of Alzheimer's disease major hallmarks is the aggregation of ß-amyloid peptide, a process in which metal ions play an important role. In the present work, an integrative computational study has been performed to identify the metal-binding regions and determine the conformational impact of Cu(II) and Al(III) ion binding to the ß-amyloid (Aß42) fibrillary structure. Through classical and Gaussian accelerated molecular dynamics, it has been observed that the metal-free fiber shows a hinge fan-like motion of the S-shaped structure, maintaining the general conformation. Upon metal coordination, distinctive patterns are observed depending on the metal. Cu(II) binds to the flexible N-terminal region and induces structural changes that could ultimately disrupt the fibrillary structure. In contrast, Al(III) binding takes place with the residues Glu22 and Asp23, and its binding reinforces the core stability of the system. These results give clues on the molecular impact of the interaction of metal ions with the aggregates and sustain their non-innocent roles in the evolution of the illness.

Relationship Between Game Load and Player's Performance in Professional Basketball.

PURPOSE: The purpose of the study was to examine the relationships between external and internal loads, and their ratio (efficiency index), with game performance between backcourt and frontcourt professional basketball players. METHODS: Game loads of 14 basketball players were monitored during 6 games. External load variables measured were total distance (TD); distance >18 km·h-1, commonly known as high-speed running (HSR); and number of accelerations (ACC) and decelerations (DEC) >3 m·s-2, whereas the internal load variable measured was average heart rate (HRmean). The ratio between external and internal load variables was calculated and defined through 4 efficiency indexes (TD:HRmean, HSR:HRmean, ACC:HRmean, and DEC:HRmean). Furthermore, basketball performance was quantified using game-related statistics. RESULTS: TD presented a small association with basketball performance, whereas the other external load variables and the 4 efficiency indexes calculated showed trivial relationships with game-related statistics. Furthermore, HRmean showed the greatest (small) associations with individual performance (P = .01-.02; r = .19 to .22). Regarding specific positions, the only 2 variables that presented significant differences were DEC (P = .01; d = 0.86) and DEC:HRmean (P = .01; d = 0.81), which showed higher values in backcourt players compared with frontcourt players. CONCLUSIONS: The results suggest that the best performances of basketball players during official competition are not associated with higher game loads. This illustrates the necessity to assess basketball performance from a holistic approach and consider more than just external and internal variables to better understand the players' performance during basketball competition.

Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide.

RAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the αH helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II). NMR spectroscopy and MD studies demonstrate that Pd(II) has a nucleating effect that facilitates the access to the bioactive α-helical conformation. The binding can be suppressed by an external metal chelator and recovered again by the addition of more Pd(II), making this system the first switchable KRAS binder, and demonstrates that folding-upon-binding mechanisms can operate in metal-nucleated peptides. In vitro experiments show that the metallopeptide can efficiently internalize into living cells and inhibit the MAPK kinase cascade.

Impact of Cu(II) and Al(III) on the conformational landscape of amyloidß1-42.

Metal ions have been found to play an important role in the formation of extracellular ß-amyloid plaques, a major hallmark of Alzheimer's disease. In the present study, the conformational landscape of Aß42 with Al(iii) and Cu(ii) has been explored using Gaussian accelerated molecular dynamics. Both metals reduce the flexibility of the peptide and entail a higher structural organization, although to different degrees. As a general trend, Cu(ii) binding leads to an increased α-helix content and to the formation of two α-helices that tend to organize in a U-shape. By contrast, most Al(iii) complexes induce a decrease in helical content, leading to more extended structures that favor the appearance of transitory ß-strands.

BioMetAll: Identifying Metal-Binding Sites in Proteins from Backbone Preorganization.

With a large amount of research dedicated to decoding how metallic species bind to proteins, in silico methods are interesting allies for experimental procedures. To date, computational predictors mostly work by identifying the best possible sequence or structural match of the target protein with metal-binding templates. These approaches are fundamentally focused on the first coordination sphere of the metal. Here, we present the BioMetAll predictor that is based on a different postulate: the formation of a potential metal-binding site is related to the geometric organization of the protein backbone. We first report the set of convenient geometric descriptors of the backbone needed for the algorithm and their parameterization from a statistical analysis. Then, the successful benchmark of BioMetAll on a set of more than 90 metal-binding X-ray structures is presented. Because BioMetAll allows structural predictions regardless of the exact geometry of the side chains, it appears extremely valuable for systems whose structures (either experimental or theoretical) are not optimal for metal-binding sites. We report here its application on three different challenging cases: (i) the modulation of metal-binding sites during conformational transition in human serum albumin, (ii) the identification of possible routes of metal migration in hemocyanins, and (iii) the prediction of mutations to generate convenient metal-binding sites for de novo biocatalysts. This study shows that BioMetAll offers a versatile platform for numerous fields of research at the interface between inorganic chemistry and biology and allows to highlight the role of the preorganization of the protein backbone as a marker for metal binding. BioMetAll is an open-source application available at https://github.com/insilichem/biometall.

Dynamic Stereoselection of Peptide Helicates and Their Selective Labeling of DNA Replication Foci in Cells*.

Although largely overlooked in peptide engineering, coordination chemistry offers a new set of interactions that opens unexplored design opportunities for developing complex molecular structures. In this context, we report new artificial peptide ligands that fold into chiral helicates in the presence of labile metal ions such as FeII and CoII . Heterochiral ß-turn-promoting sequences encode the stereoselective folding of the peptide ligands and define the physicochemical properties of their corresponding metal complexes. Circular dichroism and NMR spectroscopy in combination with computational methods allowed us to identify and determine the structure of two isochiral ΛΛ-helicates, folded as topological isomers. Finally, in addition to the in-vitro characterization of their selective binding to DNA three-way junctions, cell-microscopy experiments demonstrated that a rhodamine-labeled FeII helicate was internalized and selectively stains DNA replication factories in functional cells.

Optical Biosensors for the Detection of Rheumatoid Arthritis (RA) Biomarkers: A Comprehensive Review.

A comprehensive review of optical biosensors for the detection of biomarkers associated with rheumatoid arthritis (RA) is presented here, including microRNAs (miRNAs), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), interleukin-6 (IL-6) and histidine, which are biomarkers that enable RA detection and/or monitoring. An overview of the different optical biosensors (based on fluorescence, plasmon resonances, interferometry, surface-enhanced Raman spectroscopy (SERS) among other optical techniques) used to detect these biomarkers is given, describing their performance and main characteristics (limit of detection (LOD) and dynamic range), as well as the connection between the respective biomarker and rheumatoid arthritis. It has been observed that the relationship between the corresponding biomarker and rheumatoid arthritis tends to be obviated most of the time when explaining the mechanism of the optical biosensor, which forces the researcher to look for further information about the biomarker. This review work attempts to establish a clear association between optical sensors and rheumatoid arthritis biomarkers as well as to be an easy-to-use tool for the researchers working in this field.

Third Ventricle Width Assessed by Transcranial Sonography as Predictor of Long-Term Cognitive Impairment.

BACKGROUND: Non-invasive biomarkers of cognitive impairment are needed. We aim to evaluate transcranial sonographic markers as predictors of cognitive impairment in a prospective cohort. OBJECTIVE: To study the changes in the third ventricle diameter and the SN echogenicity between the baseline and the control visit, as well as its association with cognitive performance and the diagnosis of cognitive impairment in a prospective cohort. METHODS: From the longitudinal population-based Asymptomatic Intracranial Atherosclerosis Study, we selected those subjects that received a complete transcranial sonography (TCS) and extensive cognitive testing, both at baseline and follow-up. We evaluated third ventricle (IIIv) width, echogenicity of substantia nigra (SN), and temporal changes of these parameters. RESULTS: We included 289 participants with a median follow-up time of 7.16 years. Those subjects who developed cognitive decline (n = 23, 7.96%) had a larger IIIv at baseline than those who did not (0.54±0.14 cm versus 0.41±0.15 cm; p = 0.001). A cut-off point of 0.465 cm for the IIIv width was identified as an independent predictor of long-term cognitive impairment after adjustment for age, gender, educational level, and vascular risk score. Change in IIIv diameter after follow-up was not associated with diagnosis of cognitive impairment. The area of SN and the presence of hyperechogenicity of the SN remained stable over time and was not associated with the diagnosis of cognitive impairment. CONCLUSION: IIIv width assessed by TCS emerged as an independent predictor of long-term cognitive impairment.

Hepatic resection with thrombectomy in the treatment of hepatocellular carcinoma associated with macrovascular invasion. / Resección hepática con trombectomía en el tratamiento del carcinoma hepatocelular con invasión vascular macroscópica.

INTRODUCTION: Macrovascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) is a very poor prognostic factor. Treatment in such cases is still a matter of debate. The goal of this study is to assess short- and long-term results of liver resection and thrombectomy in a series of patients with HCC and MVI. METHODS: Retrospective cohort study of patients who underwent liver resection for HCC in the period 2007-2015 (n=120). Of all the patients, 108 did not have MVI, while 12 presented with MVI: 1patient in the common portal vein (Vp4), 8patients in first-order portal branches (Vp3), 1patient in a sectorial branch (Vp2), 1patient in a segmental branch (Vp1); another patient presented with tumor thrombus in a main hepatic venous branch in the confluence with the vena cava (Vv2). RESULTS: Patients with MVI needed major hepatic resection more frequently than patients without MVI (83.3% vs 25.9%, P<.0001), with no differences in postoperative mortality or severe morbidity. Patients with MVI required a longer operative time and developed more frequently postoperative ascites (33.3% vs 9.3%, P=.034). Global survival at 1, 3 and 5years was 66.7%, 33.3% and 22.2% in patients with IMV, and 90.7%, 72.4% and 52.2% in patients without IMV (P=.009), respectively. CONCLUSIONS: Hepatectomy associated with thrombectomy might be justified in a selected group of patients with HCC and MVI, offering a potential benefit in survival with acceptable morbidity.

Hepatic flow is an intraoperative predictor of early allograft dysfunction in whole-graft deceased donor liver transplantation: An observational cohort study.

BACKGROUND: Early allograft dysfunction (EAD) after liver transplantation (LT) is an important cause of morbidity and mortality. To ensure adequate graft function, a critical hepatocellular mass is required in addition to an appropriate blood supply. We hypothesized that intraoperative measurement of portal venous and hepatic arterial flow may serve as a predictor in the diagnosis of EAD. AIM: To study whether hepatic flow is an independent predictor of EAD following LT. METHODS: This is an observational cohort study in a single institution. Hepatic arterial blood flow and portal venous blood flow were measured intraoperatively by transit flow. EAD was defined using the Olthoff criteria. Univariate and multivariate analyses were used to determine the intraoperative predictors of EAD. Survival analysis and prognostic factor analysis were performed using the Kaplan-Meier and Cox regression models. RESULTS: A total of 195 liver transplant procedures were performed between January 2008 and December 2014 in 188 patients. A total of 54 (27.7%) patients developed EAD. The median follow-up was 39 mo. Portal venous flow, hepatic arterial flow (HAF) and total hepatic arterial flow were associated with EAD in both the univariate and multivariate analyses. HAF is an independent prognostic factor for 30-d patient mortality. CONCLUSION: Intraoperative measurement of blood flow after reperfusion appears to be a predictor of EAD; Moreover, HAF should be considered a predictor of 30-d patient mortality.

Juvenile polyautoimmunity in a rheumatology setting.

Overt polyautoimmunity (PolyA) corresponds to the presence of more than one well-defined autoimmune disease (AD) manifested clinically in a single patient. The current study aimed to describe the main characteristics of juvenile PolyA in a pediatric rheumatology setting and analyze the chronological aspects, index cases, familial autoimmunity, and clustering pattern. This was a cross-sectional and multicenter study in which 313 children with overt PolyA were included. Patients were systematically interviewed and their medical records reviewed using a questionnaire that sought information about demographic, clinical, immunological, and familial characteristics. A hierarchical cluster analysis was done to determine similarities between autoimmune diseases based on PolyA. PolyA occurred simultaneously in 138 (44%) patients. Multiple autoimmune syndrome was observed in 62 (19.8%) patients. There were 25 index diseases of which, systemic lupus erythematosus (SLE, n = 134, 42.8%), juvenile idiopathic arthritis (JIA, n = 40, 12.7%), Hashimoto's thyroiditis (HT, n = 24, 7.66%), immune thrombocytopenic purpura (ITP n = 20, 6.39%), antiphospholipid syndrome (APS, n = 15, 4.79%), and vitiligo (VIT, n = 15, 4.79%) were the most frequent and represented 79.23% of the total number of patients. Familial autoimmunity influenced PolyA. A high aggregation of autoimmunity was observed (λr = 3.5). Three main clusters were identified, of which SLE and APS were the most similar pair of diseases (based on the Jaccard index) followed by HT and JIA, which were related to ITP and Sjögren's syndrome. The third cluster was composed of localized scleroderma and VIT. Our findings may assist physicians to make an early diagnosis of this frequent condition. Pediatric patients with ADs should be systematically assessed for PolyA.

Estructura factorial y consistencia interna del Cuestionario de Evaluación de Docentes Clínicos en el Internado de Fonoaudiología / Factorial structure and internal consistency of Clinic Teachers Assessment Questionnaire in Speech Therapy Internship

Introducción : Los estudiantes del último año de la carrera de Fonoaudiología, son supervisados en la clínica, por un tutor que ejerce un rol de profesor sin necesariamente tener formación pedagógica, y, para la evaluación de su docencia, no se dispone de un instrumento con evidencias de validez y confiabilidad. Objetivo : Evaluar las propiedades psicométricas del "Cuestionario de evaluación de docentes clínicos (CEDC)" en el internado de la carrera de Fonoaudiología de una universidad tradicional de Concepción. Métodos : Estudio mixto y analítico relacional, mediante encuestas. Las encuestas fueron respondidas por 43 estudiantes elegidos mediante muestreo no probabilístico por accesibilidad, quienes efectuaron 137 valoraciones empleando el CEDC, siendo evaluados 38 tutores. Se realizó consentimiento informado y se contó con autorización de la jefatura de carrera. Resultados : Se efectuó un análisis factorial exploratorio mediante el cálculo estadístico de adecuación muestral de Kaiser-Meyer-Olkin=0,95 y la prueba de esfericidad de Bartlett c 2(325)=4092,05; p<0,001. En la estimación del número de factores se empleó el criterio de Kaiser-Guttman identificando tres factores con autovalores de 16,71, 1,23 y 1,07. Estos factores mostraron una confiabilidad con coeficientes Alfa de Cronbach de a=0,97, a=0,93 y a=0,89, y correlaciones con la nota global del tutor estadísticamente significativas y directas. Conclusiones : El CEDC presenta evidencias de confiabilidad, validez de constructo y validez de criterio. Se compone de los factores: "Promotor de un diálogo permanente", "Promotor de condiciones para un desempeño seguro" e "Instructor de técnicas". El CEDC permitirá caracterizar a los profesores clínicos, posibilitando innovaciones pedagógicas en el internado(AU)

Introduction : Final year Speech Therapy students are supervised by a tutor in the clinic, who plays a role of teacher without necessarily being qualified. There are not instruments available to evaluate if these tutors teaching is proven to be reliable. Objective: The aim is to evaluate the psychometric properties of "Clinic Teachers Assessment Questionnaire (CTAQ)" in Speech Therapy degree internships in a traditional university in Concepción. Method : Analytical, relational and mixed studies, using surveys. The surveys were answered by 43 students who were selected using a sampling method that was not probabilistic in terms of accessibility. These students carried out 137 reviews using the CTAQ, evaluating 38 tutors. Informed consent was given and it was authorized by the person in charge of the major. Results: An exploratory factor analysis was carried out using the Kaiser-Meyer-Olkin=0,95 statistical calculation of sampling adequacy and Bartlett's test of sphericity c2(325)=4092,05; p<0,001. The Kaiser-Guttman criterion was used when estimating the number of factors, identifying three factors with eigenvalues of 16,71, 1,23 and 1,07. These factors displayed reliability with Cronbach's alpha coefficients a=0,97, a=0,93 and a=0,89. They also displayed a direct correlation with the teacher's overall score of that were statistically significant. Conclusions : The CTAQ shows signs of reliability and validity of design and criteria. The CTAQ displays the following factors: "promotes ongoing dialogue", "promotes conditions for safe performance" and "teaches techniques". The CTAQ allows the clinical teachers to be characterized, and enables teaching innovation in the internships(AU)

miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS.

The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.