WIP Drives Tumor Progression through YAP/TAZ-Dependent Autonomous Cell Growth

In cancer, the deregulation of growth signaling pathways drives changes in the cell¿s architecture and its environment that allow autonomous growth of tumors. These cells then acquire a tumor-initiating ¿stemness¿ phenotype responsible for disease advancement to more aggressive stages. Here, we show that high levels of the actin cytoskeleton-associated protein WIP (WASP-interacting protein) correlates with tumor growth, both of which are linked to the tumor-initiating cell phenotype. We find that WIP controls tumor growth by boosting signals that stabilize the YAP/TAZ complex via a mechanism mediated by the endocytic/endosomal system. When WIP levels are high, the ß-catenin Adenomatous polyposis coli (APC)-axin-GSK3 destruction complex is sequestered to the multi-vesicular body compartment, where its capacity to degrade YAP/TAZ is inhibited. YAP/TAZ stability is dependent on Rac, p21-activated kinase (PAK) and mammalian diaphanous-related formin (mDia), and is Hippo independent. This close biochemical relationship indicates an oncogenic role for WIP in the physiology of cancer pathology by increasing YAP/TAZ stability.MINECO (SAF2013-45937-R to I.M.A.) and MINECO/FEDER (SAF2015-70368-R to I.M.A. and F.W.), the European Union (EU-FP7-2009-CT222887 to F.W.), the Instituto de Salud Carlos III Centro de Investigación Biomédica en Red (CIBERNED to F.W.) and by a grant from ISCIII-RETIC (RD12/0036/0009 to R.G.E.)Peer Reviewe

Incidence, prevalence and persistence of bovine venereal diseases in La Pampa (Argentina): estimations for the period 2007 - 2020

The venereal diseases Bovine Trichomoniasis (BT) and Bovine Genital Campylobacteriosis (BGC) cause economic losses in endemic areas, such as the province of La Pampa in Argentina, where bovine production is typically extensive. This study has used data compiled from 2007 to 2013 by the Official Program for the Control and Eradication (PCE) of venereal diseases, aiming to determine the prevalence, incidence and persistence of BT and BGC and to provide projections until 2020. Fourteen univariate models were used to adjust each time series. The prevalence and incidence of both diseases have significantly decreased during the studied period, while the persistence has remained constant. The prevalence of BT has diminished from 7.48% in 2007 to 3.03% in 2013, while the prevalence of BGC has diminished from 9.36% to 3.15%. The incidences have been reduced to an annual average of 0.60 for BT and 0.67 for BGC. Although the estimation models are not able to predict accurately the future epidemiologic rates of BT and BGC in La Pampa, projections show a significant decreasing trend of the prevalence and incidence of BT and BGC. The persistence of BGC is expected to remain close to the 2007-2013 average, while the persistence of BT did not adjust to any of the 14 models used. These results indicate that PCE has been effective to reduce the infection of disease-free herds. However, in order to reduce the ratio of persistent herds, other preventive and management measures should be considered. Highlights The venereal diseases Bovine Trichomoniasis (BT) and Bovine Genital Campylobacteriosis (BGC) cause economic losses. Univariate analysis was an effective tool for modeling the historical and future prevalence, incidence and persistence of BT and BGC infections. The prevalence and incidence of BT and BGC have significantly decreased during the studied period, while the persistence has remained constant. The Official Program for the Control and Eradication (PCE) of venereal diseases, has been effective to reduce the infection of disease-free herds.The venereal diseases Bovine Trichomoniasis (BT) and Bovine Genital Campylobacteriosis (BGC) cause economic losses in endemic areas, such as the province of La Pampa in Argentina, where bovine production is typically extensive. This study has used data compiled from 2007 to 2013 by the Official Program for the Control and Eradication (PCE) of venereal diseases, aiming to determine the prevalence, incidence and persistence of BT and BGC and to provide projections until 2020. Fourteen univariate models were used to adjust each time series. The prevalence and incidence of both diseases have significantly decreased during the studied period, while the persistence has remained constant. The prevalence of BT has diminished from 7.48% in 2007 to 3.03% in 2013, while the prevalence of BGC has diminished from 9.36% to 3.15%. The incidences have been reduced to an annual average of 0.60 for BT and 0.67 for BGC. Although the estimation models are not able to predict accurately the future epidemiologic rates of BT and BGC in La Pampa, projections show a significant decreasing trend of the prevalence and incidence of BT and BGC. The persistence of BGC is expected to remain close to the 2007-2013 average, while the persistence of BT did not adjust to any of the 14 models used. These results indicate that PCE has been effective to reduce the infection of disease-free herds. However, in order to reduce the ratio of persistent herds, other preventive and management measures should be considered. Highlights The venereal diseases Bovine Trichomoniasis (BT) and Bovine Genital Campylobacteriosis (BGC) cause economic losses. Univariate analysis was an effective tool for modeling the historical and future prevalence, incidence and persistence of BT and BGC infections. The prevalence and incidence of BT and BGC have significantly decreased during the studied period, while the persistence has remained constant. The Official Program for the Control and Eradication (PCE) of venereal diseases, has been effective to reduce the infection of disease-free herds

Cleaving of PMMA Microstructured Polymer Optical Fibers with 3- and 4-Ring Hexagonal Cladding Structures

The cleaving of a novel microstructured polymer optical fiber (mPOF) to obtain an acceptable connectorized fiber end-face is studied. The effect of the blade temperature and the speed of the cutting blade on the end-face is qualitatively assessed. Recently manufactured mPOFs with air-structured 3- and 4-ring hexagonal-like hole cladding structures with outer fiber diameters of around 250 μm are employed. Good quality end-faces can be obtained by cleaving mPOF fibers at room temperature for blade temperatures within the range 60–80 °C and at a low blade speed at 0.5 mm/s. The importance of the blade surface quality is also addressed, being a critical condition for obtaining satisfactory mPOF end-faces after cleaving. From our experiments, up to four fiber cuts with the same razor blade and blade surface can be carried out with acceptable and similar fiber end-face results.This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades and Comunidad de Madrid under grants RTI2018-094669-B-C32 and P2018/NMT-4326, respectively, and FSE

Incidencia, prevalencia y persistencia de enfermedades venéreas de los bovinos en La Pampa (Argentina): estimaciones para el período 2007 - 2020

The venereal diseases Bovine Trichomoniasis (BT) and Bovine Genital Campylobacteriosis (BGC) cause economic losses in endemic areas, such as the province of La Pampa in Argentina, where bovine production is typically extensive. This study has used data compiled from 2007 to 2013 by the Official Program for the Control and Eradication (PCE) of venereal diseases, aiming to determine the prevalence, incidence and persistence of BT and BGC and to provide projections until 2020. Fourteen univariate models were used to adjust each time series. The prevalence and incidence of both diseases have significantly decreased during the studied period, while the persistence has remained constant. The prevalence of BT has diminished from 7.48% in 2007 to 3.03% in 2013, while the prevalence of BGC has diminished from 9.36% to 3.15%. The incidences have been reduced to an annual average of 0.60 for BT and 0.67 for BGC. Although the estimation models are not able to predict accurately the future epidemiologic rates of BT and BGC in La Pampa, projections show a significant decreasing trend of the prevalence and incidence of BT and BGC. The persistence of BGC is expected to remain close to the 2007-2013 average, while the persistence of BT did not adjust to any of the 14 models used. These results indicate that PCE has been effective to reduce the infection of disease-free herds. However, in order to reduce the ratio of persistent herds, other preventive and management measures should be considered.Las enfermedades venéreas Tricomoniasis bovina (BT) y Campilobacteriosis genital bovina (BGC) causan pérdidas económicas en áreas endémicas, como en la provincia de La Pampa en Argentina, donde la producción bovina es típicamente de carácter extensivo. Este estudio ha utilizado datos compilados de 2007 a 2013 por el Programa Oficial para el Control y la Erradicación (PCE) de enfermedades venéreas, con el objetivo de determinar la prevalencia, incidencia y persistencia de BT y BGC y proporcionar proyecciones hasta 2020. Catorce modelos univariantes fueron utilizados para ajustar cada serie temporal. La prevalencia e incidencia de ambas enfermedades han disminuido significativamente durante el período estudiado, mientras que la persistencia se ha mantenido constante. La prevalencia de BT ha disminuido del 7,48% en 2007 al 3,03% en 2013, mientras que la prevalencia de BGC ha disminuido del 9,36% al 3,15%. Las incidencias se han reducido a un promedio anual de 0,60 para BT y 0,67 para BGC. Aunque los modelos de estimación no pueden predecir con precisión las tasas epidemiológicas futuras de BT y BGC en La Pampa, las proyecciones muestran una tendencia decreciente significativa de la preva lencia e incidencia de BT y BGC. Se espera que la persistencia de BGC se mantenga cerca del promedio de 2007-2013, mientras que la persistencia de BT no se ajustó a ninguno de los 14 modelos utilizados. Estos resultados indican que PCE ha sido eficaz para reducir la infección de rebaños libres de enfermedades. Sin embargo, para reducir la proporción de rebaños persistentes, se deben considerar otras medidas preventivas y de manejo

Electrophysiological resting‐state hyperconnectivity and poorer behavioural regulation as predisposing profiles of adolescent binge drinking

Adolescent Binge Drinking (BD) has become an increasing health and social concern, with detrimental consequences for brain development and functional integrity. However, research on neurophysiological and neuropsychological traits predisposing to BD are limited at this time. In this work, we conducted a 2-year longitudinal magnetoencephalography (MEG) study over a cohort of initially alcohol-naïve adolescents with the purpose of exploring anomalies in resting-state electrophysiological networks, impulsivity, sensation-seeking, and dysexecutive behaviour able to predict future BD patterns. In a sample of 67 alcohol-naïve adolescents (age = 14.5 ± 0.9), we measured resting-state activity using MEG. Additionally, we evaluated their neuropsychological traits using self-report ecological scales (BIS-11, SSS-V, BDEFS, BRIEF-SR and DEX). In a second evaluation, 2 years later, we measured participant's alcohol consumption, sub-dividing the original sample in two groups: future binge drinkers (22 individuals, age 14.6 ± 0.8; eight females) and future light/no drinkers (17 individuals, age 14.5 ± 0.8; eight females). Then, we searched for differences predating alcohol BD intake. We found abnormalities in MEG resting state, in a form of gamma band hyperconnectivity, in those adolescents who transitioned into BD years later. Furthermore, they showed higher impulsivity, dysexecutive behaviours and sensation seeking, positively correlated with functional connectivity (FC). Sensation seeking and impulsivity mainly predicted BD severity in the future, while the relationship between dysexecutive trait and FC with future BD was mediated by sensation seeking. These findings shed light to electrophysiological and neuropsychological traits of vulnerability towards alcohol consumption. We hypothesise that these differences may rely on divergent neurobiological development of inhibitory neurotransmission pathways and executive prefrontal circuits

Exchange Bias Optimization by Controlled Oxidation of Cobalt Nanoparticle Films Prepared by Sputter Gas Aggregation

Porous films of cobalt nanoparticles have been obtained by sputter gas aggregation and controllably oxidized by air annealing at 100 C for progressively longer times (up to more than 1400 h). The magnetic properties of the samples were monitored during the process, with a focus on the exchange bias field. Air annealing proves to be a convenient way to control the Co/CoO ratio in the samples, allowing the optimization of the exchange bias field to a value above 6 kOe at 5 K. The occurrence of the maximum in the exchange bias field is understood in terms of the density of CoO uncompensated spins and their degree of pinning, with the former reducing and the latter increasing upon the growth of a progressively thicker CoO shell. Vertical shifts exhibited in the magnetization loops are found to correlate qualitatively with the peak in the exchange bias field, while an increase in vertical shift observed for longer oxidation times may be explained by a growing fraction of almost completely oxidized particles. The presence of a hummingbird-like form in magnetization loops can be understood in terms of a combination of hard (biased) and soft (unbiased) components; however, the precise origin of the soft phase is as yet unresolved

Differences in clinical features and mortality in very old unvaccinated patients (≥ 80 years) hospitalized with COVID-19 during the first and successive waves from the multicenter SEMI-COVID-19 Registry (Spain)

Background: Old age is one of the most important risk factors for severe COVID-19. Few studies have analyzed changes in the clinical characteristics and prognosis of COVID-19 among older adults before the availability of vaccines. This work analyzes differences in clinical features and mortality in unvaccinated very old adults during the first and successive COVID-19 waves in Spain. Methods This nationwide, multicenter, retrospective cohort study analyzes unvaccinated patients >= 80 years hospitalized for COVID-19 in 150 Spanish hospitals (SEMI-COVID-19 Registry). Patients were classified according to whether they were admitted in the first wave (March 1-June 30, 2020) or successive waves (July 1-December 31, 2020). The endpoint was all-cause in-hospital mortality, expressed as the case fatality rate (CFR). Results Of the 21,461 patients hospitalized with COVID-19, 5,953 (27.7%) were >= 80 years (mean age [IQR]: 85.6 [82.3-89.2] years). Of them, 4,545 (76.3%) were admitted during the first wave and 1,408 (23.7%) during successive waves. Patients hospitalized in successive waves were older, had a greater Charlson Comorbidity Index and dependency, less cough and fever, and met fewer severity criteria at admission (qSOFA index, PO2/FiO2 ratio, inflammatory parameters). Significant differences were observed in treatments used in the first (greater use of antimalarials, lopinavir, and macrolides) and successive waves (greater use of corticosteroids, tocilizumab and remdesivir). In-hospital complications, especially acute respiratory distress syndrome and pneumonia, were less frequent in patients hospitalized in successive waves, except for heart failure. The CFR was significantly higher in the first wave (44.1% vs. 33.3%; -10.8%; p = 95 years (54.4% vs. 38.5%; -15.9%; p < 0.001). After adjustments to the model, the probability of death was 33% lower in successive waves (OR: 0.67; 95% CI: 0.57-0.79). Conclusions Mortality declined significantly between the first and successive waves in very old unvaccinated patients hospitalized with COVID-19 in Spain. This decline could be explained by a greater availability of hospital resources and more effective treatments as the pandemic progressed, although other factors such as changes in SARS-CoV-2 virulence cannot be ruled out

Characteristics of 24 SARS-CoV-2-Sequenced Reinfection Cases in a Tertiary Hospital in Spain

SARS-CoV-2; Clinical features; ReinfectionSARS-CoV-2; Características clínicas; ReinfecciónSARS-CoV-2; Característiques clíniques; ReinfeccióBackground: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the main concern is whether reinfections are possible, and which are the associated risk factors. This study aims to describe the clinical and molecular characteristics of 24 sequence-confirmed reinfection SARS-CoV-2 cases over 1 year in Barcelona (Catalonia, Spain). Methods: Patients with > 45 days between two positive PCR tests regardless of symptoms and negative tests between episodes were initially considered as suspected reinfection cases from November 2020 to May 2021. Whole-genome sequencing (WGS) was performed to confirm genetic differences between consensus sequences and for phylogenetic studies based on PANGOLIN nomenclature. Reinfections were confirmed by the number of mutations, change in lineage, or epidemiological criteria. Results: From 39 reported suspected reinfection cases, complete viral genomes could be sequenced from both episodes of 24 patients, all were confirmed as true reinfections. With a median age of 44 years (interquartile range [IQR] 32–65), 66% were women and 58% were healthcare workers (HCWs). The median days between episodes were 122 (IQR 72–199), occurring one-third within 3 months. Reinfection episodes were frequently asymptomatic and less severe than primary infections. The absence of seroconversion was associated with symptomatic reinfections. Only one case was reinfected with a variant of concern (VOC). Conclusion: Severe acute respiratory syndrome coronavirus 2 reinfections can occur in a shorter time than previously reported and are mainly found in immunocompetent patients. Surveillance through WGS is useful to identify viral mutations associated with immune evasion.This research was supported by CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU

A year living with SARS-CoV-2: an epidemiological overview of viral lineage circulation by whole-genome sequencing in Barcelona city (Catalonia, Spain)

Catalonia; SARS-CoV-2; Molecular epidemiologyCataluña; SARS-CoV-2; Epidemiología molecularCatalunya; SARS-CoV-2; Epidemiologia molecularHerein, we describe the genetic diversity of circulating SARS-CoV-2 viruses by whole-genome sequencing (WGS) in Barcelona city (Catalonia, Spain) throughout the first four pandemic waves. From weeks 11/2020–24/2021, SARS-CoV-2-positive respiratory samples were randomly selected per clinical setting (80% from primary care or 20% from the hospital), age group, and week. WGS was performed following the ARTICv3 protocol on MiSeq or NextSeq2000 Illumina platforms. Nearly complete consensus sequences were used for genetic characterization based on GISAID and PANGOLIN nomenclatures. From 2475 samples, 2166 (87%) were fully sequenced (78% from primary care and 22% from hospital settings). Multiple genetic lineages were co-circulating, but four were predominant at different periods. While B.1.5 (50.68%) and B.1.1 (32.88%) were the major lineages during the first pandemic wave, B.1.177 (66.85%) and B.1.1.7 (83.80%) were predominant during the second, third, and fourth waves, respectively. Almost all (96.4%) were carrying D614G mutation in the S protein, with additional mutations that define lineages or variants. But some mutations of concern, such as E484K from B.1.351 and P.1 lineages are currently under monitoring, together with those observed in the receptor-binding domain or N-terminal domain, such as L452R and T478K from B.1.617.2 lineage. The fact that a predominant lineage was observed in each pandemic wave suggests advantageous properties over other contemporary co-circulating variants. This genetic variability should be monitored, especially when a massive vaccination campaign is ongoing because the potential selection and emergence of novel antigenic SARS-CoV-2 strains related to immunological escapement events.This work was supported by Spanish Network for the Research in Infectious Diseases: [Grant Number REIPI RD16/0016/0003]; Centro para el Desarrollo Tecnológico Industrial (CDTI) from the Spanish Ministry of Economy and Business [Grant Number IDI-20200297]; Direcció General de Recerca i Innovació en Salut (DGRIS); European Development Regional Fund (ERDF) “A way to achieve Europe” by Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0003]