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Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy. This study aimed to investigate the expression and prognostic significance of a key epigenetic complex encompassing DNA methyltransferase-1 (DNMT1), the histone methyltransferase G9a, and the scaffold protein UHRF1 in PDAC. We also evaluated the therapeutic potential of an innovative inhibitor targeting these epigenetic effectors. Methods Immunohistochemical analysis of DNMT1, G9a, and UHRF1 expression was conducted in human PDAC tissue samples. Staining was semi-quantitatively scored, and overexpression was defined as moderate to strong positivity. The prognostic impact was assessed by correlating protein expression with patient survival. The antitumoral effects of the dual DNMT1-G9a inhibitor CM272 were tested in PDAC cell lines, followed by transcriptomic analyses to identify underlying mechanisms. The in vivo antitumoral efficacy of CM272 was evaluated in PDAC xenograft and syngeneic mouse models, both alone and in combination with anti-PD1 immunotherapy. Results DNMT1, G9a, and UHRF1 were significantly overexpressed in PDAC cells and stroma compared to normal pancreatic tissues. Simultaneous overexpression of the three proteins was associated with significantly reduced survival in resected PDAC patients. CM272 exhibited potent antiproliferative activity in PDAC cell lines, inducing apoptosis and altering key metabolic and cell cycle-related genes. CM272 also enhanced chemotherapy sensitivity and significantly inhibited tumor growth in vivo without detectable toxicity. Combination of CM272 with anti-PD1 therapy further improved antitumor responses and immune cell infiltration, particularly CD4 + and CD8 + T cells. Conclusions The combined overexpression of DNMT1, G9a, and UHRF1 in PDAC is a strong predictor of poor prognosis. CM272, by targeting this epigenetic complex, shows promising therapeutic potential by inducing apoptosis, reprogramming metabolic pathways, and enhancing immune responses. The combination of CM272 with immunotherapy offers a novel, effective treatment strategy for PDAC.

Abstract Autism spectrum disorders encompass diverse neurodevelopmental conditions marked by alterations in social communication and repetitive behaviors. Advanced maternal age is associated with an increased risk of bearing children affected by autism but the etiological factors underlying this association are not well known. Here, we investigated the effects of advanced maternal age on offspring health and behavior in two genetically divergent mouse strains: the BTBR T+ Itpr3tf/J (BTBR) mouse model of idiopathic autism, and the C57BL/6 J (B6) control strain, as a model of genetic variability. In both strains, advanced maternal age negatively affected female reproductive and pregnancy outcomes, and perturbed placental and fetal growth, and the expression of genes in the fetal brain tissues. Postnatally, advanced maternal age had strain-dependent effects on offspring sociability, learning skills, and the occurrence of perseverative behaviors, varying between male and female offspring. These findings disentangle the relationship between genetic determinants and maternal age-related factors in shaping the emergence of autism-like behaviors in mice, highlighting the interplay between maternal age, genetic variability, and prenatal programming, in the occurrence of neurodevelopmental disorders.

Abstract Gastric Cancer (GC) is the fifth most common cancer worldwide. Early stages of GC began being detected, giving rise to a new concern, Quality of Life. This study aimed to systematically assess the effects of different GC reconstruction techniques on postoperative type 2 diabetes mellitus (T2DM), hypertension (HBP), and body mass index (BMI) reduction rate and to provide an overview of recent research on oncometabolic surgery (OS). We performed a systematic review and meta-analysis by searching three databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed a meta-analysis of risk ratios and mean differences to estimate the impact of duodenal bypass, Roux-en-Y reconstruction, and residual stomach on T2DM, HBP, and BMI reduction rate. Heterogeneity was assessed using the I 2 statistics. At the end of the follow-up, the duodenal bypass group compared to Billroth I had a significantly higher postoperative remission of T2DM and HBP, with a relative risk (RR) of 1.43 (95% confidence interval (95% CI) [1.27; 1.62]) and 1.3 (95% CI [1.00; 1.69]), respectively. Compared with the Billroth II group, Roux-en-Y reconstruction had significantly greater T2DM remission after gastrectomy (RR = 1.19; 95% CI [1.08; 1.31]), while HBP showed no significant differences. Regarding the improvement of HBP, total gastrectomy was significantly superior to subtotal gastrectomy (95% CI [1.01; 2.64]). A trend towards Roux-en-Y Esophagojejunostomy as the best option for T2DM remission was observed (95% CI [0.98; 2.77]; p = 0.06). Gastrectomy with Roux-en-Y reconstruction appears to be the most effective treatment for T2DM remission. Further research is needed to assess the impact of OS on metabolic diseases.

Taybi-Linder syndrome (TALS) is a rare autosomal recessive disorder characterized by severe microcephaly with abnormal gyral pattern, severe growth retardation and bone abnormalities. It is caused by pathogenic variants in the RNU4ATAC gene. Its transcript, the small nuclear RNA U4atac, is involved in the excision of ~850 minor introns. Here, we report a patient presenting with TALS features but no pathogenic variants were found in RNU4ATAC, instead the homozygous RTTN c.2953A>G variant was detected by whole-exome sequencing. After deciphering the impact of the variant on the RTTN protein function at centrosome in engineered RTTN-depleted RPE1 cells and patient fibroblasts, we analysed neural stem cells (NSC) derived from CRISPR/Cas9-edited induced pluripotent stem cells and revealed major cell cycle and mitotic abnormalities, leading to aneuploidy, cell cycle arrest and cell death. In cortical organoids, we discovered an additional function of RTTN in the self-organisation of NSC into neural rosettes, by observing delayed apico-basal polarization of NSC. Altogether, these defects contributed to a marked delay of rosette formation in RTTN-mutated organoids, thus impeding their overall growth and shedding light on mechanisms leading to microcephaly.

En este texto, el equipo editorial actual de Estudios de Historia Moderna y Contemporánea de México reflexiona sobre la trayectoria de casi sesenta años de la revista, con énfasis en las características y retos que ha enfrentado en los últimos cinco años y que pueden ser comunes a los de otras revistas del área: el mantenimiento de su puntualidad, la actualización de sus políticas editoriales y el uso de un gestor editorial digital. Ahora debe consolidar su calidad y encarar nuevos desafíos en el avance de su proceso de digitalización.

En el marco de la sostenibilidad sociocultural es ineludible la importancia de preservar la diversidad cultural y promover el desarrollo sostenible en las comunidades latinoamericanas. Este estudio se planteó identificar y documentar la organización ejidal, las estructuras de gobierno y las prácticas de ecoturismo en el ejido El Palmito, Concordia, Sinaloa, México. El diseño metodológico fue de alcance exploratorio descriptivo bajo una perspectiva cualitativa, apoyada en el paradigma hermenéutico y el estudio de caso, observación directa, revisión de literatura y tres entrevistas semiestructuradas a integrantes de un comité. Los principales hallazgos testificaron que la organización ejidal contribuye en la preservación de los recursos naturales, la toma de decisiones y sus diversas acciones se planifican en torno a la práctica del ecoturismo. La gobernanza se distinguió en la equidad colectiva en tanto los miembros son portadores de voz y voto, las fuertes redes de colaboración de tipo gremial que se dieron dentro del comité, así como destacadas relaciones de tipo puente y vínculos con otras organizaciones no gubernamentales. Se evidenció la viabilidad de prácticas turísticas sostenibles en zonas rurales y el fortalecimiento de los lazos comunitarios, de sus tradiciones y prácticas culturales. El estudio amplió el conocimiento científico de un área escasamente investigada.

The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis, allowing for rapid identification of hundreds of genes causing human diseases. This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3% of individuals worldwide are monogenic diseases. Strikingly, a substantial fraction of the mendelian forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis. Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate “neurodevelopmental proteasomopathies”. Besides cognitive impairment, these diseases are typically associated with a series of syndromic clinical manifestations, among which facial dysmorphism, motor delay, and failure to thrive are the most prominent ones. While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes, the molecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined. In this review, we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis, management, and potential treatment of these new rare disease entities.

The characteristic length method is a non-local approach to predicting the failure of open and closed-hole composite features. This method requires the determination of the linear elastic stress field of the composite laminate at its failure load. Typically, this requires computationally expensive progressive damage and linear elastic modelling and simulation with finite element analysis (FEA). In this study, we demonstrate the benefit of machine learning methods to efficiently and accurately predict characteristic lengths of composite laminates with open holes. We find that the prediction of the load-displacement profile usefully informs ultimate failure load prediction. We also find that linear elastic stress fields are more accurately predicted using a long-short term memory neural network rather than a convolutional decoder neural network. We show indirect prediction of characteristic length, via prediction of failure loads and linear elastic stress fields independently, results in more flexible, interpretable and accurate results than direct prediction of characteristic length, given sufficient training data. Our machine learning-assisted characteristic length method shows over five orders of magnitude of time-saving benefit compared to FEA-based methods.

Abstract Background The identification of novel therapeutic strategies to overcome resistance to the MEK inhibitor trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a challenge. This study analyzes the effects of trametinib on Id1 protein, a key factor involved in the KRAS oncogenic pathway, and investigates the role of Id1 in the acquired resistance to trametinib as well as the synergistic anticancer effect of trametinib combined with immunotherapy in KRAS-mutant LUAD. Methods We evaluated the effects of trametinib on KRAS-mutant LUAD by Western blot, RNA-seq and different syngeneic mouse models. Genetic modulation of Id1 expression was performed in KRAS-mutant LUAD cells by lentiviral or retroviral transductions of specific vectors. Cell viability was assessed by cell proliferation and colony formation assays. PD-L1 expression and apoptosis were measured by flow cytometry. The anti-tumor efficacy of the combined treatment with trametinib and PD-1 blockade was investigated in KRAS-mutant LUAD mouse models, and the effects on the tumor immune infiltrate were analyzed by flow cytometry and immunohistochemistry. Results We found that trametinib activates the proteasome-ubiquitin system to downregulate Id1 in KRAS-mutant LUAD tumors. Moreover, we found that Id1 plays a major role in the acquired resistance to trametinib treatment in KRAS-mutant LUAD cells. Using two preclinical syngeneic KRAS-mutant LUAD mouse models, we found that trametinib synergizes with PD-1/PD-L1 blockade to hamper lung cancer progression and increase survival. This anti-tumor activity depended on trametinib-mediated Id1 reduction and was associated with a less immunosuppressive tumor microenvironment and increased PD-L1 expression on tumor cells. Conclusions Our data demonstrate that Id1 expression is involved in the resistance to trametinib and in the synergistic effect of trametinib with anti-PD-1 therapy in KRAS-mutant LUAD tumors. These findings suggest a potential therapeutic approach for immunotherapy-refractory KRAS-mutant lung cancers. Graphical Abstract

The aim was to determine if the presence of horns on rams defines whether they are high-ranking or low-ranking. Dorper rams (n = 20) were evaluated to determine their social rank (SR), either high (HSR) or low (LSR), under intensive management conditions. Upon SR classification, the morphometric variables horns presence (HP) or absence (HA) and distance between them, the height at the withers, body length, thoracic perimeter, and scrotal circumference, male odor, body weight, and body condition score were registered. Afterward, semen evaluations were performed, recording the ejaculated volume, sperm concentration, and mass motility. There were no differences (p > 0.05) for the morphometric variables between the groups. However, HP as well as semen quality were higher (p < 0.05) in HSR males. The presence of horns in the rams determined their social rank and the dominant males showed better semen quality than the subordinate males.

Abstract Previous studies have demonstrated that the visual system adapts to the specific aberration pattern of an individual’s eye. Alterations to this pattern can lead to reduced visual performance, even when the Root Mean Square (RMS) of the wavefront error remains constant. However, it is well-established that ocular aberrations are dynamic and can change with factors such as pupil size and accommodation. This raises an intriguing question: can the neural system adapt to continuously changing aberration patterns? To address this question, we measured the ocular aberrations in four subjects under various natural viewing conditions, which included changes in accommodative state and pupil size. We subsequently computed the associated Point Spread Functions (PSFs). For each subject, we examined the stability in the orientation of the PSFs and analyzed the cross-correlation between different PSFs. These findings were then compared to the characteristics of a distribution featuring PSF shapes akin to random variations. Our results indicate that the changes observed in the PSFs are not substantial enough to produce a PSF shape distribution resembling random variations. This lends support to the notion that neural adaptation is indeed a viable mechanism even in response to continuously changing aberration patterns.

Background/purpose(s): During a viral infection, the immune response is mediated by the toll-like receptors and myeloid differentiation Factor 88 (MyD88) that play an important role sensing infections such as SARS-CoV-2 which has claimed the lives of more than 6.8 million people around the world. Methods: We carried out a cross-sectional with a population of 618 SARS-CoV-2-positive unvaccinated subjects and further classified based on severity: 22% were mild, 34% were severe, 26% were critical, and 18% were deceased. Toll Like Receptor 7 (TLR7) single-nucleotide polymorphisms (rs3853839, rs179008, rs179009, and rs2302267) and MyD88 (rs7744) were genotyped using TaqMan OpenArray. The association of polymorphisms with disease outcomes was performed by logistic regression analysis adjusted by covariates. Results: A significant association of rs3853839 and rs7744 of the TLR7 and MyD88 genes, respectively, was found with COVID-19 severity. The G/G genotype of the rs3853839 TLR7 was associated with the critical outcome showing an Odd Ratio = 1.98 (95% IC = 1.04–3.77). The results highlighted an association of the G allele of MyD88 gene with severe, critical and deceased outcomes. Furthermore, in the dominant model (AG + GG vs. AA), we observed an Odd Ratio = 1.70 (95% CI = 1.02–2.86) with severe, Odd Ratio = 1.82 (95% CI = 1.04–3.21) with critical, and Odd Ratio = 2.44 (95% CI = 1.21–4.9) with deceased outcomes. Conclusion: To our knowledge this work represents an innovative report that highlights the significant association of TLR7 and MyD88 gene polymorphisms with COVID-19 outcomes and the possible implication of the MyD88 variant with D-dimer and IFN-α concentrations.

A hiperglicemia afeta mais de 30% dos adultos hospitalizados por doença não crítica e está associada a um risco aumentado de desfechos clínicos adversos. A insulinoterapia é amplamente utilizada pela sua segurança e eficácia. Contudo, face à disponibilidade crescente de novos fármacos antidiabéticos com benefícios além do controlo glicémico, surgem desafios quanto à sua utilização em contexto hospitalar. Este artigo tem como objetivo rever e sumariar a evidência e as recomendações mais recentemente disponibilizadas sobre o papel dos antidiabéticos não insulínicos na gestão da hiperglicemia a nível hospitalar. A insulinoterapia mantém-se como o método de eleição. Os inibidores da dipeptidil peptidase 4 podem ser considerados em casos de hiperglicemia ligeira a moderada, como alternativa ou de forma complementar à insulinoterapia. Os agonistas dos recetores do glucagon-like peptide 1 têm recentemente revelado resultados promissores, com elevada eficácia no controlo glicémico e risco baixo de hipoglicemia. Existem preocupações relativas ao risco acrescido de acidose com a metformina, sobretudo em casos de doença aguda, apesar de não existir evidência que suporte a sua suspensão em doentes selecionados e com relativa estabilidade clínica. Os inibidores do cotransportador de sódio-glicose-2 devem ser descontinuados em situações clínicas que possam predispor a cetoacidose, incluindo episódios de doença aguda. A utilização hospitalar das sulfonilureias e das tiazolidinedionas é desaconselhada.

Neste artigo, abordo algumas questões de ordem superior envolvendo o conceito de Deus que surgem dentro de um contexto pluralista: o problema da unidade conceitual, o problema da unicidade de extensão e o problema da homogeneidade/heterogeneidade. Minha proposta para resolver essas questões envolve uma teoria especial híbrida de conceitos, chamada de teoria de conceitos ideais. Argumento que, quando adicionada a uma visão pluralista de conceitos, e formalizada dentro de uma estrutura de mundos possíveis, tal teoria fornece uma resposta satisfatória a esses problemas. A formalização é feita a partir de uma versão específica da Lógica Modal Quantificada Mais Simples (SQML, do inglês Simplest Quantified Modal Logic), e sua apresentação é exclusivamente semântica, mantendo detalhes técnicos a um nível mínimo

Abstract Endothelial dysfunction (ED) is critical in the development and progression of cardiovascular (CV) disorders, yet effective therapeutic targets for ED remain elusive due to limited understanding of its underlying molecular mechanisms. To address this gap, we employed a systems biology approach to identify potential targets for ED. Our study combined multi omics data integration, with siRNA screening, high content imaging and network analysis to prioritise key ED genes and identify a pro‐ and anti‐ED network. We found 26 genes that, upon silencing, exacerbated the ED phenotypes tested, and network propagation identified a pro‐ED network enriched in functions associated with inflammatory responses. Conversely, 31 genes ameliorated ED phenotypes, pointing to potential ED targets, and the respective anti‐ED network was enriched in hypoxia, angiogenesis and cancer‐related processes. An independent screen with 17 drugs found general agreement with the trends from our siRNA screen and further highlighted DUSP1, IL6 and CCL2 as potential candidates for targeting ED. Overall, our results demonstrate the potential of integrated system biology approaches in discovering disease‐specific candidate drug targets for endothelial dysfunction.

Se analiza la visita al templo de Jesús Malverde en la ciudad de Culiacán, durante el festejo de su aniversario luctuoso. Mediante una metodología cualitativa se realizó un trabajo de tipo narrativo, apoyado con entrevistas semiestructuradas y ejercicios de observación participante y no participante, con registro cronológico y fotográfico. Se encontró que el fenómeno genera una motivación mayormente religiosa que atrae a población local, de origen nacional y extranjero, quienes conviven entre símbolos de narcocultura, práctica que también permite asociarlo al turismo oscuro.

Bird species identification is a relevant and time-consuming task for ornithologists and ecologists. With growing amounts of audio-annotated data, automatic bird classification using machine learning techniques is an important trend in the scientific community. Analyzing bird behavior and population trends helps detect other organisms in the environment and is an important problem in ecology. Bird populations react quickly to environmental changes, which make their real-time counting and tracking challenging and very useful. A reliable methodology that automatically identifies bird species from audio would therefore be a valuable tool for the experts in different scientific and applicational domains. The goal of this work is to propose a methodology to identify bird sounds. In this paper, we explore deep learning techniques that are being used in this domain, such as Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) to classify the data. In deep learning, audio problems are commonly approached by converting them into images using audio feature extraction techniques such as Mel Spectrograms and Mel Frequency Cepstral Coefficients (MFCCs). We propose and test multiple deep learning and feature extraction combinations in order to find the most suitable approach to this problem.

In mobile networks, 5G Ultra-Dense Networks (UDNs) have emerged as they effectively increase the network capacity due to cell splitting and densification. A Base Station (BS) is a fixed transceiver that is the main communication point for one or more wireless mobile client devices. As UDNs are densely deployed, the number of BSs and communication links is dense, raising concerns about resource management with regard to energy efficiency, since BSs consume much of the total cost of energy in a cellular network. It is expected that 6G next-generation mobile networks will include technologies such as artificial intelligence as a service and focus on energy efficiency. Using machine learning it is possible to optimize energy consumption with cognitive management of dormant, inactive and active states of network elements. Reinforcement learning enables policies that allow sleep mode techniques to gradually deactivate or activate components of BSs and decrease BS energy consumption. In this work, a sleep mode management based on State Action Reward State Action (SARSA) is proposed, which allows the use of specific metrics to find the best tradeoff between energy reduction and Quality of Service (QoS) constraints. The results of the simulations show that, depending on the target of the 5G use case, in low traffic load scenarios and when a reduction in energy consumption is preferred over QoS, it is possible to achieve energy savings up to 80% with 50 ms latency, 75% with 20 ms and 10 ms latencies and 20% with 1 ms latency. If the QoS is preferred, then the energy savings reach a maximum of 5% with minimal impact in terms of latency.

The capital cities of the states of the Mexican Republic present a considerable heterogeneity in terms of their level of public security, so their correct characterization is an essential requirement, but not sufficient, for the elaboration of public policies for the prevention of crimes in the common jurisdiction. In this paper, we propose a multicriteria decision model based on the hierarchical ELECTRE III method that assists in how a policy maker can carry out this task. The objective of the work is to measure and compare the incidence of crimes of common jurisdiction in the capital cities of the states of the Mexican Republic. This model compares public security in 31 capital cities, adapting the situation as a multicriteria ranking problem to order the different capitals by their level of public security. The results showed that the model could identify the level of comprehensive public security of a capital city compared to the rest. Similarly, it also shows the disparities of this phenomenon between capital cities in relation to high, medium and low impact crimes.

Ethnobotanical studies that use the participatory research approach seek to involve the residents of a community in different stages of the study, promoting the registration, dissemination and strengthening of local knowledge, as well as the empowerment of decisions related to the sustainable use and management of resources. Using the participatory methodology, this study recorded and made a comparative analysis on the use of plants in two quilombola communities (Quilombo do Cambury-QC and Quilombo da Fazenda-QF) in the State of São Paulo. After a training on anthropological and botanical methods, local researchers selected and interviewed the local experts, recording their knowledge on plant uses and collecting the indicated plants, to be identified and deposited in herbariums. In addition, participant observation and field diaries were used by the academic researchers, helping to analyze the data. To test the differences in the composition of species known to local community, a Jaccard dissimilarity matrix was created, and a Permanova test was employed. During the 178 days of fieldwork, three local researchers from the QC and two from the QF, selected nine and eight experts on the uses of the plants in each quilombo, respectively, corresponding to 214 plant species, indicated for eight ethnobotanical categories. Our hypothesis has been confirmed, since the traditional knowledge found in both quilombos, regarding plant uses and the number of plant species by category, are distinct, since each community occupies particular plant areas and different phytophysiognomies. Most of the indicated species are native to the Atlantic forest, and no significant differences were observed in the proportion of native species vs. introduced among quilombos for any of the categories of use studied. Furthermore, the innovative methodology used, participatory ethnobotany, contributed to the empowerment of community members with regard to the use of their available resources in the environment in which they live, while retaining the intellectual property rights over their own knowledge.

Electrical stimulation is a tool that has been used in various ways in the rehabilitation of spinal cord injuries. Surface i.e. electromyography is an effective method for assessing the many conditions in which the patient is. Objective:To evaluate the benefits through neuromuscular electrostimulation in patients with spinal cord injury and possible neuroplasticity gain observed in electromyography. Method:This is a pilot study on the evolution of clinical cases of different neurological levels of spinal cord injury. Conclusion:It was observed that the spinal cord injured patients analyzed in this preliminary study showed possible gain in neuroplasticity.

A educação bilíngue, em Moçambique, é uma conquista da academia e da sociedade civil. O projeto começou desde o início da década de 1990, após ter-se percebido, que uma das causas de maior influência no insucesso escolar, no seio dos alunos do ensino primário, era a língua portguesa. Isso porque a maior parte das crianças que se matriculavam nas primeiras séries do Ensino Primário não falava o português a partir do seio familiar. Na sequência disso, começou-se o projeto experimental do ensino nas línguas moçambicanas, denominado PEBIMO, ou seja, Projeto Experimental de Ensino Bilíngue em Moçambique. O Professor Feliciano Chimbutane foi uma das figuras importantes do PEBIMO, tendo sido um dos consultores do Projeto. Esta entrevista, enquadrado no âmbito de pesquisado do campo para a tese de doutoramento, em andamento, visou a gerar informações da primeira mão sobre o andamento processo da inserção das línguas moçambicanas no ensino.

Después de dos décadas transcurridas del presente siglo XXI se vive una cultura digital en todas sus dimensiones. A nivel escolar, el diseño y aplicación de estrategias didácticas basadas en el uso de tecnologías de información y comunicación han permitido incrementar el rendimiento académico de los estudiantes en diferentes niveles educativos. Ante dicho contexto educativo se estableció como propósito del estudio conocer la opinión de los alumnos sobre el uso de TIC como apoyo en la enseñanza de la asignatura de matemáticas I en el sistema de bachillerato de la Universidad Autónoma de Sinaloa durante el ciclo escolar 2021-2022. Bajo una dirección de investigación cuantitativa y un nivel descriptivo, se diseñó un cuestionario que fue aplicado de forma presencial a 40 estudiantes a mediados del 2022 entre estudiantes de dos grupos de primer grado adscritos a la Escuela Preparatoria CU Mochis, en Sinaloa, México. Entre los principales descubrimientos se tiene que el 70% de ellos reconoce tener habilidades tecnológicas, pero un 62.5% no conoce cuáles son éstas, por lo que solo el 29.7% cree que, si las aplica dentro del aula. A pesar de ello, se registraron intereses y actitudes positivas por desarrollar sus competencias tecnológicas y orientarlas en su proceso de aprendizaje de temas matemáticos, representando una oportunidad ineludible para aquel docente que se preocupa por su quehacer educativo, y que aún no ha implementado con regularidad planeaciones didácticas con este enfoque y recursos.

O estudo trata de uma pesquisa bibliográfica com ênfase nas discussões sobre a formação de profissionais na ótica da diversidade, a partir da perspectiva das interfaces da saúde com a educação como espaço de formação do ser humano. A reflexão permeia num olhar crítico em atuação conjunta e intercomplementar da Saúde com a Educação, viabilizando os processos de inclusão social, cultural e digital. Destacamos as atividades interdisciplinares que possuem como foco a minimização da marginalização na sociedade informatizada e que apontam também para a formação de profissionais com novos significados, novas exigências sociais. Concomitantemente, a pesquisa evidencia que a interrelação entre o ensino formativo, técnico e profissional determina a prioridade dos cursos formativos, levando em conta a ética, o rigor científico e intelectual e o enfoque multi e interdisciplinar, especialmente na área da educação e saúde.

ABSTRACT Objective: To evaluate the association between the patients’ characteristics and the development of endocrine toxicity and to assess the association between endocrine-related adverse effects (ERAE) development and mortality. Subjects and methods: A retrospective observational study was conducted in 98 patients submitted to immunotherapy in our centre since its introduction in 2015 until March 2021. We excluded patients for which data regarding the corticotroph axis evaluation was missing. We used linear and logistic regression models to address our aims. Results: We observed a significant negative association between ERAE development and death (OR 0.32; p = 0.028). We detected no associations between ERAE and the following characteristics: age at immune checkpoint inhibitors (ICI) initiation, sex, diabetes mellitus, medical history, immunotherapy duration and ICI type. Conclusion: The development of an ERAE may be associated with a better overall survival rate in advanced oncologic disease, supporting the role of an unleashed immune system response to malignant cells.

Abstract Introduction Down syndrome is associated with various congenital anomalies and metabolic alterations such as hematological alterations. Values for the major hematological indicators vary with age and sex, but these values have not been described for Mexican children with Down syndrome. Objective To describe the complete blood count (CBC) values of pediatric patients with Down syndrome in México and report the most common non-malignant hematological alterations. Materials and methods The analysis includes data from 450 patients with Down syndrome, 55.5% ware males, aged 0-18 years who were patients at the Mexican National Institute of Pediatrics and whose clinical charts included CBC panel results for the period January 2008 through March 2018. Results A total of 3438 CBC panels were analyzed with descriptive statistics to find the values and statistical dispersion of the major indicators, with percentiles, and reported separately by sex and age group. The most common non-malignant hematological alterations found were macrocytic anemia, leukopenia, lymphopenia, and thrombocytosis. There were differences in values in all three series. Conclusions The CBC panels and hematological alterations are summarized for patients with Down syndrome.

International migration to depopulated areas is a growing field of research; even more so in Spain, one of the European countries most affected by depopulation. This paper analyses, first, the demographic impact of immigration from other countries in Aragon, which has undergone an intense and long process of depopulation throughout most of its territory. Second, we examine the factors that explain the immigrants’ choice of destination. The analysis focuses on the period 2000–2016. The basic territorial units of the analysis are the municipality (NUTS 5) and the county (NUTS 4).

Miguel Vaz,1 Vítor Silva,1 Cristina Monteiro,2 Samuel Silvestre1,3 1CICS-UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, 6200-506, Portugal; 2UFBI – Pharmacovigilance Unit of Beira Interior, University of Beira Interior, Covilhã, 6200-506, Portugal; 3CNC- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-517, PortugalCorrespondence: Miguel Vaz; Samuel Silvestre, CICS-UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, Covilhã, 6200-506, Portugal, Tel +351 275 329002/3, Fax +351 275 329099, Email miguel.vaz@ubi.pt; sms@ubi.ptAbstract: Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying the pathophysiology of Alzheimer’s disease (AD) approved by the US Food and Drug Administration (FDA), under the accelerated approval pathway. The decision was based on the ability of aducanumab to remove Aβ plaques, without any evidence that the Aβ clearance is correlated with less cognitive or functional decline. This decision has generated a considerable debate in the scientific community, especially because the results from the two Phase 3 trials, EMERGE and ENGAGE, were divergent and, even after the post hoc analysis, the data were insufficient to prove aducanumab efficacy. Moreover, some researchers think that this approval will be an obstacle to the progress and also demonstrated concerns about aducanumab cost and its safety profile. The European Medicines Agency’s rejection of aducanumab in December 2021 just brought more controversy over FDA’s decision. Now, Biogen is designing the FDA’s required confirmatory study, named ENVISION, which should be complete in 2026. Despite the controversy, the aducanumab showed to affect downstream tau pathology, which could open doors for a combination therapy approach for AD (anti-tau and anti-amyloid drug). This review summarizes the clinical development of aducanumab until regulatory agencies’ decisions, the available trials data and the controversy over aducanumab approval for AD.Keywords: anti-Aβ monoclonal antibody, ARIA, clinical trials, European Medicines Agency, Food and Drug Administration, tau protein

Antecedentes. Los tumores óseos suelen ser subdiagnosticados, provocando un retraso en su tratamiento. El diagnóstico erróneo más frecuente es tendinitis, en el cual el 31% corresponden a osteosarcomas y el 21% a sarcomas de Ewing. Objetivo. Crear un instrumento clínico-radiográfico de alta sospecha diagnóstica de tumores óseos de rodilla. Método. Se realizó un estudio clinimétrico (sensibilidad, consistencia y validez) en el servicio de tumores óseos del Hospital de Ortopedia de la Unidad Médica de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, en Ciudad de México. Resultados. El índice se realizó tomando las características de 153 pacientes. Para la fase de sensibilidad se incluyeron tres dominios (signos, síntomas y radiología) y 12 ítems. La consistencia se evaluó con coeficiente de correlación intraclase (0.944), intervalo de confianza del 95% (0.865-0.977), p < 0.001 y a de Cronbach (0.863). Se obtuvo una sensibilidad del instrumento de 0.80 y una especificidad de 0.882. El valor predictivo positivo de la prueba fue del 66.6% y el valor predictivo negativo fue de 93.75%. La razón de verosimilitud positiva fue de 6.8 y la razón de verosimilitud negativa fue de 0.2. La validez se evaluó mediante r-Pearson (0.894; p < 0.001). Conclusiones. Se diseñó un índice clínico-radiográfico de alta sospecha para detectar tumores malignos de rodilla con adecuada sensibilidad, especificidad y validez de apariencia, de contenido, de criterio y de constructo.

In the Serra Gaúcha region, South Brazil, the occurrence of hail is common due to relief and the cold air currents coming from polar regions. Nowadays, the use of anti-hail nets to protect fruit production is increasing, but the real effects of using this coverture on vines are largely unknown. Thus, this work aimed to evaluate the impact of the use of an anti-hail net on the productivity and quality parameters of ‘Rose Niagara’ grapes grown in the region, in the 2019/2020 and 2020/2021 harvests. The studied parameters were production, number of bunches per plant, bunch length, berry diameter, mass of 100 berries, average bunch mass, juice pH, titratable acidity, soluble solids, phenolic compounds content, total anthocyanins content, and photosynthetically active radiation. The results showed that the anti-hail net influenced some quality parameters, but this change was not consistent in the two harvests, indicating a larger influence of edaphoclimatic conditions than of the use of the net. Thus, the anti-hail net may be an alternative to protect vineyards from hail and other bad weather conditions, without having important negative impacts on the production and quality of ‘Rose Niagara’ grapes.

Research background. Tomato (Solanum lycopersicum L.) fruit is highly consumed worldwide and contains high amounts of carotenoids and tocopherols, two powerful antioxidants. Native tomato genotypes are rarely used in large-scale market but serve as a reservoir to diversify the species gene pool and can be employed to obtain functional compounds. Extraction methods are currently changing towards cleaner procedures that are more efficient and environmentally friendly, including avoiding toxic or polluting solvents. Experimental approach. In this study, factorial and fractional factorial designs were used to evaluate the efficiency of digestive enzymes, sonication and green solvents to obtain lipophilic antioxidant extracts from native tomato. To monitor the efficiency of the extraction process, spectrophotometric quantification of total carotenoids and antioxidant activity was carried out, and then individual quantification of carotenoids and tocopherols in the extracts was done by HPLC. Results and conclusions. Digestive enzymes and sonication increased the carotenoid content and the antioxidant activity of the obtained extracts when applied individually. However, when these treatments were applied together and in combination with isopropyl acetate, a green solvent, the obtained extracts had the highest carotenoid and tocopherol contents as well as the maximal antioxidant activity. A correlation analysis suggested that antioxidant activity resulted from synergistic effects rather than individual compounds. Tomato extracts were obtained through a rapid and environmentally friendly extraction method and their antioxidant activity was enhanced. Novelty and scientific contribution. Tomato fruits have been the subject of numerous studies; however, functional compound extraction through environmentally friendly methods remains an attractive use of native tomato fruit, enhancing its limited production and harnessing a large amount of tomato product industry. There are few reports where environmentally friendly extraction methods are combined; even rarer are those where green solvents are also used. In this work, the combination of different environmentally friendly extraction methods improved the extraction of carotenoids and tocopherols and allowed to establish a more efficient process. These results could stimulate the use of clean technologies and make the native tomato more attractive for industrial or compound extraction processes.

This research aims to evaluate the actual level of understanding and application of Corporate Venture Capital (CVC) in the Regional Innovation System (RIS) present in the Metropolitan Region of Curitiba (MRC). The survey focuses the large and traditional industrial companies (LTIC) which have tremendous importance to State of Paraná, due to taxes and formal jobs generation. While the LTIC needs to innovate, creating or recovering competitive advantage, the startup firm seeks for partnerships or private equity. In this context, there is an opportunity of establishing linkages between different actors through the CVC. The article presents the results of a survey consisting of an online questionnaire and a focal group, where the data was analyzed through a qualitative approach. The research demonstrated a minor part of the survey respondents practicing CVC, although an expressive number of companies intends to invest in startups. It was also possible to observe that the risk aversion, anxiety for financial payback and different vocabulary between startup and LTIC are still barriers to an effective adhesion to CVC in this regional context. This work contributes to scientific literature when highlight the importance of understanding and properly narrowing large companies of startups. However, the asymmetries between parts and the maturity for dealing and absorbing knowledge from startups is an issue that the RIS organizations could be involved. Submited: September 2022 Accepted: December 2022 DOI: 10.18226/23190639.v10n2.06

Staphylococcus aureus is the main aetiologic agent of osteoarticular infections (OAIs) in paediatric patients. The aim of this prospective unicenter study was to describe the phenotypic and genotypic characteristics of S. aureus isolates obtained from OAIs in paediatric patients admitted to tertiary care hospital. Through a surveillance program called OsteoCode, a multidisciplinary team was created and we identified 27 patients with OAIs caused by S. aureus from 2019 to 2021. The susceptibility profile, virulence factors, biofilm formation, pulsed-field gel electrophoresis (PFGE), clonal complex (CC) and sequence type (ST) were determined. In addition, the clinical characteristics and evolution of the patients presented six months after the diagnosis of OAIs were described. Ninety-two percent of the isolates were methicillin-sensitive S. aureus (MSSA). In methicillin-resistant S. aureus (MRSA), SCCmec-II and SCCmec-V were detected. The pvl gene was only observed in MSSA (18.5%) and was associated with highest fever (p=0.015), multiple localization (p=0.017), and soft tissue sites of infection beyond the bone (pyomyositis, pulmonary abscess) (p=0.017). Biofilm formation was detected in 55.6% of isolates. The most common CC were CC5 and CC30 which represent the most common linages for bone and joint infections worldwide. The isolates were distributed in different STs, and ST672 was predominant. MRSA were associated with a longer duration of intravenous treatment and a prolonged hospital stay (p=0.023). Recurrent infection occurred in five children and orthopaedic complications in 33.3% of patients. This is the first study that reflects the epidemiology of S. aureus in OAIs in paediatric patients in Mexico; a clear predominance of MSSA distributed in different STs was observed. Our findings highlight that a multidisciplinary team is required for the diagnosis and treatment of OAIs.

Abstract The first determination of presence and biodistribution of PFOA in ninety specimens of sea urchin Paracentrotus lividus from two differently contaminated sites along Palermo’s coastline (Sicily) is reported. Analyses were performed on the sea urchins’ coelomic fluids, coelomocytes, gonads or mixed organs, as well as on seawater and Posidonia oceanica leaves samples from the collection sites. PFOA concentration ranged between 1 and 13 ng/L in seawater and between 0 and 794 ng/g in P. oceanica. The analyses carried out on individuals of P. lividus from the least polluted site (A) showed PFOA median values equal to 0 in all the matrices (coelomic fluid, coelomocytes and gonads). Conversely, individuals collected from the most polluted site (B) showed median PFOA concentrations of 21 ng/g in coelomic fluid, 153 ng/g in coelomocytes, and 195 ng/g in gonads. Calculated bioconcentration factors of log10BCF > 3.7 confirmed the very bioaccumulative nature of PFOA. Significant correlations were found between the PFOA concentration of the coelomic fluid versus the total PFOA concentration of the entire sea urchin. PERMANOVA (p = 0.001) end Welch's t-test (p

Abstract Background Patients with 13q-syndrome are at risk of retinoblastoma when the RB1 gene, located in the chromosomal band 13q14.2, is deleted. This syndrome is frequently associated with congenital malformations and developmental delay, although these signs could be mild. Mosaic 13q-deletion patients have been previously reported in the literature; their phenotype is variable, and they may not be recognized. Case presentation Retinoblastoma diagnosed in a child with 13q-mosaicism confirmed in blood, oral mucosa, healthy retina and retinoblastoma. A second RB1 hit is present exclusively in the retinoblastoma sample (RB1 c.958C>T p.Arg320Ter). Other detected molecular events in retinoblastoma are 6p12.3pter gain and 6q25.3qter loss. Clinical examination is unremarkable except for clinodactyly of the right fifth finger. Discussion and conclusions We describe a case of mosaic 13q deletion syndrome affected by retinoblastoma. Molecular data obtained from the tumor analysis are similar to previous data available about this malignancy. High clinical suspicion is essential for an adequate diagnosis of mosaic cases.

Introduction: Despite the advance in vaccination, the SARS-CoV-2 infection remains a challenge for the medical community. Outpatient and hospital therapy for COVID-19 are still improving. Our study aimed to report the results of a series of patients with COVID-19 who participated in an outpatient treatment protocol since the first clinical manifestation. Methods: A case series report of individuals aged ≥18 years with clinical symptoms and a confirmed test for COVID-19 submitted to a treatment protocol. Patients were enrolled between May and September 2020 and followed for at least 15 days. The assessed clinical outcomes were the need for hospitalization, admission to the intensive care unit, orotracheal intubation, and death. Results: We studied a 116 patients. The mean age was 48 ± 14 years. Females formed 53%. The main comorbidities wereobesity (15.5%), systemic arterial hypertension (10.3%) ,type II diabetes (6%), and lung diseases (6.0%). Temperature >37.7 °C (51.7%), cough (55.2%), myalgia (37.1%), headache (37.9%), and fatigue (34.5%) were the most frequent signs and symptoms. According to different disease staging, the most administered drugs were: azithromycin, ivermectin, corticosteroid, antibiotics, and anticoagulants. There was no death, and hospitalization accounted for only 8.6% of the patients (1 in ICU); none required orotracheal intubation. The mean length of hospital stay was 5.8 days. Resumen: Introducción: a pesar del avance en la vacunación, la infección por SARS-CoV-2 sigue siendo un desafío para la comunidad médica. La terapia ambulatoria y hospitalaria para COVID-19 sigue mejorando. Nuestro estudio tuvo como objetivo informar los resultados de una serie de pacientes con COVID-19 que participaron en un protocolo de tratamiento ambulatorio desde la primera manifestación clínica. Métodos: estudio prospectivo con reportes de casos de personas ≥ 18 años con síntomas clínicos y pruebas confirmadas de COVID-19 en protocolo de tratamiento. Los pacientes se trataron consecutivamente entre mayo y septiembre de 2020 y se les dio seguimiento durante al menos 15 días. Los desenlaces clínicos evaluados fueron: la necesidad de hospitalización, la unidad de cuidados intensivos, la intubación orotraqueal y la muerte. Resultados: se estudiaron 116 pacientes. La edad media fue de 48 ± 14 años. Las hembras formaron el 53%. Las principales comorbilidades fueron obesidad (15,5%), hipertensión arterial sistémica (10,3%), hipertensión arterial sistémica (10,3%), diabetes tipo II (6%), y enfermedades pulmonares (6,0%). Tos (55,2%), temperatura > 37,7 °C (51,7%), cefalea (37,9%), mialgia (37,1%) y fatiga (34,5%) fueron los signos y síntomas más frecuentes. Según los diferentes estadios de la enfermedad, los fármacos más administrados fueron: azitromicina, ivermectina, corticoides, antibióticos y anticoagulantes. La hospitalización representó solo el 8,6% de los pacientes (uno en UCI); ninguno requirió intubación orotraqueal y ningún fallecimiento. La estancia hospitalaria media fue de 5,8 días.

The FOOT (FragmentatiOn Of Target) experiment is an international project designed to carry out the fragmentation cross-sectional measurements relevant for charged particle therapy (CPT), a technique based on the use of charged particle beams for the treatment of deep-seated tumors. The FOOT detector consists of an electronic setup for the identification of Z≥3Z\ge 3 fragments and an emulsion spectrometer for Z≤3Z\le 3 fragments. The first data taking was performed in 2019 at the GSI facility (Darmstadt, Germany). In this study, the charge identification of fragments induced by exposing an emulsion detector, embedding a C2H4{{\rm{C}}}_{2}{{\rm{H}}}_{4} target, to an oxygen ion beam of 200 MeV/n is discussed. The charge identification is based on the controlled fading of nuclear emulsions in order to extend their dynamic range in the ionization response.

Antimicrobial resistance (AMR) developed by microorganisms is considered one of the most critical public health issues worldwide. This problem is affecting the lives of millions of people and needs to be addressed promptly. Mainly, antibiotics are the substances that contribute to AMR in various strains of bacteria and other microorganisms, leading to infectious diseases that cannot be effectively treated. To avoid the use of antibiotics and similar drugs, several approaches have gained attention in the fields of materials science and engineering as well as pharmaceutics over the past five years. Our focus lies on the design and manufacture of polymeric-based materials capable of incorporating antimicrobial agents excluding the aforementioned substances. In this sense, two of the emerging techniques for materials fabrication, namely, electrospinning and 3D printing, have gained significant attraction. In this article, we provide a summary of the most important findings that contribute to the development of antimicrobial systems using these technologies to incorporate various types of nanomaterials, organic molecules, or natural compounds with the required property. Furthermore, we discuss and consider the challenges that lie ahead in this research field for the coming years.

Abstract Development of assisted reproductive technologies to address infertility has favored the birth of many children in the last years. The majority of children born with these treatments are healthy, but some concerns remain on the safety of these medical procedures. We have retrospectively analyzed both the fertilization method and the microarray results in all those children born between 2010 and 2019 with multiple congenital anomalies, developmental delay and/or autistic spectrum disorder (n = 486) referred for array study in our center. This analysis showed a significant excess of pathogenic copy number variants among those patients conceived after in vitro fertilization with donor oocyte with respect to those patients conceived by natural fertilization (p = 0.0001). On the other hand, no significant excess of pathogenic copy number variants was observed among patients born by autologous oocyte in vitro fertilization. Further studies are necessary to confirm these results and in order to identify the factors that may contribute to an increased risk of genomic rearrangements, as well as consider the screening for genomic alterations after oocyte donation in prenatal diagnosis.

Graves’ disease is secondary to the presence of anti-thyrotropin receptor antibodies (TRAb), which stimulate thyroid hormones. TRab determination is crucial for etiological diagnosis. The objectives of this study were (i) to compare two methods for determining TRab by chemoluminiscence vs. standard TRACE-immunofluorescence; (ii) to determine the diagnostic validity of the three methods.

IntroductionSevere acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) infection triggers inflammatory clinical stages that affect the outcome of patients with coronavirus disease 2019 (COVID-19). Disease severity may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. The aim of this study was to characterize the profile of amino acids and acylcarnitines in COVID-19 patients. A multicenter, cross-sectional study was carried out. A total of 453 individuals were classified by disease severity. Levels of 11 amino acids, 31 acylcarnitines, and succinylacetone in serum samples were analyzed by electrospray ionization–triple quadrupole tandem mass spectrometry. Different clusters were observed in partial least squares discriminant analysis, with phenylalanine, alanine, citrulline, proline, and succinylacetone providing the major contribution to the variability in each cluster (variable importance in the projection >1.5). In logistic models adjusted by age, sex, type 2 diabetes mellitus, hypertension, and nutritional status, phenylalanine was associated with critical outcomes (odds ratio=5.3 (95% CI 3.16-9.2) in the severe vs. critical model, with an area under the curve of 0.84 (95% CI 0.77-0.90). In conclusion the metabolic imbalance in COVID-19 patients might affect disease progression. This work shows an association of phenylalanine with critical outcomes in COVID-19 patients, highlighting phenylalanine as a potential metabolic biomarker of disease severity.

1850-1950. Cambridge: Cambridge University Press, 322. pp. ISBN 978-1-108-83127-7.