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The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

El presente proyecto de innovación docente se crea con la idea de formar un HackLab para fomentar el uso de las herramientas de fabricación digital dentro de la Facultad de Bellas Artes de la Universidad Complutense de Madrid. En las últimas décadas estos laboratorios informáticos han sido espacios donde aprender, compartir y mostrar proyectos relacionados con la tecnología, la ciencia y la electrónica a todas aquellas personas que tengan interés en este ámbito. A través de este proyecto de innovación docente se pretende crear uno de estos espacios en la Facultad, en el que el profesorado de los diferentes departamentos, el alumnado de cualquier nivel formativo y el personal técnico del centro generen una comunidad abierta en la que adquirir y transferir conocimientos relativos a dichas áreas.

The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

La enfermedad arterial periférica (EAP) se caracteriza por la obstrucción de las arterias de las piernas y los pies debido a la acumulación de grasa. La neuropatía periférica (NP) afecta a la función de los nervios, incluidos los responsables de regular la sudoración y la humedad de los pies. Estos problemas aumentan significativamente el riesgo de úlceras y heridas en las extremidades. Este artículo presenta una metodología de análisis de la presión plantar con el equipo F-Scan64 para identificar puntos críticos durante las actividades diarias. El objetivo es diseñar plantillas personalizadas que monitoricen estos puntos y reduzcan el riesgo de lesiones en pacientes con estas afecciones. Los resultados se discuten en relación con estudios previos sobre los umbrales de riesgo que deben evitarse en estos casos. Además, se ofrece una perspectiva sobre la distribución sensorial de las plantillas personalizadas., Peripheral arterial disease (PAD) is characterized by blockage of the arteries in the legs and feet due to fatty deposits. Peripheral neuropathy (PN) affects the function of nerves, including those responsible for regulating sweat and moisture in the feet. These problems significantly increase the risk of ulcers and wounds in the extremities. This article presents a methodology for plantar pressure analysis using the F-Scan64 device to identify critical points during daily activities. The goal is to design customized insoles that monitor these points and reduce the risk of injury in patients with these conditions. The results are discussed in relation to previous studies on risk thresholds to avoid in these cases. In addition, a perspective on the sensory distribution of customized insoles is provided.

The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

Fibrous capsule (FC) formation, secondary to the foreign body response (FBR), impedes molecular transport and is detrimental to the long-term efficacy of implantable drug delivery devices, especially when tunable, temporal control is necessary. We report the development of an implantable mechanotherapeutic drug delivery platform to mitigate and overcome this host immune response using two distinct, yet synergistic soft robotic strategies. Firstly, daily intermittent actuation (cycling at 1 Hz for 5 minutes every 12 hours) preserves long-term, rapid delivery of a model drug (insulin) over 8 weeks of implantation, by mediating local immunomodulation of the cellular FBR and inducing multiphasic temporal FC changes. Secondly, actuation-mediated rapid release of therapy can enhance mass transport and therapeutic effect with tunable, temporal control. In a step towards clinical translation, we utilise a minimally invasive percutaneous approach to implant a scaled-up device in a human cadaveric model. Our soft actuatable platform has potential clinical utility for a variety of indications where transport is affected by fibrosis, such as the management of type 1 diabetes.

C.M.O. and J.A.E. designed the study, performed the experiments, analyzed and interpreted the results, and wrote the draft manuscript. C.M.-E. collected the samples, provided the isolates for this study, and revised and approved the final version of the manuscript. N.M. performed the experiments, D.T.L. and G.M. analyzed and interpreted the results, and A.H. revised the manuscript. B.G.Z. conceived, designed, and coordinated the study and revised and approved the final versión of the manuscript., In this study, we characterized two tigecycline-resistant Klebsiella pneumoniae isolates from dog urine samples. The isolates were genetically unrelated, belonging to sequence type 11 (ST11) and ST147, both classically related to human isolates. To the best of our knowledge, this is the first identification of tigecycline-resistant isolates from animals. We unveil here the worrisome circulation among animals of bacterial clones resistant to this last-resort antibiotic., Unión Europea (EvoTAR282004-FP7; EFFORT613754FP7), Comunidad de Madrid (2016-T1/BIO-1105), Depto. de Sanidad Animal, Fac. de Veterinaria, TRUE, pub

Photonic integrated circuits play an important role in the field of optical computing, promising faster and more energy-efficient operations compared to their digital counterparts. This advantage stems from the inherent suitability of optical signals to carry out matrix multiplication. However, even deterministic phenomena such as thermal crosstalk make precise programming of photonic chips a challenging task. Here, we train and experimentally evaluate three models incorporating varying degrees of physics intuition to predict the effect of thermal crosstalk in different locations of an integrated programmable photonic mesh. We quantify the effect of thermal crosstalk by the resonance wavelength shift in the power spectrum of a microring resonator implemented in the chip, achieving modelling errors <0.5 pm. We experimentally validate the models through compensation of the crosstalk-induced wavelength shift. Finally, we evaluate the generalization capabilities of one of the models by employing it to predict and compensate for the effect of thermal crosstalk for parts of the chip it was not trained on, revealing root-mean-square-errors of <2.0 pm., Comment: 10 pages, 10 figures. The paper has been submitted to the Journal of Lightwave Technology, a special issue on Photonic Computing, as an invited paper. It is under review

One key piece of evidence for dark matter is the flat rotation curve problem: the disagreement between measured galactic rotation curves and their luminous mass. A novel solution to this problem is presented here. A model of relativistic frame effects on Doppler shifts due to the slightly curved frames of an emitting galaxy and the Milky Way is derived. This model predicts observed Doppler shifted spectra (in excess of the luminous mass) based only on the observed luminous matter profile and one free model parameter. Fits to the 175 galaxies reported in the SPARC database of galactic rotation profiles and accurate photometry measurements are compared between this novel model and dark matter and MOND (RAR) models. We find on the SPARC sample of 175 galaxies; that MOND-RAR has an average reduced chisquare of $\chi^2_r = 4.22$ for 175 galaxies fitted, the isothermal dark matter model has $\chi^2_r = 1.90$ for 165 galaxies fitted, and the new model we present has $\chi^2_r = 2.39$ for 172 galaxies fitted. Implications of this model are discussed., Comment: 27 pages, 9 figures

Real-time semantic segmentation is a challenging task that requires high-accuracy models with low-inference times. Implementing these models on embedded systems is limited by hardware capability and memory usage, which produces bottlenecks. We propose an efficient model for real-time semantic segmentation called JetSeg, consisting of an encoder called JetNet, and an improved RegSeg decoder. The JetNet is designed for GPU-Embedded Systems and includes two main components: a new light-weight efficient block called JetBlock, that reduces the number of parameters minimizing memory usage and inference time without sacrificing accuracy; a new strategy that involves the combination of asymmetric and non-asymmetric convolutions with depthwise-dilated convolutions called JetConv, a channel shuffle operation, light-weight activation functions, and a convenient number of group convolutions for embedded systems, and an innovative loss function named JetLoss, which integrates the Precision, Recall, and IoUB losses to improve semantic segmentation and reduce computational complexity. Experiments demonstrate that JetSeg is much faster on workstation devices and more suitable for Low-Power GPU-Embedded Systems than existing state-of-the-art models for real-time semantic segmentation. Our approach outperforms state-of-the-art real-time encoder-decoder models by reducing 46.70M parameters and 5.14% GFLOPs, which makes JetSeg up to 2x faster on the NVIDIA Titan RTX GPU and the Jetson Xavier than other models. The JetSeg code is available at https://github.com/mmontielpz/jetseg.

Significant immunological, physical and neurological benefits of breastfeeding in infancy are well-established, but to what extent these gains persist into later childhood remain uncertain. This study examines the association between breastfeeding duration and subsequent domain-specific cognitive performance in a diverse sample of 9-10-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) Study®. The analyses included 9,116 children that attended baseline with their biological mother and had complete neurocognitive and breastfeeding data. Principal component analysis was conducted on data from an extensive battery of neurocognitive tests using varimax-rotation to extract a three-component model encompassing General Ability, Executive Functioning, and Memory. Propensity score weighting using generalized boosted modeling was applied to balance the distribution of observed covariates for children breastfed for 0, 1-6, 7-12, and more than 12 months. Propensity score-adjusted linear regression models revealed significant association between breastfeeding duration and performance on neurocognitive tests representing General Ability, but no evidence of a strong association with Executive Function or Memory. Benefits on General Ability ranged from a 0.109 (1-6 months) to 0.301 (>12 months) standardized beta coefficient difference compared to those not breastfed. Results indicate clear cognitive benefits of breastfeeding but that these do not generalize to all measured domains, with implications for public health policy as it pertains to nutrition during infancy.

Significant immunological, physical and neurological benefits of breastfeeding in infancy are well-established, but to what extent these gains persist into later childhood remain uncertain. This study examines the association between breastfeeding duration and subsequent domain-specific cognitive performance in a diverse sample of 9-10-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) Study®. The analyses included 9,116 children that attended baseline with their biological mother and had complete neurocognitive and breastfeeding data. Principal component analysis was conducted on data from an extensive battery of neurocognitive tests using varimax-rotation to extract a three-component model encompassing General Ability, Executive Functioning, and Memory. Propensity score weighting using generalized boosted modeling was applied to balance the distribution of observed covariates for children breastfed for 0, 1-6, 7-12, and more than 12 months. Propensity score-adjusted linear regression models revealed significant association between breastfeeding duration and performance on neurocognitive tests representing General Ability, but no evidence of a strong association with Executive Function or Memory. Benefits on General Ability ranged from a 0.109 (1-6 months) to 0.301 (>12 months) standardized beta coefficient difference compared to those not breastfed. Results indicate clear cognitive benefits of breastfeeding but that these do not generalize to all measured domains, with implications for public health policy as it pertains to nutrition during infancy.

A large number of robotic and human-assisted missions to the Moon and Mars are forecast. NASA's efforts to learn about the geology and makeup of these celestial bodies rely heavily on the use of robotic arms. The safety and redundancy aspects will be crucial when humans will be working alongside the robotic explorers. Additionally, robotic arms are crucial to satellite servicing and planned orbit debris mitigation missions. The goal of this work is to create a custom Computer Vision (CV) based Artificial Neural Network (ANN) that would be able to rapidly identify the posture of a 7 Degree of Freedom (DoF) robotic arm from a single (RGB-D) image - just like humans can easily identify if an arm is pointing in some general direction. The Sawyer robotic arm is used for developing and training this intelligent algorithm. Since Sawyer's joint space spans 7 dimensions, it is an insurmountable task to cover the entire joint configuration space. In this work, orthogonal arrays are used, similar to the Taguchi method, to efficiently span the joint space with the minimal number of training images. This ``optimally'' generated database is used to train the custom ANN and its degree of accuracy is on average equal to twice the smallest joint displacement step used for database generation. A pre-trained ANN will be useful for estimating the postures of robotic manipulators used on space stations, spacecraft, and rovers as an auxiliary tool or for contingency plans.

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29-34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans.

Interleukin-22 (IL-22) is a cytokine mainly produced by T cells and innate lymphoid cells (ILC). IL-22 primarily targets non-hematopoietic cells such as epithelial cells and fibroblasts. In the skin, IL-22 promotes the proliferation of keratinocytes and dermal fibroblasts. IL-22 furthermore regulates innate immune responses as it induces the production of antimicrobial proteins and neutrophil-attracting chemokines. IL-22 plays an important role in wound healing and in the protection against skin infections. However, IL-22 can also contribute to the pathogenesis of several inflammatory skin diseases such as psoriasis, atopic dermatitis and allergic contact dermatitis. In this review, current information regarding the structure, function and regulation of IL-22 is discussed with a special focus on the role of IL-22 in the skin and in skin diseases.

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29-34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans.

Interleukin-22 (IL-22) is a cytokine mainly produced by T cells and innate lymphoid cells (ILC). IL-22 primarily targets non-hematopoietic cells such as epithelial cells and fibroblasts. In the skin, IL-22 promotes the proliferation of keratinocytes and dermal fibroblasts. IL-22 furthermore regulates innate immune responses as it induces the production of antimicrobial proteins and neutrophil-attracting chemokines. IL-22 plays an important role in wound healing and in the protection against skin infections. However, IL-22 can also contribute to the pathogenesis of several inflammatory skin diseases such as psoriasis, atopic dermatitis and allergic contact dermatitis. In this review, current information regarding the structure, function and regulation of IL-22 is discussed with a special focus on the role of IL-22 in the skin and in skin diseases.

Stem cell derived insulin producing cells or islets have shown promise in reversing Type 1 Diabetes (T1D), yet successful transplantation currently necessitates long-term modulation with immunosuppressant drugs. An alternative approach to avoiding this immune response is to utilize an islet macroencapsulation device, where islets are incorporated into a selectively permeable membrane that can protect the transplanted cells from acute host response, whilst enabling delivery of insulin. These macroencapsulation systems have to meet a number of stringent and challenging design criteria in order to achieve the ultimate goal of reversing T1D. In this progress report, the design considerations and functional requirements of macroencapsulation systems are reviewed, specifically for stem-cell derived islets (SC-islets), highlighting distinct design parameters. Additionally, a perspective on the future for macroencapsulation systems is given, and how incorporating continuous sensing and closed-loop feedback can be transformative in advancing toward an autonomous biohybrid artificial pancreas., Juvenile Diabetes Research Fund (Grant 1-PNF-2019-778-S-B)

Vasovagal reactions may occur occasionally during electrical stimulation using interferential current (IFC). The purpose of this study was to examine variations in autonomic activity during the application of IFC in asymptomatic participants by analysis of their heart rate variability (HRV). Seventy-three male volunteers were randomly assigned to a placebo group (n = 36; HRV was documented for 10 min, both at rest and during a placebo intervention) and an intervention group (n = 37; HRV was documented for 10 min in two conditions labelled as (1) rest and (2) application of IFC technique on the lumbar segment). The diameters of the Poincaré plot (SD1, SD2), stress score (SS), and the ratio between sympathetic and parasympathetic activity (S/PS) were measured. After interventions, differences amongst the placebo group and the IFC group were found in SD2 (p < 0.001), SS (p = 0.01) and S/PS ratio (p = 0.003). The IFC technique was associated with increased parasympathetic modulation, which could induce a vasovagal reaction. Monitorization of adverse reactions should be implemented during the application of IFC technique. HRV indicators might have a part in prevention of vasovagal reactions. Further studies in patients with lumbar pain are needed to explore possible differences in HRV responses due to the presence of chronic pain., Depto. de Enfermería, Fac. de Enfermería, Fisioterapia y Podología, TRUE, pub

The coronavirus disease 2019 (COVID-19) pandemic has severely impacted daily life all over the world. Any measures to slow down the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease disease severity are highly requested. Recent studies have reported inverse correlations between plasma levels of vitamin D and susceptibility to SARS-CoV-2 infection and COVID-19 severity. Therefore, it has been proposed to supplement the general population with vitamin D to reduce the impact of COVID-19. However, by studying the course of COVID-19 and the immune response against SARS-CoV-2 in a family with a mutated, non-functional vitamin D receptor, we here demonstrate that vitamin D signaling was dispensable for mounting an efficient adaptive immune response against SARS-CoV-2 in this family. Although these observations might not directly be transferred to the general population, they question a central role of vitamin D in the generation of adaptive immunity against SARS-CoV-2.

Vasovagal reactions may occur occasionally during electrical stimulation using interferential current (IFC). The purpose of this study was to examine variations in autonomic activity during the application of IFC in asymptomatic participants by analysis of their heart rate variability (HRV). Seventy-three male volunteers were randomly assigned to a placebo group (n = 36; HRV was documented for 10 min, both at rest and during a placebo intervention) and an intervention group (n = 37; HRV was documented for 10 min in two conditions labelled as (1) rest and (2) application of IFC technique on the lumbar segment). The diameters of the Poincaré plot (SD1, SD2), stress score (SS), and the ratio between sympathetic and parasympathetic activity (S/PS) were measured. After interventions, differences amongst the placebo group and the IFC group were found in SD2 (p < 0.001), SS (p = 0.01) and S/PS ratio (p = 0.003). The IFC technique was associated with increased parasympathetic modulation, which could induce a vasovagal reaction. Monitorization of adverse reactions should be implemented during the application of IFC technique. HRV indicators might have a part in prevention of vasovagal reactions. Further studies in patients with lumbar pain are needed to explore possible differences in HRV responses due to the presence of chronic pain., Depto. de Enfermería, Fac. de Enfermería, Fisioterapia y Podología, TRUE, pub

Even though colorectal cancer (CRC) is one of the most preventable cancers, it is one of the deadliest, and recent data show that the incidence in people <50 years has unexpectedly increased. While new techniques for CRC molecular classification are emerging, no molecular feature is as yet firmly associated with prognosis. Imaging mass spectrometry (IMS) lipidomic analyses have demonstrated the specificity of the lipid fingerprint in differentiating pathological from healthy tissues. During IMS lipidomic analysis, the formation of ionic adducts is common. Of particular interest is the [Na+]/[K+] adduct ratio, which already functions as a biomarker for homeostatic alterations. Herein, we show a drastic shift of the [Na+]/[K+] adduct ratio in adenomatous colon mucosa compared to healthy mucosa, suggesting a robust increase in K+ levels. Interrogating public databases, a strong association was found between poor diagnosis and voltage-gated potassium channel subunit beta-2 (KCNAB2) overexpression. We found this overexpression in three CRC molecular subtypes defined by the CRC Subtyping Consortium, making KCNAB2 an interesting pharmacological target. Consistently, its pharmacological inhibition resulted in a dramatic halt in commercial CRC cell proliferation. Identification of potential pharmacologic targets using lipid adduct information emphasizes the great potential of IMS lipidomic techniques in the clinical field.

Even though colorectal cancer (CRC) is one of the most preventable cancers, it is one of the deadliest, and recent data show that the incidence in people <50 years has unexpectedly increased. While new techniques for CRC molecular classification are emerging, no molecular feature is as yet firmly associated with prognosis. Imaging mass spectrometry (IMS) lipidomic analyses have demonstrated the specificity of the lipid fingerprint in differentiating pathological from healthy tissues. During IMS lipidomic analysis, the formation of ionic adducts is common. Of particular interest is the [Na+]/[K+] adduct ratio, which already functions as a biomarker for homeostatic alterations. Herein, we show a drastic shift of the [Na+]/[K+] adduct ratio in adenomatous colon mucosa compared to healthy mucosa, suggesting a robust increase in K+ levels. Interrogating public databases, a strong association was found between poor diagnosis and voltage-gated potassium channel subunit beta-2 (KCNAB2) overexpression. We found this overexpression in three CRC molecular subtypes defined by the CRC Subtyping Consortium, making KCNAB2 an interesting pharmacological target. Consistently, its pharmacological inhibition resulted in a dramatic halt in commercial CRC cell proliferation. Identification of potential pharmacologic targets using lipid adduct information emphasizes the great potential of IMS lipidomic techniques in the clinical field.

Uppsatsen syftar till att studera nattvardssynen i tre systerkyrkor; Svenska Missionskyrkan, Covenant Church i USA och Pactokyrkan i Ecuador. Dessa samfund eftersom de alla delar samma teologiska rötter. Covenant Church och Pactokyrkan är båda direkt och indirekt frukt av Svenska Missionskyrkan. Metoden som använts är en jämförande kvalitativ studie där samfundens dokument kring nattvarden varit centrala. Resultatet visar att kyrkorna delar synen på att Jesus instiftade nattvarden åt sina lärjungar kvällen innan Han korsfästes. De delar också syn på att nattvarden är ett tecken på försoningen i Honom. Covenant Church och Svenska Missionskyrkan har båda öppna nattvardsbord och Pactokyrkan har ett stängt nattvardsbord.

Uppsatsen syftar till att studera nattvardssynen i tre systerkyrkor; Svenska Missionskyrkan, Covenant Church i USA och Pactokyrkan i Ecuador. Dessa samfund eftersom de alla delar samma teologiska rötter. Covenant Church och Pactokyrkan är båda direkt och indirekt frukt av Svenska Missionskyrkan. Metoden som använts är en jämförande kvalitativ studie där samfundens dokument kring nattvarden varit centrala. Resultatet visar att kyrkorna delar synen på att Jesus instiftade nattvarden åt sina lärjungar kvällen innan Han korsfästes. De delar också syn på att nattvarden är ett tecken på försoningen i Honom. Covenant Church och Svenska Missionskyrkan har båda öppna nattvardsbord och Pactokyrkan har ett stängt nattvardsbord.

The Adolescent Brain Cognitive Development (ABCD) Study is the largest single-cohort prospective longitudinal study of neurodevelopment and children's health in the United States. A cohort of n = 11,880 children aged 9-10 years (and their parents/guardians) were recruited across 22 sites and are being followed with in-person visits on an annual basis for at least 10 years. The study approximates the US population on several key sociodemographic variables, including sex, race, ethnicity, household income, and parental education. Data collected include assessments of health, mental health, substance use, culture and environment and neurocognition, as well as geocoded exposures, structural and functional magnetic resonance imaging (MRI), and whole-genome genotyping. Here, we describe the ABCD Study aims and design, as well as issues surrounding estimation of meaningful associations using its data, including population inferences, hypothesis testing, power and precision, control of covariates, interpretation of associations, and recommended best practices for reproducible research, analytical procedures and reporting of results.

Even though colorectal cancer (CRC) is one of the most preventable cancers, it is one of the deadliest, and recent data show that the incidence in people <50 years has unexpectedly increased. While new techniques for CRC molecular classification are emerging, no molecular feature is as yet firmly associated with prognosis. Imaging mass spectrometry (IMS) lipidomic analyses have demonstrated the specificity of the lipid fingerprint in differentiating pathological from healthy tissues. During IMS lipidomic analysis, the formation of ionic adducts is common. Of particular interest is the [Na+]/[K+] adduct ratio, which already functions as a biomarker for homeostatic alterations. Herein, we show a drastic shift of the [Na+]/[K+] adduct ratio in adenomatous colon mucosa compared to healthy mucosa, suggesting a robust increase in K+ levels. Interrogating public databases, a strong association was found between poor diagnosis and voltage-gated potassium channel subunit beta-2 (KCNAB2) overexpression. We found this overexpression in three CRC molecular subtypes defined by the CRC Subtyping Consortium, making KCNAB2 an interesting pharmacological target. Consistently, its pharmacological inhibition resulted in a dramatic halt in commercial CRC cell proliferation. Identification of potential pharmacologic targets using lipid adduct information emphasizes the great potential of IMS lipidomic techniques in the clinical field.

The coronavirus disease 2019 (COVID-19) pandemic has severely impacted daily life all over the world. Any measures to slow down the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease disease severity are highly requested. Recent studies have reported inverse correlations between plasma levels of vitamin D and susceptibility to SARS-CoV-2 infection and COVID-19 severity. Therefore, it has been proposed to supplement the general population with vitamin D to reduce the impact of COVID-19. However, by studying the course of COVID-19 and the immune response against SARS-CoV-2 in a family with a mutated, non-functional vitamin D receptor, we here demonstrate that vitamin D signaling was dispensable for mounting an efficient adaptive immune response against SARS-CoV-2 in this family. Although these observations might not directly be transferred to the general population, they question a central role of vitamin D in the generation of adaptive immunity against SARS-CoV-2.

The active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)(2)D-3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)(2)D-3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)(2)D-3-induced gene regulation was reduced by similar to 50% indicating that the expression level of wild-type VDR determines 1,25(OH)(2)D-3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)(2)D-3-induced translocation of the VDR to the nucleus and 1,25(OH)(2)D-3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.

The coronavirus disease 2019 (COVID-19) pandemic has severely impacted daily life all over the world. Any measures to slow down the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease disease severity are highly requested. Recent studies have reported inverse correlations between plasma levels of vitamin D and susceptibility to SARS-CoV-2 infection and COVID-19 severity. Therefore, it has been proposed to supplement the general population with vitamin D to reduce the impact of COVID-19. However, by studying the course of COVID-19 and the immune response against SARS-CoV-2 in a family with a mutated, non-functional vitamin D receptor, we here demonstrate that vitamin D signaling was dispensable for mounting an efficient adaptive immune response against SARS-CoV-2 in this family. Although these observations might not directly be transferred to the general population, they question a central role of vitamin D in the generation of adaptive immunity against SARS-CoV-2.

The active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)(2)D-3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)(2)D-3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)(2)D-3-induced gene regulation was reduced by similar to 50% indicating that the expression level of wild-type VDR determines 1,25(OH)(2)D-3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)(2)D-3-induced translocation of the VDR to the nucleus and 1,25(OH)(2)D-3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.

Phytophthora infestans is a pathogenic oomycete that causes the infamous potato late blight disease. Resistance (R) genes from diverse Solanum species encode intracellular receptors that trigger effective defense responses upon the recognition of cognate RXLR avirulence (Avr) effector proteins. To deploy these R genes in a durable fashion in agriculture, we need to understand the mechanism of effector recognition and the way the pathogen evades recognition. In this study, we cloned 16 allelic variants of the Rpi-chc1 gene from Solanum chacoense and other Solanum species, and identified the cognate P. infestans RXLR effectors. These tools were used to study effector recognition and co-evolution. Functional and non-functional alleles of Rpi-chc1 encode coiled-coil nucleotide-binding leucine-rich repeat (CNL) proteins, being the first described representatives of the CNL16 family. These alleles have distinct patterns of RXLR effector recognition. While Rpi-chc1.1 recognized multiple PexRD12 (Avrchc1.1) proteins, Rpi-chc1.2 recognized multiple PexRD31 (Avrchc1.2) proteins, both belonging to the PexRD12/31 effector superfamily. Domain swaps between Rpi-chc1.1 and Rpi-chc1.2 revealed that overlapping subdomains in the leucine-rich repeat (LRR) domain are responsible for the difference in effector recognition. This study showed that Rpi-chc1.1 and Rpi-chc1.2 evolved to recognize distinct members of the same PexRD12/31 effector family via the LRR domain. The biased distribution of polymorphisms suggests that exchange of LRRs during host–pathogen co-evolution can lead to novel recognition specificities. These insights will guide future strategies to breed durable resistant varieties.

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In this work, different nanocomposite electrospun fiber mats were obtained based on poly(e-caprolactone) (PCL) and reinforced with both organic and inorganic nanoparticles. In particular, on one side, cellulose nanocrystals (CNC) were synthesized and functionalized by “grafting from” reaction, using their superficial OH– group to graft PCL chains. On the other side, commercial chitosan, graphene as organic, while silver, hydroxyapatite, and fumed silica nanoparticles were used as inorganic reinforcements. All the nanoparticles were added at 1 wt% with respect to the PCL polymeric matrix in order to compare the different behavior of the woven no-woven nanocomposite electrospun fibers with a fixed amount of both organic and inorganic nanoparticles. From the thermal point of view, no difference was found between the effect of the addition of organic or inorganic nanoparticles, with no significant variation in the Tg (glass transition temperature), Tm (melting temperature), and the degree of crystallinity, leading in all cases to high crystallinity electrospun mats. From the mechanical point of view, the highest values of Young modulus were obtained when graphene, CNC, and silver nanoparticles were added to the PCL electrospun fibers. Moreover, all the nanoparticles used, both organic and inorganic, increased the flexibility of the electrospun mats, increasing their elongation at break., Ministerio de Economía y Competitividad (MINECO)/FEDER, Ministerio de Economía y Competitividad (MINECO), Fac. de Óptica y Optometría, TRUE, pub

Methods to involve users in design have long been used to create relevant content and increase the accuracy of product development. Demographic trends have raised the issue of the needs and demands of older people, especially with regard to digitization. In contrast to the high number of publications discussing the importance of involving people in the design of their daily life, very few publications suggest how to do it. While participatory design is used with older people, there is no common understanding about which methods are used for what purposes. This paper presents a framework methodology that further advances the opportunity to involve older people in the design process and increase understanding of old people’s subjective experience of getting their lives digitized and how to involve them in design. Given that digitalization, with its systemic complexity, requires an understanding of how technology is contextualized, the need to understand what it means to age in today’s digital society is part of successful design. One objective is to go beyond stereotypes that often characterize generalizations of older people. We are using the concept of co-design, which is well established but not specifically adapted to older users. The goal is a matrix of tested co-design methods to be used by citizens, researchers, businesses or anyone who is interested in increasing the impact of old people on the design of new technologies.

In this work, different nanocomposite electrospun fiber mats were obtained based on poly(e-caprolactone) (PCL) and reinforced with both organic and inorganic nanoparticles. In particular, on one side, cellulose nanocrystals (CNC) were synthesized and functionalized by “grafting from” reaction, using their superficial OH– group to graft PCL chains. On the other side, commercial chitosan, graphene as organic, while silver, hydroxyapatite, and fumed silica nanoparticles were used as inorganic reinforcements. All the nanoparticles were added at 1 wt% with respect to the PCL polymeric matrix in order to compare the different behavior of the woven no-woven nanocomposite electrospun fibers with a fixed amount of both organic and inorganic nanoparticles. From the thermal point of view, no difference was found between the effect of the addition of organic or inorganic nanoparticles, with no significant variation in the Tg (glass transition temperature), Tm (melting temperature), and the degree of crystallinity, leading in all cases to high crystallinity electrospun mats. From the mechanical point of view, the highest values of Young modulus were obtained when graphene, CNC, and silver nanoparticles were added to the PCL electrospun fibers. Moreover, all the nanoparticles used, both organic and inorganic, increased the flexibility of the electrospun mats, increasing their elongation at break., Ministerio de Economía y Competitividad (MINECO)/FEDER, Ministerio de Economía y Competitividad (MINECO), Fac. de Óptica y Optometría, TRUE, pub