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Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacologic inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation) and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncovered a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells. Significance: These findings uncover a novel function of CDK4 in lysosomal biology, which promotes cancer progression by activating mTORC1; targeting this function offers a new therapeutic strategy for cancer treatment.

Asphalt pavements in cold regions are susceptible to thermal cracking. Current construction practice of adding reclaimed asphalt pavement to virgin materials further deteriorates the low-temperature performance of asphalt concrete. This study concentrates on finding equivalence between short-term aging of loose asphalt mixtures and long-term aging of compacted mixtures by following the AASHTO TP125-16. Asphalt mixtures made from two Superpave® mix designs, four different Reclaimed Asphalt Pavement (RAP) contents and six different aging periods at two different temperatures were analyzed in this study. RAP and Aging Indices were proposed to demonstrate the combined change in the performance of asphalt mixtures due to the addition of RAP and aging. It was found that four hours of additional loose-mixture-aging at 135 °C yields low-temperature performances similar to five days of compact-mixture-aging at 80 °C. Results found from this study contribute to the benefits of Bending Beam Rheometer as a potential quality control tool for low-temperature performance during construction.

espanol?Cuales son los costos y beneficios de perder la aplicacion de una politica monetaria convencional en una economia emergente? En este articulo para responder esta pregunta nos enfocamos en el impacto de la dolarizacion en Ecuador, sobre la incertidumbre institucional o macroeconomica y el crecimiento economico. Adoptamos una perspectiva de economia institucional dentro de la cual la estrategia empirica que implementamos aqui, refleja la relevancia de entornos macroeconomicos con certidumbre de reglas para que agentes economicos produzcan mejor. Esta estrategia empirica tiene como novedad el diseno de un Indice de Incertidumbre Institucional basado en un analisis de componentes principales. Este indice se usa dentro de un modelo VAR de la economia ecuatoriana para entender como la incertidumbre afecta al crecimiento. Las funciones impulso respuesta para los periodos previo y posterior a la dolarizacion en Ecuador, ano 2000, arrojan resultados de como el cambio en la institucion monetaria redujo la incertidumbre lo que ha llevado a mejoras en el crecimiento. EnglishWhat are the trade-offs of losing the capacity of implementing a conventional monetary policy within an emergent economy? In this paper, to answer this question we focus on the impact of dollarization on institutional or macroeconomic uncertainty and economic growth in Ecuador. Our empirical strategy is embedded within a new institutional economics framework. This shed light on the relevance of certainty in macroeconomic environments in order for economic agents to improve production. The novelty in this empirical approach is the design of an Index of Institutional Uncertainty based upon the method of Principal Component Analysis. In turn, this index is used with a VAR model developed for the Ecuadorian economy to study how uncertainty affects economic growth. The impulse response functions for periods before and after dollarization, in 2000, yield results that this policy helped to reduce uncertainty and via this mechanism promoted economic growth.

Anti-PD-1/PD-L1 blockade can restore tumour-specific T-cell immunity and is an emerging therapy in non-small-cell lung cancer (NSCLC). We investigated the correlation between 18F-FDG PET/CT-based markers and tumour tissue expression of PD-L1, necrosis and clinical outcome in patients receiving checkpoint inhibitor treatment. PD-Li expression in biopsy or resection specimens from 49 patients with confirmed NSCLC was investigated by immunohistochemistry. Maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were obtained from 18F-FDG PET/CT images. The ratio of metabolic to morphological lesion volumes (MMVR) and its association with PD-L1 expression in each lesion were calculated. The associations between histologically reported necrosis and 18F-FDG PET imaging patterns and radiological outcome (evaluated by iRECIST) following anti-PD-1/PD-L1 therapy were also analysed. In 14 patients, the association between necrosis and MMVR and tumour immune contexture were analysed by multiple immunofluorescent (IF) staining for CD8, PD-1, granzyme B (GrzB) and NFATC2. In total, 25 adenocarcinomas and 24 squamous cell carcinomas were analysed. All tumours showed metabolic 18F-FDG PET uptake. MMVR was correlated inversely with PD-L1 expression in tumour cells. Furthermore, PD-L1 expression and low MMVR were significantly correlated with clinical benefit. Necrosis was correlated negatively with MMVR. Multiplex IF staining showed a greater frequency of activated CD8+ cells in necrotic tumours than in nonnecrotic tumours in both stromal and epithelial tumour compartments. This study introduces MMVR as a new imaging biomarker and its ability to noninvasively capture increased PD-L1 tumour expression and predict clinical benefit from checkpoint blockade in NSCLC should be further evaluated.

espanolSe determino el efecto del ultrasonido a diferentes tiempos y temperatura sobre el pH, la estabilidad de la emulsion y la textura de emulsiones preparadas con carne de bufalo. Se prepararon emulsiones, se trataron con ultrasonido a 37 kHz durante 3, 5 y 10 min, se escaldaron, empacaron al vacio y almacenaron a 4°C. La calidad de la emulsion se evaluo midiendo el pH, la estabilidad de la emulsion y un analisis de perfil de textura. El pH de la emulsion preparada con carne de bufalo disminuye cuando es tratada con ultrasonido a 3 y 5 min mientras que a 10 min no presento diferencia significativa con el control (muestras no tratadas con ultrasonido). La estabilidad de la emulsion aumenta con el tratamiento de ultrasonido. La dureza y la masticabilidad disminuyeron significativamente (significancia de 5%) respecto al control, mientras que la elasticidad y la cohesividad no fueron afectadas por el tratamiento. EnglishThe effect of ultrasound at different times and temperatures on pH, emulsion stability and texture of buffalo meat emulsions was determined. Emulsions were prepared, treated with ultrasound at 37 kHz for 3, 5 and 10 min, blanched, vacuum packed and stored at 4°C. Emulsion quality was evaluated by measuring pH, emulsion stability and a texture profile analysis. The pH of the emulsion prepared with buffalo meat decreases when it is treated with ultrasound at 3 and 5 min while at 10 min it does not present a significant difference with the control (samples not treated with ultrasound). The stability of the emulsion increases with ultrasound treatment. Hardness and chewiness decreased significantly (significance of 5%) with respect to control, while elasticity and cohesiveness were not affected by treatment.

microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8+ T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8+ T cells. In B16 tumors expressing a low-affinity antigen ligand, tumor-specific infiltrating CD8+ T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti–PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8+ T cells. In addition, miR-155 overexpression enhanced exhausted CD8+ T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8+ T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8+ tumor-infiltrating T cells may be a surrogate marker of the relative potency of in situ antigen-specific CD8+ T-cell responses.

The transition to formal education is a critical transition in children’s lives that has importance for socio-emotional and behavioral functioning. In the transition process, teachers are key players who work intensively with children and their families. This article focuses on teachers’ perceptions of children´s socio-emotional behavior during the transition from preschool to primary school. We collected qualitative teacher interviews from 112 teachers from five different countries—Australia, China, Finland, Japan and Spain. The research questions were: (1) How do teachers in the five countries perceive children’s abilities in expressing and regulating emotions. (2) How are children’s emotions linked to their family relationships? (3) What similarities and differences across countries exist in teachers’ perceptions of children’s emotions? Overall, the interviewed teachers considered children’s emotional skills of crucial importance in the first grade and emphasized the importance of teaching children emotional skills, emotion management and regulation. The teachers reported that children can be stressed, worried or anxious during the transition. The educators also reported that transitions in the family such as parental divorce, the birth of a sibling or the death of a family member can manifest in children at school as restlessness, excitement, sadness or instability. Similarities and differences in the emphasis placed on children’s emotions by teachers were found across the five countries. We interpret these results to reflect differences in teacher education, school culture, resources and teachers’ freedom of choice in the educational system in the different participating countries. These factors all impact on how teachers think about children and emotions., This study was funded by Academy of Finland (Grant No. SA-21000035941)

Diabetes mellitus, more simply called diabetes, is a chronic condition that occurs when blood glucose levels rise because the body cannot produce any or enough of the hormone insulin or cannot effectively use the insulin it produces [...]

Las paternidades van cambiando a lo largo del tiempo junto con, entre otros factores, innovaciones en políticas familiares. Este artículo testa la influencia en la implicación paterna en el cuidado de niños a través del incremento de la duración del permiso de paternidad de dos a cinco semanas llevado a cabo desde 2007 a 2018. Se utilizan los datos de la encuesta de fecundidad de 2018. El tamaño muestral es de 3.388 entrevistas. Se realizan modelos de regresión logística para diez tareas de cuidado de niños. Los resultados apuntan a que el permiso de paternidad de dos semanas conlleva una mayor implicación paterna en actividades de cuidado que incluyen la interacción y juego. Mientras que la utilización del permiso de paternidad de cuatro y cinco semanas favorece la implicación en tareas de cuidado físico. No obstante, no se observan cambios en las tareas de cuidado más feminizadas.

Juvenile gangrenous vasculitis of the scrotum was described by the Girona dermatologist Joaquín Piñol Aguadéin 1973. The objectives of this article are to review the world publications and provide a clinical case of this disease between urological and/or dermatological.A review of juvenile gangrenous vasculitis of the scrotum between 1973 and 2019 is carried out and a new clinical case is contributed. The identification of articles in Medline was carried outwith MeSH terms "juvenile gangrenous vasculitis scrotum" and in Google with "juvenile gangrenous vasculitisscrotum". Ten clinical-epidemiological variables were studied in the articles: year, source, authors, number of cases, age, previous pharyngo-tonsillitis, biopsy of the lesion, treatment, days to healing, city and country. The results of the variables were analyzed with descriptive statistics. A new clinical case is described.We found 26 world references, 18 of them Spanish, corresponding to 24 publications and 2 conference papers with a total of 29 patients. The meanage of the patients was 23.6 years. The treatments used were exeresis of the lesion (23%), cephalosporins and/or corticoids i.v. (15.3%), tetracyclines, ciprofloxacin or oral amoxicillin-clavulanate (15.3%), local cure and oral corticoids (11.5%) and mupirocin or topical tetracyclines (7.6%). Healing took place in an average of 21 days. The cities with the most cases reported were Barcelona with 11 (37.9%) and Pontevedra with 2 (6.8%). By country, Spain contributed 22 cases (75.8%) and Chile, Argentina, Portugal, Italy, Tunisia, Turkey and Great Britainthe remaining 7 cases (24.1%).Juvenile gangrenous vasculitis of the scrotum is a benign entity with a self-limiting course. The process is preceded by pharyngo-tonsillitis in about half of the patients. The results of the study confirm the endemic nature of the disease in Mediterranean countries, including Spain.INTRODUCCIÓN Y OBJETIVOS: La vasculitis gangrenosa juvenil del escroto fue descrita por el dermatólogo gerundense Joaquín Piñol Aguadé en1973. Los objetivos de este artículo son realizar una revisión de las publicaciones mundiales y aportar un caso clínico de esta enfermedad a caballo entre urológica y/o dermatológica.MATERIAL Y MÉTODOS: Se realiza una revisión sobre la vasculitis gangrenosa juvenil del escroto entre 1973 y 2019 y se aporta un nuevo caso clínico. La identificación de artículos en Medline se llevó a cabo con términos MeSH en inglés “juvenile gangrenous vasculitis scrotum” y en Google con “vasculitis gangrenosa juvenil del escroto”. En los artículos se ha estudiado 10 variables clínico-epidemiológicas: año, fuente, autores, nº decasos, edad, faringoamigdalitis previa, biopsia de la lesión, tratamiento, días hasta curación, ciudad y país. Los resultados de las variables se analizaron con estadísticas descriptivas. Se describe un nuevo caso clínico.RESULTADOS: Hemos encontrado 26 referencias mundiales que correspondían a 24 publicaciones y 2 comunicaciones a congresos con un total de 29 pacientes. La edad media de los pacientes fue 23,6 años. Los tratamientos empleados fueron exéresis de la lesión (23%), cefalosporinas y/o corticoides i.v (15,3%), tetraciclinas, ciprofloxacino o amoxicilina-clavulánico orales (15,3%), cura local y corticoides orales (11,5%) y mupirocinao tetraciclinas tópicas (7,6%). La curación se produjo en una media de 21 días. Las ciudades con más casos aportados fueron Barcelona con 11 (37,9%) y Pontevedra con 2 (6,8%). Por países España aporta 22 casos (75,8%) y Chile, Argentina, Portugal, Italia, Túnez, Turquía, Gran Bretaña los 7 casos restantes (24,1%).CONCLUSIONES: La vasculitis gangrenosa juvenil del escroto es una entidad benigna de curso autolimitado. El proceso viene precedido de faringoamigdalitis en cerca de la mitad de los pacientes. Los resultados del trabajo confirman el carácter endémico de la enfermedad en los países mediterráneos entre los que destaca España.

The development of sensors for pH monitoring is of extreme importance in the monitoring of concrete and reinforced concrete structures. Imidazole derivatives are promising probes for pH sensing due to the amphoteric nature of their heterocyclic ring, which can be protonated/deprotonated upon pH changes. In this work, a triarylimidazole was synthesised and used as a dopant in an organic-inorganic hybrid (OIH) sol-gel matrix to obtain a pH-sensitive membrane for further application in optical fibre sensors (OFS). The triarylimidazole probe shows fluorimetric response in pH between 9 and 13, which is the desired range for monitoring carbonation of concrete. This degradation process lowers the highly alkaline pH of concrete (12.5-13) to values below 9, which creates favourable conditions for corrosion of concrete reinforcement. The OIH membranes used were based on Jeffamine THF170 and 3-glycidoxypropytrimethoxysilane precursors, which had already been shown to be suitable and resistant in contact with cement-based materials. The OIHs were doped with three different contents of the triarylimidazole and the structural, dielectric, thermal and optical properties of the pure and doped OIH materials were evaluated. The structural analysis showed that the presence of the triarylimidazole did not change the structural properties of the OIH material. Electrochemical impedance spectroscopy showed that in the doped samples the conductivity increased with the imidazole concentration. Theεrobtained for the doped samples ranged approximately from 11 to 19 and for the pure matrices was 8. Thermal analysis showed that these materials are stable up to 350 °C and that the presence of the probe did not change that feature. The optical properties showed that the prepared OIH materials have promising properties to be used as pH sensitive fluorimetric probes., FCT - Fundação para a Ciência e a Tecnologia(UIDB/04029/2020), Thanks are due to Fundação para a Ciência e Tecnologia (FCT) and FEDER (European Fund for Regional Development)- COMPETE-QRENEU for financial support through the Chemistry Research Centre of the University of Minho (Ref. CQ/UM (UID/QUI/00686/2019 and UID/QUI/00686/2020)), project “Sol-Sensors — Development of Advanced Fiber Optic Sensors for Monitoring the Durability of Concrete Structures” (www.solsensors.eu), reference POCI-01-0145-FEDER-031220, and a PhD grant to Rui P. C. L. Sousa (SFRH/BD/145639/ 2019). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). Thanks are also due to FCT/MCTES through national funds (PIDDAC) under the R&D Unit Institute for Sustainability and Innovation in Structural Engineering (ISISE), under reference UIDB/04029/2020.

The linearized Euler equations (LEE) provide an accurate — yet computationally efficient — description of propagation and damping of acoustic waves in geometrically complex, non-uniform reactive mean flows like those found in gas turbine combustion chambers. However, direct application of the LEE to perfectly premixed combustors with highly turbulent flows overestimates entropy waves as the LEE solution inherently contains coupled acoustic, vortical and entropy modes. In the present work, the LEE are decomposed into isentropic and non-isentropic parts ultimately obtaining a simplified set of isentropic LEE, in which only acoustic and vortical modes propagate. In the isentropic LEE, only continuity and momentum equations need to be solved. The energy equation is replaced by the isentropic relation between acoustic pressure and density. From the decomposition, the unsteady heat release term, which acts as a source in the energy equation, naturally arises as a source in the continuity equation. This way, the thermoacoustic coupling is still preserved in the isentropic formulation. The derived isentropic set of equations is first tested with a one-dimensional benchmark configuration consisting of a mean flow temperature jump, non-uniform mean flow velocity and unsteady heat release sources. Solutions of the non-isentropic and isentropic set of LEE are compared and the avoidance of entropy waves proved. Finally, isentropic LEE are used for reproducing the frequency of the self-excited first transversal mode of a lab-scale swirl-stabilized premixed combustor. Furthermore, isentropic and non-isentropic LEE solutions are compared. The non-isentropic LEE yield too high levels of entropy at the combustor exit that may explain the increased damping rate of the non-isentropic LEE solution compared to the isentropic LEE solution. This shows the relevance of isentropic LEE for correctly predicting thermoacoustic stability limits at high frequencies in relevant industrial applications.

Understanding of ecosystem structure and functioning requires detailed knowledge about plant–animal interactions, especially when keystone species are involved. The recent consideration of parrots as legitimate seed dispersers has widened the range of mechanisms influencing the lifecycle of many plant species. We examined the interactions between the burrowing parro tCyanoliseus patagonus and two dominant algarrobo trees (Prosopis alba and Prosopis nigra) in the Monte Desert, Argentina. We recorded the abundance and foraging behaviour of parrots; quantified the handling, consumption, wasting, and dispersal of ripe and unripe pods; and tested the viability of soft and hardripe seeds wasted and transported by parrots. We found a high abundance of burrowing parrots.They predated on soft seeds from unripe pods while exclusively feeding upon pulp wrapping hardseeds from ripe pods. Frequent pod wasting beneath the plant or transport at a distance invariablyimplied the dispersal of multiple seeds in each event. Moreover, soft seeds retained viability afterdesiccation outside the mother plant, suggesting effective seed dispersal after partial pod predation due to a predator satiation effect. In about half of the foraging flocks, at least one parrot departed in flight with pods in its beak, with 10–34% of the flock components moving pods at distances averaging 238 m (P. alba) and 418 m (P. nigra). A snapshot sampling of faeces from livestock and wildmammals suggested a low frequency of seed dispersal by endozoochory and secondary dispersalby ants and dung beetles. The nomadic movements and long flights of burrowing parrots betweenbreeding and foraging sites can lead to the dispersal of huge amounts of seeds across large areas thatare sequentially exploited. Further research should evaluate the role of the burrowing parrot as afunctionally unique species in the structure of the Monte Desert woods and the genetic structure ofalgarrobo species., This research was funded by the Loro Parque Fundación (grant reference: PP-146-2018-1).

Immunotherapy has become a standard treatment in many cancers and it is based on three main therapeutic axes: immune checkpoint blockade (ICB), vaccination and adoptive cell transfer (ACT). If originally these therapies mainly focused on exploiting CD8 T cells given their role in the direct elimination of tumor cells, increasing evidence highlights the crucial role CD4 T cells play in the antitumor immune response. Indeed, these cells can profoundly modulate the tumor microenvironment (TME) by secreting different types of cytokine or by directly eliminating cancer cells. In this review, we describe how different CD4 T cell subsets can contribute to tumor immune responses during immunotherapy and the novel high-throughput immune monitoring tools that are expected to facilitate the study of CD4 T cells, at antigen-specific and single cell level, thus accelerating bench-to-bed translational research in cancer.

Emerging urinary infections by rare germs are a public health problem. The objectives of this article are to review urinary tract infections caused by an emerging genus of bacteria called Raoultella and to report a case of asymptomatic urinary tract infection by Raoultella ornithinolytica. A review of publications on urinary tract infections caused by the genus Raoultella between 2009 and 2018 is carried out and a case of asymptomatic urinary tract infection by Raoultella ornithinolytica is reported. The search of articles in Medline/ Pubmed and Google was performed with the keywords: Raoultella, Raoultella ornithinolytica, urinary tract infection. Twelve variables were studied: year of publication, authors, specialty, type of infection, number of cases, sex, age, immunosuppression, oncological patient, urological instrumentation, urological surgery and neurogenic bladder. Results were analyzed using descriptive statistics. A new case is described. 24 publications were found with 120 cases of urinary infections of the genus Raoultella between 2009 and 2018, corresponding to Raoultella ornithinolytica 40.8%, Raoultella planticola 28.3%, Raoultella terrigena 30.8% and Raoultella electrica 0%. The series included 43 men (35.8%), 53 women (44.1%) and 24 patients with this data not provided (20%). The minimum age was 14 days, the maximum was 97 years and the average age was 56.6. The types of infection detected were: uncomplicated UTI 94.1%, UTI in newborn 1.6%, acute prostatitis 0.8%, chronic prostatitis 0.8%, giant kidney cyst infection 0.8%, calculous pyelonephritis 0.8% and recurrent cystitis 0.8%. Urinary tract infections by species of the genus Raoultella occur in immunocompromised, oncological, instrumented or basic urological patients. The species Raoultella ornithinolytica described in 2011 is an emerging germ in urinary infections. This contribution is the second Spanish publication and twelfth worldwide of urinary infection by Raoultella ornithinolytica. Las infecciones urinarias emergentes por gérmenes raros son un problema de salud pública. Los objetivos de este artículo son realizar una revisión sobre infecciones urinarias causadas por un género emergente de bacterias denominado Raoultella y comunicar un caso de infección urinaria asintomática por Raoultella ornithinolytica.MATERIAL Y MÉTODOS: Se realiza una revisión de las publicaciones sobre infecciones urinarias producidas por el género Raoultella entre 2009 y 2018 y se aporta un caso de infección urinaria asintomática por Raoultella ornithinolytica. La búsqueda de artículos en Medline/Pubmed y Google se realizó con las palabras clave en inglés: Raoultella, Raoultella ornithinolytica, urinary tract infection. Se estudiaron 12 variables: año publicación, autores, especialidad, tipo infección, nº casos, sexo, edad, inmunodepresión, paciente oncológico, instrumentación urológica, cirugía urológica y vejiga neurógena. Los resultados se analizaron utilizando estadísticas descriptivas. Se describe un nuevo caso. Se hallaron 24 publicaciones con 120 casos de infecciones urinarias por el género Raoultella entre 2009 y 2018 que correspondían a Raoultella ornithinolytica 40,8%, Raoultella planticola 28,3%, Raoultella terrigena 30,8% y Raoultella electrica 0%. En la serie había 43 hombres (35,8%), 53 mujeres (44,1%) y 24 pacientes con este dato no facilitado (20%). La edad mínima fue de 14 días, la máxima de 97 años y la edad media de 56,6. Los tipos de infección detectados fueron: ITU no complicada 94,1%, ITU en recién nacido 1,6%, prostatitis aguda 0,8%, prostatitis crónica 0,8%, infección quiste renal gigante 0,8%, pielonefritis calculosa 0,8% y cistitis recurrente 0,8%. Las infecciones urinarias por especies del género Raoultella ocurren en pacientes inmunodeprimidos, oncológicos, sometidos a instrumentación o con patologías urológicas de base. La especie Raoultella ornithinolytica descrita en 2011 es un germen emergente en infecciones urinarias. Esta aportación es la segunda publicación española y duodécima mundial de infección urinaria por Raoultella ornithinolytica.

Plant–animal interactions are key to sustaining whole communities and ecosystem function. However, their complexity may limit our understanding of the underlying mechanisms and the species involved. The ecological effects of epizoochory remain little known compared to other seed dispersal mechanisms given the few vectors identified. In addition, epizoochory is mostly considered non-mutualistic since dispersers do not obtain nutritional rewards. Here, we show a widespread but unknown mutualistic interaction between parrots and plants through epizoochory. Combining our observations with photos from web-sources, we recorded nearly 2000 epizoochory events in 48 countries across five continents, involving 116 parrot species and nearly 100 plant species from 35 families, including both native and non-native species. The viscid pulp of fleshy fruits and anemochorous structures facilitate the adherence of tiny seeds (mean 3.7 2.56 mm) on the surface of parrots while feeding, allowing the dispersion of these seeds over long distances (mean = 118.5 m). This parrot–plant mutualism could be important in ecosystem functioning across a wide diversity of environments, also facilitating the spread of exotic plants. Future studies should include parrots for a better understanding of plant dispersal processes and for developing effective conservation actions against habitat loss and biological invasions

Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate. Little is known about people's preferred responses to norm violations across countries. Here, in a study of 57 countries, the authors highlight cultural similarities and differences in people's perception of the appropriateness of norm violations., Swedish Foundation for Humanities and Social Sciences; Riksbankens Jubileumsfond; Czech Science Foundation; Czech Academy of Sciences; Institute of Psychology; Stockholm University

Background. The aim of the present study was to determine the prevalence and incidence of diabetic retinopathy (DR) and its changes in the last 20 years in type 2 diabetes mellitus (T2DM) patients in Spain. Methods. A systematic review with a meta-analysis was carried out on the studies published between 2001–2020 on the prevalence and incidence of DR and sight-threatening diabetic retinopathy (STDR) in Spain. The articles included were selected from four databases and publications of the Spanish Ministry of Health and Regional Health Care System (RHCS). The meta-analysis to determine heterogeneity and bias between studies was carried out with the MetaXL 4.0. Results. Since 2001, we have observed an increase in the detection of patients with DM, and at the same time, screening programs for RD have been launched; thus, we can deduce that the increase in the detection of patients with DM, many of them in the initial phases, far exceeds the increased detection of patients with DR. The prevalence of DR was higher between 2001 and 2008 with values of 28.85%. These values decreased over the following period between 2009 and 2020 with a mean of 15.28%. Similarly the STDR prevalence decrease from 3.67% to 1.92% after 2008. The analysis of the longitudinal studies determined that the annual DR incidence was 3.83%, and the STDR annual incidence was 0.41%. Conclusion. In Spain, for T2DM, the current prevalence of DR is 15.28% and 1.92% forSTDR. The annual incidence of DR is 3.83% and is 0.41% for STDR.

Tang and colleagues show that a half-life-extended IL-10-Fc fusion protein acts directly on terminally exhausted PD1(+)TIM-3(+)CD8(+) T cells to enhance their proliferation and effector function by reprogramming the cellular metabolism to oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. Treatment of tumor-bearing mice with IL-10-Fc and adoptive T cell therapy led to eradication of their established solid tumors and durable cures. T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8(+) tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8(+) tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

Fully functional, tumor-specific, SLAMF7-expressing cytotoxic CD4 T cells directly mediate immunity against human cancer., CD4 T cells have been implicated in cancer immunity for their helper functions. Moreover, their direct cytotoxic potential has been shown in some patients with cancer. Here, by mining single-cell RNA-seq datasets, we identified CD4 T cell clusters displaying cytotoxic phenotypes in different human cancers, resembling CD8 T cell profiles. Using the peptide-MHCII-multimer technology, we confirmed ex vivo the presence of cytolytic tumor-specific CD4 T cells. We performed an integrated phenotypic and functional characterization of these cells, down to the single-cell level, through a high-throughput nanobiochip consisting of massive arrays of picowells and machine learning. We demonstrated a direct, contact-, and granzyme-dependent cytotoxic activity against tumors, with delayed kinetics compared to classical cytotoxic lymphocytes. Last, we found that this cytotoxic activity was in part dependent on SLAMF7. Agonistic engagement of SLAMF7 enhanced cytotoxicity of tumor-specific CD4 T cells, suggesting that targeting these cells might prove synergistic with other cancer immunotherapies.

Parrots stand out among birds because of their poor conservation status and the lack of available information on their population sizes and trends. Estimating parrot abundance is complicated by the high mobility, gregariousness, patchy distributions, and rarity of many species. Roadside car surveys can be useful to cover large areas and increase the probability of detecting spatially aggregated species or those occurring at very low densities. However, such surveys may be biased due to their inability to handle differences in detectability among species and habitats. We conducted 98 roadside surveys, covering > 57,000 km across 20 countries and the main world biomes, recording ca. 120,000 parrots from 137 species. We found that larger and more gregarious species are more easily visually detected and at greater distances, with variations among biomes. However, raw estimates of relative parrot abundances (individuals/km) were strongly correlated (r = 0.86–0.93) with parrot densities (individuals/km2) estimated through distance sampling (DS) models, showing that variability in abundances among species (>40 orders of magnitude) overcomes any potential detectability bias. While both methods provide similar results, DS cannot be used to study parrot communities or monitor the population trends of all parrot species as it requires a minimum of encounters that are not reached for most species (64% in our case), mainly the rarest and more threatened. However, DS may be the most suitable choice for some species-specific studies of common species. We summarize the strengths and weaknesses of both methods to guide researchers in choosing the best–fitting option for their particular research hypotheses, characteristics of the species studied, and logistical constraints., This research was funded by Fundación Biodiversidad (Spanish Ministerio de Medio Ambiente, project 52I.CA2109), Fundación Repsol, Spanish Ministerio de Ciencia e Innovación (Project CGL2015-71378-P), and mostly by Loro Parque Fundación (Project SEJI/2018/024).

Purpose: To validate a clinical decision support system (CDSS) that estimates risk of diabetic retinopathy (DR) and to personalize screening protocols in type 2 diabetes mellitus (T2DM) patients. Methods: We utilized a CDSS based on a fuzzy random forest, integrated by fuzzy decision trees with the following variables: current age, sex, arterial hypertension, diabetes duration and treatment, HbA1c, glomerular filtration rate, microalbuminuria, and body mass index. Validation was made using the electronic health records of a sample of 101,802 T2DM patients. Diagnosis was made by retinal photographs, according to EURODIAB guidelines and the International Diabetic Retinopathy Classification. Results: The prevalence of DR was 19,759 patients (19.98%). Results yielded 16,593 (16.31%) true positives, 72,617 (71.33%) true negatives, 3165 (3.1%) false positives, and 9427 (9.26%) false negatives, with an accuracy of 0.876 (95% confidence interval [CI], 0.858–0.886), sensitivity of 84% (95% CI, 83.46–84.49), specificity of 88.5% (95% CI, 88.29–88.72), positive predictive value of 63.8% (95% CI, 63.18–64.35), negative predictive value of 95.8% (95% CI, 95.68–95.96), positive likelihood ratio of 7.30, and negative likelihood ratio of 0.18. The type 1 error was 0.115, and the type 2 error was 0.16. Conclusions: We confirmed a good prediction rate for DR from a representative sample of T2DM in our population. Furthermore, the CDSS was able to offer an individualized screening protocol for each patient according to the calculated risk confidence value. Translational Relevance: Results from this study will help to establish a novel strategy for personalizing screening for DR according to patient risk factors. The authors thank Phil Hoddy for his language assistance and for editing and correcting the English text. Supported by Instituto de Investigaciones Carlos III (research projects PI18/00169, PI12/01535, and PI15/01150) and by the European Regional Development Fund (FEDER). The authors thank Phil Hoddy for his language assistance and for editing and correcting the English text. Supported by Instituto de Investigaciones Carlos III (research projects PI18/00169, PI12/01535, and PI15/01150) and by the European Regional Development Fund (FEDER).

Families rely on both parental and non-parental involvement when confronting the challenge of caring for children till the age of three. Drawing from the 2016 edition of the EU’s Survey on Income and Living Conditions, this study analyses non-parental childcare options in France, Norway, and Spain, taken as examples of different welfare state models. It addresses the degree to which parents of children under 3 years old in each country resort to non-parental agents (grandparents and other relatives, professional care providers, and pre-school services). The results reveal the existence of significant differences in non-parental care strategies in the three countries analysed, though some convergence towards defamilialisation and the important impact of household income on the types of non-parental care prevalent in France and Spain.

Aims/hypothesis Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. Methods Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). Results Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p p Conclusions/interpretation Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality.

Purpose: CD40 agonists hold great promise for cancer immunotherapy (CIT) as they enhance dendritic cell (DC) activation and concomitant tumor-specific T-cell priming. However, the broad expression of CD40 accounts for sink and side effects, hampering the efficacy of anti-CD40 antibodies. We hypothesized that these limitations can be overcome by selectively targeting CD40 agonism to the tumor. Therefore, we developed a bispecific FAP-CD40 antibody, which induces CD40 stimulation solely in presence of fibroblast activation protein α (FAP), a protease specifically expressed in the tumor stroma. Experimental Design: FAP-CD40's in vitro activity and FAP specificity were validated by antigen-presenting cell (APC) activation and T-cell priming assays. In addition, FAP-CD40 was tested in subcutaneous MC38-FAP and KPC-4662-huCEA murine tumor models. Results: FAP-CD40 triggered a potent, strictly FAP-dependent CD40 stimulation in vitro. In vivo, FAP-CD40 strongly enhanced T-cell inflammation and growth inhibition of KPC-4662-huCEA tumors. Unlike nontargeted CD40 agonists, FAP-CD40 mediated complete regression of MC38-FAP tumors, entailing long-term protection. A high dose of FAP-CD40 was indispensable for these effects. While nontargeted CD40 agonists induced substantial side effects, highly dosed FAP-CD40 was well tolerated. FAP-CD40 preferentially accumulated in the tumor, inducing predominantly intratumoral immune activation, whereas nontargeted CD40 agonists displayed strong systemic but limited intratumoral effects. Conclusions: FAP-CD40 abrogates the systemic toxicity associated with nontargeted CD40 agonists. This enables administration of high doses, essential for overcoming CD40 sink effects and inducing antitumor immunity. Consequently, FAP-targeted CD40 agonism represents a promising strategy to exploit the full potential of CD40 signaling for CIT.

PD-1/PD-L1 pathway plays a role in inhibiting immune response. Therapeutic antibodies aimed at blocking the PD-1/PD-L1 interaction have entered clinical development and have been approved for a variety of cancers. However, the clinical benefits are reduced to a group of patients. The research in combined therapies, which allow for a greater response, is strongly encouraging. We previously characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) with antitumor activity in both melanoma and breast carcinoma, as well as immunomodulatory activity. We hypothesize that the combined treatment with P2Et and anti-PD-L1 can improve the antitumor response through an additive antitumor effect. We investigated the antitumor and immunomodulatory activity of P2Et and anti-PD-L1 combined therapy in B16-F10 melanoma and 4T1 breast carcinoma. We analyzed tumor growth, hematologic parameters, T cell counts, cytokine expression, and T cell cytotoxicity. In the melanoma model, combined P2Et and anti-PD-L1 therapy has the following effects: decrease in tumor size; increase in the number of activated CD4 + and CD8 + T cells; decrease in the number of suppressor myeloid cells; increase in PD-L1 expression; decrease in the frequency of CD8 + T cell expressing PD-1; improvement in the cytotoxic activity of T cells; and increase in the IFN γ secretion. In the breast cancer model, P2Et and PD-L1 alone or in combination show antitumor effect with no clear additive effect. This study shows that combined therapy of P2Et and anti-PD-L1 can improve antitumor response in a melanoma model by activating the immune response and neutralizing immunosuppressive mechanisms.

Background While cancer immunotherapy has mainly focused on exploiting CD8 T cells given their role in the direct elimination of tumor cells, increasing evidence highlights the crucial roles played by CD4 T cells in anti-tumor immunity. However, their very low frequency, the lack of robust algorithms to predict peptide binding to MHC class II molecules and the high polymorphism of MHC class II molecules render the study and use of circulating tumor antigen-specific CD4 T cells challenging. In this regard, the HLA-DRB3*02:02 gene encoding an HLA allele that is expressed by half of the Caucasian population, offers a way to identify CD4 T cell-defined tumor antigens with broad cancer patient coverage. Methods Here, we aim to identify, isolate and functionally characterize ‘quasi-universal’ human tumor antigen-specific HLA-DRB3*02:02-restricted CD4 T cells in cancer patients. Using an algorithm we recently developed in house,1 tumor-associated antigenic peptides binding to this allele are identified. We have generated a large collection of HLA-DRB3*02:02-restricted CD4 T cell clones of different tumor-antigen specificities. We will perform in vitro co-cultures of CD4 T cell clones with tumor cells to measure cytokine secretion, their tumor cell killing and their phenotypic profile (PD-1, TIM3, TIGIT, 4-1BB, CD40L, LAG3, VISTA, OX40). We will sequence and clone the TCR of the most promising candidates for adoptive cell transfer therapy. Lastly, we will directly evaluate the presence of these cells ex-vivo and longitudinally monitor them in patients. Results N/A Conclusions Together, these results should contribute valuable targets for coordinated CD4 and CD8 T cell-based immunotherapy of cancer. Reference Racle, J., et al., Robust prediction of HLA class II epitopes by deep motif deconvolution of immunopeptidomes. Nat Biotechnol 2019. 37(11): p. 1283–1286.

Introduction: Severe eosinophilic asthma is an incapacitating disease requiring the patient to take many drugs, amongst which are oral corticoids (OCS), for its control. Mepolizumab is a monoclonal antibody capable of blocking the binding of Interleukin 5 (IL-5) to the eosinophils, and, in this way reducing the exacerbations, symptoms and need for OCS. Our objective was to evaluate the experience with this drug on patients being treated for severe asthma in real-life conditions. Methods: Retrospective, multicentric study carried out in eight hospitals in the Principality of Asturias, in which the demographic, clinical, analytical, lung function and ACT (Asthma Control Questionnaire) data of the patients with severe eosinophilic asthma being treated with Mepolizumab for three years were collected. Results: Sixty-nine patients (72% women) were included, with a mean age of 56±13 years. The eosinophil blood count before treatment was 856 cels/mm3 (SD 754), decreasing after 6 months to 101 cels/mm3 (SD 98). Annual exacerbations decreased from 4.7 (SD 3.7) to 1.3 (SD 2.5) (p=0.001), while the FEV1% increased from 68% (SD 20) to 76% (SD 21) (Conclusions: Mepolizumab has demonstrated to be efficacious and safe in real life in the treatment of patients with badly controlled eosinophilic asthma.

CD73 converts AMP to adenosine, an immunosuppressive metabolite that promotes tumorigenesis. This study presents a systematic evaluation of CD73 expression in benign, hyperplastic, and neoplastic thyroid. CD73 expression was assessed by immunohistochemistry in 142 thyroid samples. CD73 was expressed in normal thyroid (3/6) and goiter (5/6), with an apical pattern and mild intensity. Apical and mild CD73 expression was also present in oncocytic cell adenomas/carcinomas (9/10; 5/8) and in follicular adenomas/carcinomas (12/18; 23/27). In contrast, papillary thyroid carcinomas featured extensive and intense CD73 staining (49/50) (vs. normal thyroid/goiter, p < 0.001). Seven of nine anaplastic carcinomas were CD73-positive with heterogeneous extensiveness of staining. Medullary and poorly differentiated carcinomas were mostly CD73-negative (1/6; 2/2). These results were corroborated by NT5E mRNA profiling. Papillary carcinomas feature enhanced CD73 protein and mRNA expression with distinct and intense staining, more pronounced in the invasive fronts of the tumors. Supplementary Information The online version contains supplementary material available at 10.1007/s00428-021-03100-x.

Recent advances in immuno-oncology have generated renewed optimism for therapeutic anti-tumor vaccination, and peptide vaccines in particular are being extensively employed in clinical studies. However, peptide vaccines generally suffer from poor immunogenicity. Here, we pharmacokinetically tune vaccine responses via fusion of peptide epitopes to carrier proteins to optimize vaccine potency. Antigen-carrier fusions enable three factors to be simultaneously optimized: a) efficient uptake in draining lymphatics from the site of injection, b) protection of epitope payloads from proteolytic degradation, and c) reduction of antigen presentation in uninflamed distal lymphoid organs. We find that peptides expressed as fusions with protein carriers like transthyretin can solve all three pharmacokinetic challenges, enhancing vaccine immunogenicity up to 90-fold in mice. We demonstrate the utility of this approach with several clinically relevant antigens, including viral antigens, tumor-associated antigens, oncofetal antigens, and shared neoantigens. Protein-epitope fusions represent a facile and generalizable approach to enhance T cell responses elicited by subunit vaccines.

The hypoxia and profound inflammatory response associated with the pneumonitis observed with the severe acute respiratory virus coronavirus-2 (SARS-COV-2) virus responsible for the recent COVID-19 pandemic has overwhelmed intensive care facilities in the epicenters of infection including Wuhan

Innate lymphoid cells (ILCs) represent the most recently identified subset of effector lymphocytes, with key roles in the orchestration of early immune responses. Despite their established involvement in the pathogenesis of many inflammatory disorders, the role of ILCs in cancer remains poorly defined. Here we assessed whether human ILCs can actively interact with the endothelium to promote tumor growth control, favoring immune cell adhesion. We show that, among all ILC subsets, ILCPs elicited the strongest upregulation of adhesion molecules in endothelial cells (ECs) in vitro, mainly in a contact-dependent manner through the tumor necrosis factor receptor- and RANK-dependent engagement of the NF-κB pathway. Moreover, the ILCP-mediated activation of the ECs resulted to be functional by fostering the adhesion of other innate and adaptive immune cells. Interestingly, pre-exposure of ILCPs to human tumor cell lines strongly impaired this capacity. Hence, the ILCP–EC interaction might represent an attractive target to regulate the immune cell trafficking to tumor sites and, therefore, the establishment of an anti-tumor immune response.