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Abstract Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

Abstract Using experiments and theory, we investigate the behavior of nonlinear acoustic modes in a physical system composed of an array of three coupled acoustic waveguides, two of which are externally driven with two different frequencies. Nonlinear modes with frequency given by linear combinations of the driving frequencies are realizations of so-called logical phi-bits. A phi-bit is a two-state degree of freedom of an acoustic wave, which can be in a coherent superposition of states with complex amplitude coefficients, i.e., a qubit analogue. We demonstrate experimentally that phi-bit modes are supported in the array of waveguides. Using perturbation theory, we show that phi-bits may result from the intrinsic nonlinearity of the material used to couple the waveguides. We have also isolated possible effects on phi-bit states associated with the systems’ electronics, transducers and ultrasonic coupling agents used to probe the array and that may introduce extrinsic nonlinearities. These extrinsic effects are shown to be easily separable from the intrinsic behavior. The intrinsic behavior includes sharp jumps in phi-bit phases occurring over very narrow ranges of driving frequency. These jumps may also exhibit hysteretic behavior dependent on the direction of driving frequency tuning. The intrinsic states of phi-bits and multiple nonlinearly correlated phi-bits may serve as foundation for robust and practical quantum-analogue information technologies.

How the bone marrow microenvironment evolves during induction chemotherapy to facilitate acute lymphoblastic leukaemia (ALL) survival remains unclear. Here the authors show that adipocytes emergent during ALL therapy aid the survival of ALL cells through a restrictive effect on the ALL proteome.

This study investigates the pedagogical competence of elementary school teachers in integrating educational technology in the classroom. Pedagogical competence involves creating effective learning environments, designing activities that cater to different learning styles, and using appropriate teaching strategies. Technology integration in education has opened up new opportunities for interactive learning experiences. The study found that elementary school teachers had a positive attitude towards educational technology, and most reported having high levels of competence in its use. However, the level of pedagogical competence toward educational technology varied significantly among teachers. Hence, the study emphasizes the need for programs and interventions to improve teachers' pedagogical competence in integrating educational technology into their teaching practices. Teachers must identify appropriate technological tools and resources to effectively incorporate educational technology to support their teaching objectives and engage students in meaningful learning experiences. Teachers must also assess students' technical skills and design activities appropriate for their technological competency level. The study recommends that elementary school teachers undergo training to improve their pedagogical competence in using educational technology. Thus, integrating technology into education is crucial in providing high-quality education in the 21st century. Programs are needed to improve teachers' pedagogical competence in incorporating it into their teaching practices.

This study explores the integration of technology platforms in online modular learning and proposes an enhanced learning continuity framework using online teaching as an alternative delivery modality. The study captures participants' experiences related to online modular education through surveys by employing a qualitative approach. The findings demonstrate that integrating technological platforms enhances learning continuity. Online teaching offers flexible and accessible learning experiences, fostering effective teaching and learning. The study emphasizes the significance of comprehensive technical infrastructure, blended learning approaches, pedagogical and learner support services, continuous assessment, and a healthy learning environment in crafting the framework. The framework emphasizes robust technological infrastructure, training programs, blended learning approaches, pedagogical support, diverse assessment strategies, and a healthy learning environment by addressing challenges like the digital divide, technical difficulties, and lack of face-to-face interaction, flexibility, adaptability, and continuous evaluation are emphasized to address specific institutional and learner needs. Implementing the framework requires collaboration among educational institutions, policymakers, and communities to create inclusive online learning environments. Efforts should be made to ensure equitable access to reliable internet connections, support disadvantaged learners, and foster creativity through interactive activities. Monitoring and evaluation play a vital role in tracking progress and making informed decisions for improvement. This study provides a foundation for institutions to develop an enhanced learning continuity framework using online teaching. By optimizing the benefits of online modular learning while addressing challenges, the framework promotes effective teaching and learning in the online education landscape.

This study assessed the effectiveness of a professional development program for junior high school mathematics teachers in the Philippines and analyzed their achievement test results in Mathematics. The study aimed to identify the factors affecting the quality of mathematics instruction and propose solutions to these challenges. The study found that while most teachers were consistent in their lesson planning and content delivery, they need to improve their questioning techniques, differentiated techniques, and strategies to develop higher-order thinking skills. The study suggests that teachers need to enhance their teaching practices to achieve the K to 12 curriculum goals, prepare students for better work opportunities, and contribute to the nation's economy. Professional development programs can provide opportunities for mathematics teachers to increase their knowledge and confidence in the subject. By improving their teaching practices, teachers can help enhance the quality of mathematics education in the Philippines. This study highlights the challenges mathematics teachers face in the country and the need for professional development programs to help them improve their teaching practices. The findings have important implications for mathematics education in the country, which can help raise the quality of education and the nation's economy.

This study explored the relationship between mathematics performance and learning styles among Grade 8 students in the Philippines. The study used a descriptive correlation research design to achieve its objectives, which included determining the profile of Grade 8 students, identifying their learning styles, and examining the relationship between mathematics performance and age, gender, and learning styles. The data was collected through an adapted questionnaire from David Kolb's learning style inventory. The findings revealed no significant relationship between learning styles and academic performance in mathematics. However, it is worth noting that the lack of a significant relationship does not necessarily mean that there is no relationship at all. Motivation, teacher quality, and cultural background may also influence mathematics performance. The findings suggest that educators should consider students' different learning styles when developing effective teaching strategies to enhance mathematics performance among Grade 8 students. This study contributes to the literature on mathematics education and has practical implications for educators seeking to enhance their students' mathematics performance.

Introduction: Adherence to nutritional medical treatments is essential for attaining clinical benefits. Yet, the evidence regarding the impact of various factors on adherence to these treatments is limited, highlighting the need for strategies that facilitate early identification of prognostic adherence factors. Objectives: This study aims to identify factors that may influence adherence to nutritional medical treatment. Methods: A cross-sectional prospective study was conducted using a validated 25-item questionnaire targeted at specialists in Endocrinology, Nutrition, Rehabilitation, and Dysphagia. Results: A total of 296 health professionals participated, providing pertinent data for 614 patients with dysphagia and malnutrition during routine clinical practice in public hospitals. Several factors potentially impairing adherence were identified, such as a patient's lack of appetite, satiety, disinterest and fatigue. Texture was recognized as a facilitating factor in 96% of cases. A statistically significant correlation was found between the value patients place on the intake of oral nutrition supplements in their recovery process and their compliance with the prescribed doses. Conclusions: The results emphasize the importance of communicating with patients and caregivers about the necessity of complying with the prescribed nutritional regimen and its potential benefits. The analysis of habits also underlined the need to offer flexible, patient-tailored nutritional solutions to enhance treatment adherence.

Abstract Background Cystic fibrosis (CF) has a vast and heterogeneous mutational spectrum in Europe. This variability has also been described in Spain, and there are numerous studies linking CFTR variants with the symptoms of the disease. Most of the studies analysed determinate clinical manifestations or specific sequence variants in patients from clinical units. Others used registry data without addressing the genotype–phenotype relationship. Therefore, the objective of this study is to describe the genetic and clinical characteristics of people with CF and to analyse the relationship between both using data from the rare disease registry of a region in southeastern Spain. Methods A cross-sectional study was carried out in people with a confirmed diagnosis of CF registered in the Rare Diseases Information System (SIER) of the Region of Murcia (Spain). The patients were classified into two genotypes according to the functional consequence that the genetic variants had on the CFTR protein. Results There were 192 people diagnosed with CF reported in the Region of Murcia as of 31 December 2018. Seventy-six genotypes and 49 different variants were described, with c.1521_1523delCTT (p. Phe508del) being the most common in 58.3% of the CF patients and 37.0% of the alleles. In addition, 67% of the patients were classified as a high-risk genotype, which was associated with a lower percentage of FEV1 (OR: 5.3; 95% CI: 1.2, 24.4), an increased risk of colonization by Pseudomonas aeruginosa (OR: 7.5; 95% CI: 1.7, 33.0) and the presence of pancreatic insufficiency (OR: 28.1; 95% CI: 9.3, 84.4) compared to those with a low-risk genotype. Conclusions This is the first study in Spain that describes the mutational spectrum and its association with clinical manifestations in patients with CF using data from a rare disease registry. The results obtained allow planning for the health resources needed by people with this disease, thus contributing to the development of personalized medicine that helps to optimize health care in CF patients.

Trichuriasis is considered a neglected tropical disease, being the second most common helminthiasis in humans. Detection of Trichuris in routine diagnosis is usually done by microscopic detection of eggs in fecal samples. Other molecular analyses are more reliable and could be used, but these analyses are not routinely available in clinical microbiology laboratories. The use of matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS) is increasing since the last decades due to its recent evidence as a potential role for reliable identification of microorganisms and a few nematodes. But, for parasites detection, normalized protocols and the acquisition and introduction of new species to the database are required. We carried out a preliminary study confirming the usefulness of MALDI-TOF MS for the rapid and reliable identification of Trichuris suis used as control and the creation of an internal database. To create main spectra profiles (MSPs), the different parts of five whipworms (esophagus and intestine) were used, developing different tests to verify the repeatability and reproducibility of the spectra. Thus, to validate the new internal database, 20 whipworms, separating the esophagus and intestine, were used, of which 100% were accurately identified as T. suis, but could not distinguish between both parts of the worm. Log score values ranged between 1.84 and 2.36, meaning a high-quality identification. The results confirmed that MALDI-TOF MS was able to identify Trichuris species. Additionally, a MALDI-TOF MS profile of T. suis proteome was carried out to develop the first internal database of spectra for the diagnosis of trichuriasis and other Trichuris spp.

Abstract Background Recent studies have reported the existence of a Trichuris species complex parasitizing primate. Nevertheless, the genetic and evolutionary relationship between Trichuris spp. parasitizing humans and Non-Human Primates (NHP) is poorly understood. The hypothesised existence of different species of Trichuris in primates opens the possibility to evaluate these primates as reservoir hosts of human trichuriasis and other putative new species of whipworms. Results In this paper, we carried out a morphological, biometrical and molecular study of Trichuris population parasitizing Macaca sylvanus from Spain based on traditional morpho-biometrical methods, PCA analysis and ribosomal (ITS2) and mitochondrial (cox1 and cob) DNA sequencing. Morphological results revealed that Trichuris sp. from M. sylvanus is Trichuris trichiura. Ribosomal datasets revealed that phylogenetic relationships of populations of Trichuris sp. from M. sylvanus were unresolved. The phylogeny inferred on mitochondrial datasets (partitioned and concatenated) revealed similar topologies; Thus, phylogenetic trees supported the existence of clear molecular differentiation between individuals of Trichuris sp. from M. sylvanus appearing in two different subclades. Conclusions Based on morphological parameters, biometrical measurements, and molecular sequence analysis, we conclude that the whipworms isolated from M. sylvanus were T. trichiura. Further, the evolutionary relationship showed that these worms belonged to two genotypes within the T. trichiura lineage. Since T. trichiura is of public health importance, it is important to carry out further studies to improve the understanding of its hosts range, evolution and phylogeography.

Abstract The effect of anomalies of foliar mineral nutrients on the nutritional behavior of apple crops has been evaluated using parameters obtained by means of remote sensing techniques. Twenty-five plots in commercial orchards were selected in the five most important municipalities of Chihuahua State, Mexico in which the main nutritional parameters were measured (N, P, K, Ca, Mg, Fe, Zn, Mn, Cu, and B). Important deficiencies of these nutrients were detected in 88% of the analyzed crops. These deficiencies showed significant correlation with the spectral data (SPOT5) and with the NDVI elaborated from these data. The mathematical models obtained showed high determination coefficients for most of the mineral elements; concretely, nitrogen and calcium presented the best results (0.80 and 0.76, respectively). Resumen Se ha evaluado el efecto en las anomalías de los nutrientes minerals foliares en el comportamiento nutricional de los cultivos de manzanos utilizando parámetros obtenidos mediante técnicas de teledetección. Se seleccionaron veinticinco parcelas en fincas comerciales de los cinco municipios más importantes del estado de Chihuahua (México), en los que se midieron en campo los principales parámetros nutricionales (N, P, K, Ca, Mg, Fe, Zn, Mn, Cu y B). Se detectaron importantes deficiencias de estos nutrientes en el 88% de los cultivos analizados. Estas deficiencias mostraron una correlación significativa con los datos espectrales (SPOT5) y con el NDVI elaborado a partir de estos datos. Los modelos matemáticos obtenidos proporcionaron altos coeficientes de determinación para la mayoría de los elementos minerales; concretamente, el nitrógeno y el calcio presentaron los mejores resultados (0.80 y 0.76, respectivamente).

There is currently intense international debate about the benefits of offering breast cancer screening tests (BCST) to all women aged 50 and older, as it is not clear that they outweigh the risks. Also, public perception is unrealistic. Participants overestimate the benefits and are oblivious to the negative physical or psychological impact of overdiagnosis and false positives. In addition, there is no clear strategy to make easier for them to make informed decisions about their participation in the test. In this context, a deliberative democracy (DD) process was carried out in Cadiz (Spain) with the dual objective of knowing the opinion of the participants on the PCCM; and knowing which strategies they consider would improve the information reception process and facilitate informed decision making. Participated thirteen women between the ages of 50 and 65. The DD process took place over three afternoons: (1) information on mammographic screening was provided; (2) arguments were given for and against the PCCM; and (3) participants deliberated on the information provided, and proposed changes to the information they receive. Participants expressed their opinion about the BCST in terms of its objectives, the sources of information, and the people to whom it is addressed, the clarity of the information, and when and how they receive it. They also indicated how they would like to receive information about the BCST –mode of arrival—, the moment, the contents about which they would like to be informed, the target persons and the action protocol. It is concluded that it is necessary to know the point of view of the participants about the information that they receive of the BCST in order to improve their quality and adapt it to their needs.

Trichuris trichiura is a nematode considered as the whipworm present in humans and primates. The systematics of the genus Trichuris is complex. Morphological studies of Trichuris isolated from primates and humans conclude that the species infecting these hosts is the same. Furthermore, numerous molecular studies have been carried out so far to discriminate parasite species from humans and Non-Human Primates using molecular techniques, but these studies were not performed in combination with a parallel morphological study. The hypothesised existence of more species of Trichuris in primates opens the possibility to revise the zoonotic potential and host specificity of T. trichiura and other putative new species of whipworms.In the present work, a study of Trichuris Roederer, 1761 (Nematoda:Trichuridae) parasitizing C. g. kikuyensis, P. ursinus, Macaca sylvanus, Pan troglodytes, and Sus scrofa domestica has been carried out using modern morphometric techniques in order to differentiate populations of Trichuris isolated from four species of captive NHP from different geographical regions, and swine, respectively.The results obtained revealed strong support for geometrical morphometrics as a useful tool to differentiate male Trichuris populations. Therefore, morphometrics in combination with other techniques, such as molecular biology analyses, ought to be applied to further the differentiation of male populations.On the other hand, morphometrics applied to female Trichuris species does not seem to contribute new information as all the measurements combinations of obtained from females always showed similar results. Keywords: Primates, Trichuris, specific differentiation, Morphometrics

Perineural invasion (PNI) is a common and characteristic feature of pancreatic ductal adenocarcinoma (PDAC) that is associated with poor prognosis, tumor recurrence, and generation of pain. However, the molecular alterations in cancer cells and nerves within PNI have not previously been comprehensively analyzed. Here, we describe our proteomic analysis of the molecular changes underlying neuro‐epithelial interactions in PNI using liquid chromatography–mass spectrometry (LC‐MS/MS) in microdissected PNI and non‐PNI cancer, as well as in invaded and noninvaded nerves from formalin‐fixed, paraffin‐embedded PDAC tissues. In addition, an in vitro model of PNI was developed using a co‐culture system comprising PDAC cell lines and PC12 cells as the neuronal element. The overall proteomic profiles of PNI and non‐PNI cancer appeared largely similar. In contrast, upon invasion by cancer cells, nerves demonstrated widespread plasticity with a pattern consistent with neuronal injury. The up‐regulation of SCG2 (secretogranin II) and neurosecretory protein VGF (nonacronymic) in invaded nerves in PDAC tissues was further validated using immunohistochemistry. The tested PDAC cell lines were found to be able to induce neuronal plasticity in PC12 cells in our in vitro established co‐culture model. Changes in expression levels of VGF, as well as of two additional proteins previously reported to be overexpressed in PNI, Nestin and Neuromodulin (GAP43), closely recapitulated our proteomic findings in PDAC tissues. Furthermore, induction of VGF, while not necessary for PC12 survival, mediated neurite extension induced by PDAC cell lines. In summary, here we report the proteomic alterations underlying PNI in PDAC and confirm that PDAC cells are able to induce neuronal plasticity. In addition, we describe a novel, simple, and easily adaptable co‐culture model for in vitro study of neuro‐epithelial interactions.

Abstract Background Glucose is the main secretagogue of pancreatic beta-cells. Uptake and metabolism of the nutrient stimulates the beta-cell to release the blood glucose lowering hormone insulin. This metabolic activation is associated with a pronounced increase in mitochondrial respiration. Glucose stimulation also initiates a number of signal transduction pathways for the coordinated regulation of multiple biological processes required for insulin secretion. Methods Shotgun proteomics including TiO2 enrichment of phosphorylated peptides followed by liquid chromatography tandem mass spectrometry on lysates from glucose-stimulated INS-1E cells was used to identify glucose regulated phosphorylated proteins and signal transduction pathways. Kinase substrate enrichment analysis (KSEA) was applied to identify key regulated kinases and phosphatases. Glucose-induced oxygen consumption was measured using a XF96 Seahorse instrument to reveal cross talk between glucose-regulated kinases and mitochondrial activation. Results Our kinetic analysis of substrate phosphorylation reveal the molecular mechanism leading to rapid activation of insulin biogenesis, vesicle trafficking, insulin granule exocytosis and cytoskeleton remodeling. Kinase-substrate enrichment identified upstream kinases and phosphatases and time-dependent activity changes during glucose stimulation. Activity trajectories of well-known glucose-regulated kinases and phosphatases are described. In addition, we predict activity changes in a number of kinases including NUAK1, not or only poorly studied in the context of the pancreatic beta-cell. Furthermore, we pharmacologically tested whether signaling pathways predicted by kinase-substrate enrichment analysis affected glucose-dependent acceleration of mitochondrial respiration. We find that phosphoinositide 3-kinase, Ca2+/calmodulin dependent protein kinase and protein kinase C contribute to short-term regulation of energy metabolism. Conclusions Our results provide a global view into the regulation of kinases and phosphatases in insulin secreting cells and suggest cross talk between glucose-induced signal transduction and mitochondrial activation.

El objetivo principal de este trabajo se centra en la determinación y análisis de las variables ambientales que influyen en las divergencias de las estimaciones de erosionabilidad a partir de dos métodos, aplicando tres algoritmos de estimación del Factor K. La exploración de esta información permite conocer el peso que ejerce el origen de los datos de entrada a los modelos en el cómputo de erosionabilidad y qué importancia tiene en función del algoritmo elegido para la estimación del Factor K. Los resultados muestran que las pendientes, así como los índices de vegetación (NDVI) y de composición mineralógico (IOI) obtenidos mediantes técnicas de teledetección han mostrado los valores de asociación más elevados entre ambos métodos. The main goal of this work is to determine and analyze the influence of environmental variables on the changes of two erodibility methods, through the application of three estimation algorithms of K Factor. The analysis of this information allows knowing the significance of the input data to the models in the erodibility estimation, and likewise the consequence of the algorithm selected for the estimation of K Factor. The results show that the slopes, as well as the vegetation index (NDVI) and the mineralogical composition index (IOI), generated both by remote sensing techniques, have shown the highest values of association between methods.

Abstract Glioblastoma (GBM) is the most aggressive type of primary brain tumours. Anti-angiogenic therapies (AAT), such as bevacizumab, have been developed to target the tumour blood supply. However, GBM presents mechanisms of escape from AAT activity, including a speculated direct effect of AAT on GBM cells. Furthermore, bevacizumab can alter the intercellular communication of GBM cells with their direct microenvironment. Extracellular vesicles (EVs) have been recently described as main acts in the GBM microenvironment, allowing tumour and stromal cells to exchange genetic and proteomic material. Herein, we examined and described the alterations in the EVs produced by GBM cells following bevacizumab treatment. Interestingly, bevacizumab that is able to neutralise GBM cells-derived VEGF-A, was found to be directly captured by GBM cells and eventually sorted at the surface of the respective EVs. We also identified early endosomes as potential pathways involved in the bevacizumab internalisation by GBM cells. Via MS analysis, we observed that treatment with bevacizumab induces changes in the EVs proteomic content, which are associated with tumour progression and therapeutic resistance. Accordingly, inhibition of EVs production by GBM cells improved the anti-tumour effect of bevacizumab. Together, this data suggests of a potential new mechanism of GBM escape from bevacizumab activity.

Summary: Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance. : Fearon et al. use unbiased transcriptomic and phosphoproteomic analysis to identify PHLDA1 as a mediator of acquired resistance to kinase-targeted therapies in cancer. Using a range of cell models and clinical data, they uncover a mechanism underpinning the re-wiring of Akt signaling in cancer drug resistance. Keywords: tyrosine kinase inhibitor, drug resistance, FGF, Akt, targeted therapy, cancer