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It is widely believed that cellular senescence plays a critical role in both aging and cancer, and that senescence is a fundamental, permanent growth arrest that somatic cells cannot avoid. Here we show that Myc plays an important role in self-renewal of esophageal epithelial cells, contributing to their resistance to cellular senescence. Myc is homogeneously expressed in basal cells of the esophageal epithelium and Myc positively regulates their self-renewal by maintaining their undifferentiated state. Indeed, Myc knockout induced a loss of the undifferentiated state of esophageal epithelial cells resulting in cellular senescence while forced MYC expression promoted oncogenic cell proliferation. A superoxide scavenger counteracted Myc knockout-induced senescence, therefore suggesting that a mitochondrial superoxide takes part in inducing senescence. Taken together, these analyses reveal extremely low levels of cellular senescence and senescence-associated phenotypes in the esophageal epithelium, as well as a critical role for Myc in self-renewal of basal cells in this organ. This provides new avenues for studying and understanding the links between stemness and resistance to cellular senescence.

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.

The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.

Real-world evidence on the impact of monoclonal antibodies as first-line treatment in Spain is limited. This observational, retrospective and prospective, multicenter, descriptive study included 117 transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients divided into Group A, who received no daratumumab standard regimens, and the DVMP group (daratumumab, bortezomib, melphalan, and prednisone treatment). More than 90% of the patients in Group A received bortezomib, lenalidomide, or a combination of them. The median follow-up time for Group A was 38.2 months in comparison to 25.8 months for the DVMP group (p < 0.0001). The rate of DVMP patients that experienced disease progression or death from any cause was 36.8%, compared to 67.3% of Group A patients at 36 months of follow-up. The DVMP group had a higher 36-month progression-free survival (PFS) rate (52.9% vs. 31.7%). During the retrospective period, 73.0% of patients reported adverse drug reactions, while in the prospective period, 40.5% experienced adverse events, with no clinical differences between groups. The study supports the use of daratumumab regimens in frontline therapy based on real-world data. The findings provide valuable insights into the clinical outcomes of daratumumab therapy, which can help physicians make informed decisions regarding the optimal treatment approach for this patient population.

The African swine fever virus (ASFV) causes fatal disease in pigs and is currently spreading globally. Commercially safe vaccines are urgently required. Aiming to generate a novel live attenuated vaccine (LAV), a recombinant ASFV was generated by deleting the viral O174L (PolX) gene. However, during in vitro generation, an additional spontaneous deletion of genes belonging to the multigene families (MGF) occurred, creating a mixture of two viruses, namely, Arm-ΔPolX and Arm-ΔPolX-ΔMGF. This mixture was used to inoculate pigs in a low and high dose to assess the viral dynamics of both populations in vivo. Although the Arm-ΔPolX population was a much lower proportion of the inoculum, in the high-dose immunized animals, it was the only resulting viral population, while Arm-ΔPolX-ΔMGF only appeared in low-dose immunized animals, revealing the role of deleted MGFs in ASFV fitness in vivo. Furthermore, animals in the low-dose group survived inoculation, whereas animals in the high-dose group died, suggesting that the lack of MGF and PolX genes, and not the PolX gene alone, led to attenuation. The two recombinant viruses were individually isolated and inoculated into piglets, confirming this hypothesis. However, immunization with the Arm-ΔPolX-ΔMGF virus did not induce protection against challenge with the virulent parental ASFV strain. This study demonstrates that deletion of the PolX gene alone neither leads to attenuation nor induces an increased mutation rate in vivo.

Mediterranean Temporary Ponds (MTPs) represent a priority habitat according to Directive 92/43/EEC (Natura 2000 code: 3170*). These are very shallow water habitats only seasonally flooded, with a flora mainly composed of Mediterranean therophytic and geophytic species. Its extreme seasonality and small size make this habitat highly vulnerable and hard to manage. In recent Italian monitoring campaigns, the conservation status of MTP 3170* was considered inadequate. In Apulia, where the habitat is considered as “the most vulnerable type”, 73 sites were censused, with a total coverage of about 10,000 m2. The present work refers to the monitoring for three years of a total of 16 habitat 3170* sites, with the aim of better describing faunal indicator species for this priority habitat. A total of 158 taxa of flora and 103 of fauna were identified from 54 floristic and 44 faunistic samplings in total, with a robust updating of the listed biodiversity. For the first time a group of faunal species is proposed as an indicator of the habitat MTP 3170*. The conservation status, assessed on the basis of structural and functional criteria, gave a satisfactory status for seven sites and an unsatisfactory one (variously rated as inadequate or bad) for nine.

(1) Background: Given the autoimmune nature of Alopecia Areata (AA) and the immunomodulatory properties of probiotics, this trial was conducted to evaluate the efficacy of a probiotic mixture, consisting of Lactobacillus rhamnosus and Bifidobacterium longum strains, as an adjuvant treatment in a group of AA patients. (2) Method: This study was a 24-week, randomized, double-blind, placebo-controlled clinical trial. Twenty-six patients with AA were included in this study, and their clinical progression, along with changes in gut and skin microbiota, were analyzed. (3) Results: A higher proportion of AA patients treated with the probiotic formula showed improvement compared to the placebo group, based on both the reduction in the number of AA plaques (56% vs. 30%) and the affected scalp surface area (45% vs. 20%). For “activity”, “inactivity”, and “regrowth”, an improvement in 55%, 67%, and 55% of patients was, respectively, observed in the probiotic group, compared to 50%, 40%, and 30% in the placebo group. No changes were observed in the gut microbiota during the intervention period. Regarding skin microbiota, changes were detected in the probiotic group, with reductions in characteristic genera during the study. (4) Conclusions: To our knowledge, this is the first clinical trial assessing the efficacy of a probiotic product in patients with AA. This probiotic mixture in a routine clinical practice setting appears to improve the course of patients. In addition, the skin microbiota of scalp lesions was modified using the probiotic treatment.

Thoracic aortic aneurysms (TAAs) represent a serious health concern, as they are associated with early aortic dissection and rupture. TAA formation is triggered by genetic conditions, in particular Marfan syndrome (MFS) and bicuspid aortic valve (BAV). During the aneurysmatic process, aortic endothelial cells can undergo endothelial-to-mesenchymal transition (End–MT) with consequent phenotypic and functional alterations. We previously documented that MFS TAA is characterized by miR-632–driven End–MT exacerbation, whereas in BAV aortopathy, the occurrence of this process remains still controversial. We investigated the End–MT process and the underlined regulatory mechanisms in BAV, TAV and MFS TAA tissues. Gene expression and immunohistochemical analysis were performed in order to analyze some important miRNAs and genes characterizing End–MT. We documented that BAV endothelium maintains the expression of the endothelial homeostasis markers, such as ERG, CD31 and miR-126-5p, while it shows lower levels of miR-632 and mesenchymal markers compared with MFS. Interestingly, we also found higher levels of miR-632 in MFS patients’ blood. Our findings definitively demonstrate that the End–MT process does not characterize BAV that, among the other TAAs, better maintains the endothelial features. In addition, our results suggest miR-632 as a promising diagnostic/prognostic factor in MFS aortopathy.

The ageing of the population needs the automation of patient monitoring. The objective of this is twofold: to improve care and reduce costs. Frailty, as a state of increased vulnerability resulting from several diseases, can be seen as a pandemic for older people. One of the most common detection tests is gait speed. This article compares the gait speed measured outdoors using smartphones with that measured using manual tests conducted in medical centres. In the experiments, the walking speed was measured over a straight path of 80 m. Additionally, the speed was measured over 2.4 m in the middle of the path, given that this is the minimum distance used in medical frailty tests. To eliminate external factors, the participants were healthy individuals, the weather was good, and the path was flat and free of obstacles. The results obtained are promising. The measurements taken with common smartphones over a straight path of 80 m are within the same order of error as those observed in the manual tests conducted by practitioners.

Background: Hospitalized children need adequate sleep to favor early recovery. Methods: To study the sleep pattern of children admitted to a pediatric inpatient unit, a cross-sectional study was carried out at a reference hospital in northern Spain. The main study variables were medical specialty of admission, sleep-inducing treatment, hours of sleep at home and during admission, number of nocturnal awakenings, and reasons for awakening. Differences in the hours of sleep and nighttime awakenings between the initial period and at six months were calculated using the Student’s t-test. Results: We included 100 baseline patients and 100 post-intervention patients. Up to 4% of the baseline sample and 3% of the six-month sample had been prescribed a sleep-promoting drug. Regarding awakenings, 79% of the children in the baseline sample suffered awakenings, with a mean of 1.98 awakenings (range 1–13). At six months, the percentage of children who experienced awakenings decreased by 17%, with a mean of 1.34 (range 1–5). In the baseline sample, 48% were caused by nursing care, decreasing to 34% after the intervention. Conclusions: An educational intervention with the implementation of targeted evidence-based practices is a useful measure for improving the sleep pattern by decreasing the number of awakenings.

The progress of technology in the field of education has led to the development of new professional skills in the teaching community, such as digital competence. Likewise, it has propagated the appearance of new learning environments mediated by technological resources that favor the generation of a large volume of data, known as Big Data, derived from the interactions of educational agents in virtual environments. This study aims to determine the level of digital competence in the informational area of teachers and to determine the projection of Big Data in them. For this study, a descriptive and correlational quantitative method was followed. The study sample consists of 832 Spanish teachers, with data collected through a questionnaire. The results reveal that the teaching staff have a medium level of digital competence in the informational area. The teachers obtained better valuations in the dimensions concerning storage and recovery, postulating themselves as connoisseurs of the Big Data concept to a large extent. In some instances, the teachers affirmed that sometimes they access and interpret the data generated by the digital interactions, transforming it into useful information to improve their teaching processes. Finally, our research shows that the level of digital competence in the informational area influences the degree of knowledge about Big Data.

Technological impact and immigration have resulted in ICT playing a significant role in educational adaptation to multicultural environments. This study focuses on flipped learning as an innovative teaching method. The overall objectives of this research are, on the one hand, to carry out a review of the scientific literature about flipped learning, and, on the other hand, to know the extent of its scope amongst teaching staff in cross-border regions. To achieve these objectives, a quantitative method has been developed through a descriptive model. 316 teachers from different educational centres of the Spanish Autonomous City of Ceuta (Spain) were selected as a sample, and an ad hoc questionnaire was used as an instrument for collecting personal data. Statistical procedures were performed through SPSS software, using location and scattering parameters (median and standard deviation), measurements (Pearson's asymmetry coefficient and Fisher's pointing coefficient) and association tasks between variables. The results show that teachers claim to have the necessary knowledge to implement flipped learning in their programmes, but they still have certain deficiencies in their specific training. A significant number of these teachers do not use it because they lack training and digital assets, and also because of a certain apprehension towards innovative practices. The main benefits include the improvement in the student's autonomy, their participation, interaction and motivation, as well as the teachers' satisfaction. Regarding the teachers' perception, it therefore follows that flipped learning contributes to the attention towards diversity created by the multicultural environments, which in this case is a result of the migration phenomenon.

Chimeric antigen receptor T (CAR-T) cell therapy has been proven to be successful against different leukaemias and lymphomas. Its success has led, in recent years, to its use being tested for different solid tumours, including glioblastoma, a type of primary brain tumour, characterised by aggressiveness and recurrence. This paper presents an analytical study of a mathematical model describing the competition of CAR-T and glioblastoma tumour cells, taking into account their immunosuppressive capacity. The model is formulated in a general way, and its basic properties are investigated. However, most of the analysis considers the model with exponential tumour growth, assuming this growth type for simplicity. The existence and stability of steady states are studied, and the subsequent focus is on two different types of treatment: constant and periodic. Finally, protocols for CAR-T cell therapy of glioblastoma are numerically derived; these are aimed at preventing the tumour from reaching a critical size and at prolonging the patients’ survival time as much as possible. The analytical and numerical results provide theoretical support for the treatment of glioblastoma using CAR-T cells.

Abstract The Coronavirus 2019 (COVID-19) pandemic has had a considerable impact on the incidence of severe community-acquired pneumonia (CAP) worldwide. The aim of this study was to assess the early impact of the COVID-19 pandemic in the Reunion Island. This multicenter retrospective observational study was conducted from 2016 to 2021 in the hospitals of Reunion Island. The incidence of severe non-SARS-CoV-2 CAP, microorganisms, characteristics and outcomes of patients hospitalized in intensive care unit were compared between the pre-COVID-19 period (January 1, 2016 to February 29, 2020) and the early COVID-19 period (March 1, 2020 to October 31, 2021). Over the study period, 389 patients developed severe non-SARS-CoV-2 CAP. The incidence of severe non-SARS-CoV-2 CAP significantly decreased between the two periods (9.16 vs. 4.13 cases per 100,000 person-years). The influenza virus was isolated in 43.5% patients with severe non-SARS-CoV-2 CAP in the pre-COVID-19 period and in none of the 60 patients in the early COVID-19 period (P

Abstract Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.

Abstract Background Insulin resistance (IR) is considered the main driver of obesity related metabolic complications, and is related to oxidative stress and inflammation, which in turn promote each other. There is currently no specific definition of IR in children, rather, that for adult population is used by pediatric endocrinologists instead. Altered insulin secretion dynamics are associated with worse metabolic profiles and type 2 diabetes mellitus development, thus we aimed to test whether insulin response relates to oxidative stress and inflammation in children. Methods We conducted a case–control study, including 132 children classified as follows: 33 children without obesity (Lean); 42 with obesity but no IR according to the American Diabetes Association criteria for adults (OBIR-); 25 with obesity and IR and an early insulin response to an oral glucose tolerance test (OGTT) (EP-OBIR +); 32 with obesity, IR, and a late insulin peak (LP-OBIR +); and studied variables associated with lipid and carbohydrate metabolism, oxidative stress, inflammation and inflammasome activation. Results The measured parameters of children with obesity, IR, and an early insulin response were similar to those of children with obesity but without IR. It was late responders who presented an impaired antioxidant system and elevated oxidative damage in erythrocytes and plasma, and inflammasome activation at their white blood cells, despite lower classical inflammation markers. Increased uric acid levels seems to be one of the underlying mechanisms for inflammasome activation. Conclusions It is insulin response to an OGTT that identifies children with obesity suffering oxidative stress and inflammasome activation more specifically. Uric acid could be mediating this pathological inflammatory response by activating NLRP3 in peripheral blood mononuclear cells. Graphical Abstract

La constante incorporación de didácticas tecnológicas al escenario educativo ha provocado una verdadera revolución en la concepción de la enseñanza y el aprendizaje. El presente estudio realizado con una muestra de 256 estudiantes, se enmarca dentro del proceso de difusión de resultados de un proyecto colaborativo interuniversitario entre profesores de la Universidad de Murcia y Salamanca, con la finalidad de conocer la valoración que realizan los estudiantes, futuros profesionales de la educación, sobre el uso de Kahoot! como herramienta docente de gamificación en la asignatura de Metodología de Investigación Educativa, analizando la influencia del género en dichas valoraciones. Los resultados obtenidos, planteados como evaluación de necesidades para la toma de decisiones futuras en materia de igualdad, muestran que pese a que todos los estudiantes consideran que Kahoot! y su metodolgoía lúdica, constituyen un buen recurso didáctico que potencia y favorece el desarrollo de competencias, son los estudiantes varones quienes se posicionan más a favor de la utilidad y practicidad de esta herramienta y sus benificios en el proceso de enseñanza-aprendizaje

Abstract Gene fusions and MET exon skipping drive oncogenesis in 8–9% and 3% of non-small cell lung cancers (NSCLC) respectively. Their detection are essential for the management of patients since they confer sensitivity to specific targeted therapies with significant clinical benefit over conventional chemotherapy. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) account for historical reference techniques however molecular-based technologies (RNA-based sequencing and RT-PCR) are emerging as alternative or complementary methods. Here, we evaluated the analytical performance of the fully-automated RT-PCR Idylla GeneFusion assay compared to reference methods using 35 fixed NSCLC samples. Idylla demonstrated overall agreement, sensitivity and specificity of 100% compared to RNASeq. Interestingly, it succeeded in retrieving 10 out of 11 samples with inconclusive results due to insufficient RNA quality for sequencing. Idylla showed an overall agreement, sensitivity and specificity of 90.32%, 91.67% and 89.47% compared to IHC/FISH respectively. Using commercial standards, the limit of detection of the Idylla system for the most frequent fusions and exon skipping ranges between 5 and 10 ng RNA input. These results support that the Idylla assay is a reliable and rapid option for the detection of these alterations, however a particular attention is needed for the interpretation of the expression imbalance.

Nuclear Power Plants (NPP) are widely utilized around the globe from different base forms as it is one of the most dependable renewable resources that technological advancements have offered. However, different perceptions of the usage of NPPs emerged from different generations. The purpose of this study was to investigate the acceptance of nuclear energy as an alternative source of energy among Generation Z in the Philippines by utilizing an extended Theory of Planned Behavior (TPB) approach. An online questionnaire which consisted of 31 items was distributed using a purposive sampling approach and 450 respondents of Generation Z voluntarily answered. Structural Equation Modeling (SEM) showed that the knowledge regarding NPP had significant effects on risk perception and benefit perception which subsequently led to subjective norms. In addition, perceived behavioral control and subjective norms had significant effects on behavioral intention which led to nuclear acceptance. Interestingly, the respondents perceived the benefit of NPP as slightly higher than the perceived risk. With these, it was clear that the commissioning Nuclear Power Plant must consider as an alternative source of electric energy in the Philippines. Moreover, this study is one of the first studies that investigated the acceptance of NPP among Generation Z. Lastly, the model could be a basis to strengthen the acceptance strategy of opening NPP among Generation Z, particularly in developing countries.

Clinical, epidemiologic, and microbiologic analyses revealed emergence of 26 cases of Corynebacterium diphtheriae species complex infections on Réunion Island, France, during 2015–2020. Isolates were genetically diverse, indicating circulation and local transmission of several diphtheria sublineages. Clinicians should remain aware of the risk for diphtheria and improve diagnostic methods and patient management.

Introducción. La revalorización de un tiempo de disfrute compartido en las familias, que suponga una oportunidad para el encuentro lúdico-educativo y las relaciones dialógicas, junto al amplio abanico de actividades de ocio que se potencian en una sociedad consumista, induce a cuestionarnos cuáles de ellas forman parte de la microcultura familiar. Además, la sensibilidad contextual del ocio se hace extensible al ámbito familiar, de manera que las variables de índole socioeconómico-cultural asociadas a este agente educativo condicionan el perfil de ocio que se ejerce. Metodología. Con el objetivo de conocer si existen diferencias significativas en la práctica de las diferentes tipologías de actividades de ocio familiar en función del tipo de familia, la persona que responde el cuestionario y el número de libros en el hogar, se realizó un estudio descriptivo-inferencial, transversal, no experimental y cuantitativo en el que participaron 407 familias con hijos/as en el segundo tramo de Educación Primaria cumplimentando un cuestionario acerca de las tipologías de actividades que éstos practicaron, extrayendo, a través del programa SPSS los estadísticos descriptivos e inferenciales con las variables sociodemográficas objeto del estudio. Resultados. De las 16 actividades contempladas en el cuestionario, el visionado de televisión y las comidas conjuntas son las más frecuentes frente a las deportivas comunitarias, al aire libre y acuáticas, encontrando diferencias significativas en función del tipo de familia, la persona que cumplimenta el cuestionario y el número de libros que hay en el hogar, siendo las familias nucleares, cuando el cuestionario es cumplimentado por la madre o los hogares con más de 100 libres aquellos que tienen una práctica más diversificada. Discusión. Los resultados coinciden con otros estudios al encontrar que las prácticas de ocio familiar están disminuyendo y son menos diversificadas ante la existencia de una sociedad en las que los seres humanos son presos de su ámbito laboral, mermando otros agentes como, en este caso, la familia. Además, persiste una feminización del ocio familiar, recayendo todo el peso sobre la figura de la madre, lo cual resulta más estresante cuando esta se halla en situación monofamiliar. Conclusiones. De esta forma, se pone el alza el papel de las instituciones sociales, de medicina de atención primaria-familiar y los centros educativos como agentes encargados de educar respecto al ocio familiar a cada uno de los miembros de las familias desde sus diferentes vías de participación y asesoramiento.

Abstract Background CPX‐351 is approved for the treatment of therapy related acute myeloid leukemia (t‐AML) and AML with myelodysplastic related changes (MRC‐AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real‐life patients. Methods Retrospective analysis of AML patients treated with CPX‐351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. Results Median age of 79 patients treated with CPX‐351 was 67 years old (interquartile range 62–71), 53 were MRC‐AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX‐351 was 52%, 60‐days mortality 18%, measurable residual disease

This paper reports an exploratory, descriptive study on the emotions of content and language-integrated learning preservice teachers. The study, carried out in a Spanish university, aimed at analysing the internship experience of 19 preservice teachers in the context of a master’s degree in bilingual education (Spanish–English) for primary and secondary school teachers to determine the emotions experienced and the causative factors. The participants completed a questionnaire which showed that positive emotions were more frequent than negative ones. The variable causing such feelings included the subject taught, the sex of the teaching staff, previous experience, attitudes of educational centre tutors, and the students themselves. Therefore, the study highlights the affective dimension of teaching content and language-integrated learning.

Abstract Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 –/– motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 –/– iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

Introduction: Older patients are more likely to have cognitive dysfunction, and a great proportion of patients undergone surgical procedures are older adults. Postoperative cognitive dysfunction (POCD) has been shown as a consistent complication after major surgical procedures such as heart surgery. Aim: To determine the presence of long-term POCD in ≥65-year-old patients undergoing coronary artery bypass grafting and aortic valve replacement, and to establish related risk factors. Methods: We prospectively and sequentially included 44 patients with coronary disease and aortic stenosis scheduled for heart surgery. Follow-up of all patients was standardized and a neurocognitive evaluation were performed preoperatively and at 1, 6 and 12 months after surgery. Results: Patients experienced a significantly postoperative cognitive dysfunction (33.5%, 63.4% and 38.9% at 1, 6 and 12 months, respectively) from baseline (20.5%). Patient-associated aspects such as age (p

La moneda romana presenta una gran variedad de mensajes iconográficos que muestran la gran relación que hubo entre la religión tradicional, la transmisión de mensajes por parte del Estado y la moneda. En este artículo se analizan algunos de estos mensajes y la vinculación existente entre la moneda y el sacrilegio. Para ello se han seleccionado piezas clave dentro de la amonedación romana tardorrepublicana y altoimperial, abarcando un marco cronológico que data, de manera aproximada entre el 133 a.C. y el 192 d.C. y se ha estudiado la vinculación existente entre los tipos expuestos y su contexto sociopolítico.

El objetivo general de esta investigación es comprobar el impacto de una intervención en alumnos con Trastorno del Espectro Autista (TEA) desde dos perspectivas diferentes, tradicional e innovadora con realidad aumentada (RA) y virtual (RV). Se trata de un estudio de investigación cuantitativo con un diseño cuasi-experimental pretest-postest en un mismo grupo de sujetos. Se establecieron dos tipos de variables, la acción formativa desplegada (enfoque tradicional y RA-RV) y el efecto causado en las distintas dimensiones presentadas (motivación, atención, comunicación, autonomía y resultados de aprendizaje). La muestra estuvo formada por 23 personas con TEA, con una edad media de 10,52 años. Se concluye que el diseño y la adaptación de las tecnologías a las necesidades individuales de los alumnos con TEA son importantes. La comorbilidad puede afectar a los resultados del aprendizaje en los enfoques tradicionales, pero no en los innovadores. El uso adecuado y equilibrado de la RA y la RV puede maximizar los beneficios y minimizar los posibles efectos negativos para los alumnos con TEA.

Summary: Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response. Methods: Methods involved RNA-SEQ on NSCLC cells with depleted hMENA isoforms. A retrospective observational study assessed tissues from surgically treated N0 patients with NSCLC, using immunohistochemistry for tumoral and stromal hMENA isoforms, fibronectin, and TLS presence. ICB-treated patient tumors were analyzed using Nanostring nCounter and GeoMx spatial transcriptomics. Multiparametric flow cytometry characterized B cells and tissue-resident memory T cells (TRM). Survival and ICB response were estimated in the cohort and validated using bioinformatics pipelines in different datasets. Findings: Findings indicate that hMENA11a in NSCLC cells upregulates the TLS regulator LTβR, decreases fibronectin, and favors CXCL13 production by TRM. Conversely, hMENAΔv6 in CAFs inhibits LTβR-related NF-kB pathway, reduces CXCL13 secretion, and promotes fibronectin production. These patterns are validated in N0 NSCLC tumors, where hMENA11ahigh expression, CAF hMENAΔv6low, and stromal fibronectinlow are associated with intratumoral TLS, linked to memory B cells and predictive of longer survival. The hMENA isoform pattern, fibronectin, and LTβR expression broadly predict ICB response in tumors where TLS indicates an anti-tumor immune response. Interpretation: This study uncovers hMENA alternative splicing as an unexplored contributor to TLS-related Tumor Immune Microenvironment (TIME) and a promising biomarker for clinical outcomes and likely ICB responsiveness in N0 patients with NSCLC. Funding: This work is supported by AIRC (IG 19822), ACC (RCR-2019-23669120), CAL.HUB.RIA Ministero Salute PNRR-POS T4, “Ricerca Corrente” granted by the Italian Ministry of Health.

ABSTRACT Neural leprosy, which is characterized by nerve involvement without visible skin lesions, presents a diagnostic challenge. This case report examined the significance of diverse diagnostic modalities in the identification of pure neural leprosy. A 28-year-old patient with symptoms of edema, pain, paresthesia, and diminished sensitivity in the lower limbs underwent various tests. A stilt skin smear yielded negative results on bacilloscopy, whereas a Fast ML Flow leprosy test and electroneuromyography supported the diagnosis. This discussion highlights the importance of accessible methods for early investigation. This study emphasizes the multidisciplinary approach and value of the Fast ML Flow leprosy test and electroneuromyography for diagnosing neural leprosy.

El acceso a ChatGPT supone un avance en el desarrollo de tareas diversas y complejas, pero su potencial no está exento de amenazas para distintos ámbitos, entre ellos el educativo. Con este estudio presentamos una experiencia docente de integración de ChatGPT en asignaturas del grado de Ingeniería Informática con el objetivo de mostrar su utilización eficaz y ética como recurso formativo por parte de docentes y estudiantes (hombres y mujeres) y su grado de aceptación por parte del estudiantado y del profesorado. Los resultados muestran que la mayoría de los estudiantes (92,50 %) considera que ChatGPT es una herramienta de utilidad y fácil de usar para el desempeño académico. En cambio, el profesorado sostiene este argumento en menor proporción (80 %). Además, el estudiantado señala como desventajas la dificultad de comprobar la veracidad del resultado y que este es muy genérico si no se afina con las preguntas. La mayoría del alumnado afirma tener bastante experiencia en el uso de ChatGPT para la búsqueda de información y, si bien no lo considera apto para generar trabajos completos, le resulta beneficioso para su proceso de aprendizaje cuando se utiliza de forma complementaria y equilibrada.

The study aimed to assess sleep quality in PCC patients and its predictors by analysing its relationship with emotional, cognitive and functional variables, as well as possible differences based on COVID-19 severity. We included 368 individuals with PCC and 123 healthy controls (HCs) from the NAUTILUS Project (NCT05307549 and NCT05307575). We assessed sleep quality (Pittsburgh Sleep Quality Index, PSQI), anxiety (Generalized Anxiety Disorder, GAD-7), depression (Patient Health Questionnaire, PHQ-9), global cognition (Montreal Cognitive Assessment, MoCA), everyday memory failures (Memory Failures of Everyday Questionnaire, MFE-30), fatigue (Chadler Fatigue Questionnaire, CFQ), quality of life (European Quality of Life-5 Dimensions, EQ-5D), and physical activity levels (International Physical Activity Questionnaire, IPAQ). 203 were nonhospitalized, 83 were hospitalized and 82 were admitted to the intensive care unit (ICU). We found statistically significant differences in the PSQI total score between the PCC and HC groups (p

The partitioning of precipitation into interception, throughfall and stemflow is essential for the hydrological balance in forests, particularly in the Brazilian forest system, regulating the amount of water input and leaf distribution in the ecosystem. This study aimed to present the dynamics of interception loss in yerba mate monoculture, agroforestry and native mixed ombrophilous forest systems, in experimental producing areas in the municipality of Guarapuava, Southern Brazil. The total gross rainfall was 788 mm, distributed in 33 events between July 2019 and March 2020. The throughfall, stemflow and interception loss of rainfall were respectively 78.7, 0.2 and 21.1 % in the native mixed ombrophilous forest; 85.3, 0.1 and 14.6 % in the agroforestry system; and 86.1, 0.3 and 13.6 % in the monoculture system. It was observed that different canopy characteristics influence the variability of rainfall partitioning. The mixed ombrophilous forest showed a higher interception capacity, when compared to the monoculture and agroforestry systems, determined by plant density and meteorological conditions.

Fusarium head blight (FHB) is a devastating fungal disease responsible for significant yield losses in wheat and other cereal crops across the globe. FHB infection of wheat spikes results in grain contamination with mycotoxins, reducing both grain quality and yield. Breeding strategies have resulted in the production of FHB-resistant cultivars, however, the underlying molecular mechanisms of resistance in the majority of these cultivars are still poorly understood. To improve our understanding of FHB-resistance, we performed a transcriptomic analysis of FHB-resistant AC Emerson, FHB-moderately resistant AC Morley, and FHB-susceptible CDC Falcon in response to Fusarium graminearum. Wheat spikelets located directly below the point of inoculation were collected at 7-days post inoculation (dpi), where dual RNA-sequencing was performed to explore differential expression patterns between wheat cultivars in addition to the challenging pathogen. Differential expression analysis revealed distinct defense responses within FHB-resistant cultivars including the enrichment of physical defense through the lignin biosynthesis pathway, and DON detoxification through the activity of UDP-glycosyltransferases. Nucleotide sequence variants were also identified broadly between these cultivars with several variants being identified within differentially expressed putative defense genes. Further, F. graminearum demonstrated differential expression of mycotoxin biosynthesis pathways during infection, leading to the identification of putative pathogenicity factors.

Background: While SBRT to the prostate has become a valuable option as a radical treatment, limited data support its use in the postoperative setting. Here, we report the updated results of the multicentric Post-Prostatectomy Ablative Radiation Therapy (POPART) trial, investigating possible predictors of toxicities and patient-reported outcomes. Methods: Patients with PSA levels between 0.1–2.0 ng/mL after radical prostatectomy received Linac-based SBRT to the prostate bed in five fractions every other day for a total dose of 32.5 Gy (EQD21.5 = 74.3 Gy). Late toxicity was assessed using CTCAE v.5 scale, while EPIC-CP, ICIQ-SF, IIEF 5 questionnaires and PSA levels measured quality of life and biochemical control. Pre- and post-treatment scores were compared using a paired t-test, with MID established at > 0.5 pooled SD from the baseline. A logistic regression analysis was performed to evaluate potential associations between specific patient/tumor/treatment factors and outcome deterioration. Results: From April 2021 to April 2023 a total of 50 pts were enrolled and treated. Median follow-up was 12.2 (3–27) months. No late ≥ G2 GI or GU toxicity was registered. Late G1 urinary and rectal toxicities occurred in 46 % and 4 % of patients, respectively. Among 47 patients completing all EPIC-CP domains, four (9 %) showed worsened QoL, and eleven (26 %) developed erectile dysfunction correlating with PTV D2% (P = 0.032). At Multivariate analysis bladder wall D10cc independently correlated with late G1 GU toxicity (P = 0.034). Median post-treatment PSA nadir was 0.04 ng/mL (0.00 – 0.84). At the last follow-up, six patients presented with biochemical failure, including two nodal relapses. Conclusions: Our findings show that post-prostatectomy SBRT did not result in increased toxicity nor a significant decline in QoL measures, thus showing that it can be safely extended to the postoperative setting. Long-term follow-up and randomized comparisons with different RT schedules are needed to validate this approach.