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Instruments for gamma-ray astronomy at Very High Energies (E>100GeV) have traditionally derived their scientific results through proprietary data and software. Data standardisation has become a prominent issue in this field both as a requirement for the dissemination of data from the next generation of gamma-ray observatories and as an effective solution to realise public data legacies of current-generation instruments. Specifications for a standardised gamma-ray data format have been proposed as a community effort and have already been successfully adopted by several instruments. We present the first production of standardised data from the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes. We converted 166hof observations from different sources and validated their analysis with the open-source software Gammapy. We consider six data sets representing different scientific and technical analysis cases and compare the results obtained analysing the standardised data with open-source software against those produced with the MAGIC proprietary data and software. Aiming at a systematic production of MAGIC data in this standardised format, we also present the implementation of a database-driven pipeline automatically performing the MAGIC data reduction from the calibrated down to the standardised data level. In all the cases selected for the validation, we obtain results compatible with the MAGIC proprietary software, both for the manual and for the automatic data productions. Part of the validation data set is also made publicly available, thus representing the first large public release of MAGIC data. This effort and this first data release represent a technical milestone toward the realisation of a public MAGIC data legacy.

La sección de Vía Aérea de la Sociedad Española De Anestesiología, Reanimación y Terapéutica del Dolor (SEDAR), la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) y la Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello (SEORL-CCC) presentan la Guía para el manejo integral de la vía aérea difícil en el paciente adulto. Este documento proporciona recomendaciones respaldadas por la evidencia científica actual, herramientas teórico-educativas y herramientas de implementación, fundamentalmente ayudas cognitivas, aplicables al tratamiento de la vía aérea en el campo de la anestesiología, cuidados críticos, urgencias y medicina prehospitalaria. Sus principios están focalizados en los factores humanos, los procesos cognitivos para la toma de decisiones en situaciones críticas y la optimización en la progresión de la aplicación de estrategias para preservar una adecuada oxigenación alveolar con el objeto de mejorar la seguridad y la calidad asistencial.

Multivesicular bodies are key endosomal compartments implicated in cellular quality control through their degradation of membrane-bound cargo proteins1–3. The ATP-consuming ESCRT protein machinery mediates the capture and engulfment of membrane-bound cargo proteins through invagination and scission of multivesicular-body membranes to form intraluminal vesicles4,5. Here we report that the plant ESCRT component FREE16forms liquid-like condensates that associate with membranes to drive intraluminal vesicle formation. We use a minimal physical model, reconstitution experiments and in silico simulations to identify the dynamics of this process and describe intermediate morphologies of nascent intraluminal vesicles. Furthermore, we find that condensate-wetting-induced line tension forces and membrane asymmetries are sufficient to mediate scission of the membrane neck without the ESCRT protein machinery or ATP consumption. Genetic manipulation of the ESCRT pathway in several eukaryotes provides additional evidence for condensate-mediated membrane scission in vivo. We find that the interplay between condensate and machinery-mediated scission mechanisms is indispensable for osmotic stress tolerance in plants. We propose that condensate-mediated scission represents a previously undescribed scission mechanism that depends on the physicomolecular properties of the condensate and is involved in a range of trafficking processes. More generally, FREE1 condensate-mediated membrane scission in multivesicular-body biogenesis highlights the fundamental role of wetting in intracellular dynamics and organization.

Natural products (NPs) are secondary metabolites of natural origin with broad applications across various human activities, particularly the discovery of bioactive compounds. Structural elucidation of new NPs entails significant cost and effort. On the other hand, the dereplication of known compounds is crucial for the early exclusion of irrelevant compounds in contemporary pharmaceutical research. NAPROC-13 stands out as a publicly accessible database, providing structural and 13C NMR spectroscopic information for over 25 000 compounds, rendering it a pivotal resource in natural product (NP) research, favoring open science. This study seeks to quantitatively analyze the chemical content, structural diversity, and chemical space coverage of NPs within NAPROC-13, compared to FDA-approved drugs and a very diverse subset of NPs, UNPD-A. Findings indicated that NPs in NAPROC-13 exhibit properties comparable to those in UNPD-A, albeit showcasing a notably diverse array of structural content, scaffolds, ring systems of pharmaceutical interest, and molecular fragments. NAPROC-13 covers a specific region of the chemical multiverse (a generalization of the chemical space from different chemical representations) regarding physicochemical properties and a region as broad as UNPD-A in terms of the structural features represented by fingerprints.

Ultrasound tomography is an emerging imaging modality that uses the transmission of ultrasound through tissue to reconstruct images of its mechanical properties. Initially, ray-based methods were used to reconstruct these images, but their inability to account for diffraction often resulted in poor resolution. Waveform inversion overcame this limitation, providing high-resolution images of the tissue. Most clinical implementations, often directed at breast cancer imaging, currently rely on a frequency-domain waveform inversion to reduce computation time. For ring arrays, ray tomography was long considered a necessary step prior to waveform inversion in order to avoid cycle skipping. However, in this paper, we demonstrate that frequency-domain waveform inversion can reliably reconstruct high-resolution images of sound speed and attenuation without relying on ray tomography to provide an initial model. We provide a detailed description of our frequency-domain waveform inversion algorithm with open-source code and data that we make publicly available.

ABSTRACTScientific knowledge of the training of elite athletic sprinters is limited, and much of their training relies on the intuition and expertise of experienced coaches. Therefore, the objective of this study is to provide an overview of the training practices employed by elite Spanish sprint coaches. A descriptive analysis was conducted using customised questionnaires from 14 sprint-specialised coaches who volunteered to participate. These coaches used both traditional (50%) and block periodisation (50%). Many coaches (78.6%) divided training into three phases within each of the two macrocycles. Additionally, all coaches incorporated a tapering phase of varying durations. During the general preparation phase, the focus was on strength training (78.6%) and tempo training (85.7%). In the specific preparation phase, priority was strength-speed (92.9%) and speed-endurance (100%). The competitive phase emphasised speed-strength (100%), acceleration and maximal velocity (92.9%). Coaches incorporated technique work prior to sprint sessions (100%) and conducted specific monitoring/testing sessions (78.6%). Most coaches also monitored indicators of fatigue (78.6%) and recovery parameters (100%). In conclusion, elite Spanish sprint coaches employ relatively similar strength and sprint training methods throughout the season, gradually shifting the focus towards competition specificity. However, these coaches implement different macro-periodisation models.

La sección de Vía Aérea de la Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor (SEDAR), la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) y la Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello (SEORL-CCC) presentan la Guía para el manejo integral de la vía aérea difícil en el paciente adulto. Sus principios están focalizados en el factor humano, los procesos cognitivos para la toma de decisiones en situaciones críticas y la optimización en la progresión de la aplicación de estrategias para preservar una adecuada oxigenación alveolar con el objeto de mejorar la seguridad y la calidad asistencial. El documento proporciona recomendaciones basadas en la evidencia científica actual, herramientas teórico-educativas y de implementación, fundamentalmente ayudas cognitivas, aplicables al tratamiento de la vía aérea (VA) en el campo de la anestesiología, cuidados críticos, urgencias y medicina prehospitalaria. Para ello, se realizó una amplia búsqueda bibliográfica según las directrices PRISMA-R y se analizó utilizando la metodología GRADE. Las recomendaciones se formularon de acuerdo con esta metodología. Las recomendaciones de aquellas secciones con evidencia de baja calidad se basaron en la opinión de expertos mediante el consenso alcanzado a través de un cuestionario Delphi.

Immunotherapy has become a key new pillar of cancer treatment, and this has sparked interest in understanding mechanisms of cancer immune evasion. It has long been appreciated that cancers are constituted by heterogeneous populations of tumour cells. This feature is often fuelled by specialized cells that have molecular programs resembling tissue stem cells. Although these cancer stem cells (CSCs) have capacity for unlimited self-renewal and differentiation, it is increasingly evident that some CSCs are capable of achieving remarkable immune resistance. Given that most immunotherapy regiments have overlooked CSC-specific immune-evasive mechanisms, many current treatment strategies often lead to cancer relapse. This Review focuses on advancements in understanding how CSCs in solid tumours achieve their unique immune-evasive properties, enabling them to drive tumour regrowth. Moreover, as cancers often arise from tissue stem cells that acquired oncogenic mutations, we discuss how tissue stem cells undergoing malignant transformation activate intrinsic immune-evasive mechanisms and establish close interactions with suppressive immune cells to escape immune surveillance. In addition, we summarize how in advanced disease stages, CSCs often hijack features of normal stem cells to resist antitumour immunity. Finally, we provide insights in how to design a new generation of cancer immunotherapies to ensure elimination of CSCs.

Study design: Double-blind, randomized, placebo-controlled, parallel-group multicentric phase IIA clinical trial. Objective: To assess the safety and tolerability of oral administration of NFX-88 in subjects with chronic spinal cord injury (SCI) and explore its efficacy in pain control. Setting: A total of 7 spinal cord injury rehabilitation units in Spain. Methods: A total of 61 adult with traumatic complete or incomplete spinal cord injury (C4-T12 level), were randomised 1:1:1:1 to a placebo, NFX88 1.05 g, 2.1 g, 4.2 g/day for up to 12 weeks. The placebo or NFX-88 was administered as add-on therapy to pre-existing pregabalin (150–300 mg per day). Safety and tolerability were evaluated, and the Visual Analogue Scale (VAS) was the primary measure to explore the efficacy of NFX-88 in pain control. Results: No severe treatment-related adverse effects were reported for any of the four study groups. 44 SCI individuals completed the study and were analysed. The data obtained from the VAS analysis and the PainDETECT Questionnaire (PD-Q) suggested that the combination of NFX88 with pregabalin is more effective than pregabalin with placebo at reducing neuropathic pain (NP) in individuals with SCI and that the dose 2.10 g/day causes the most dramatic pain relief. Conclusions: NFX88 treatment was found to be highly safe and well tolerated, with the dose of 2.10 g/day being the most effective at causing pain relief. Thus, the promising efficacy of this first-in-class lipid mediator deserves further consideration in future clinical trials.

Recent gender literature has highlighted that boys and girls devote their out-of-school time in dissimilar ways, which may differentially influence their academic achievement. Furthermore, this literature indicates that these gender differences may be rooted in society’s gender stereotypes when using this time. To analyse this issue we employ longitudinal and census data for the Spanish region of Andalusia, making use of recent methodological innovations in the Oaxaca-Blinder gender decomposition technique. Our results have shown that girls outperform boys in reading, whereas boys get better grades in mathematics. We also found that there are no significant gender differences in the educational returns on time devoted to homework and that the gender differences in the time devoted to watching television and in the time devoted to playing video games and computer games narrow the female advantage in reading and widen the male advantage in mathematics.

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.

Perinatal derivatives have been proposed as adjunct therapeutic strategies or innovative treatments. Undoubtedly, perinatal derivatives can offer the opportunity and source material to isolate multipotent stem cells, but both maternal- and fetal-derived tissues can be processed and transformed into engineered tissues or advanced biomedical devices, whose potential remains to be fully elucidated. Promising preclinical and clinical results collected so far clearly foresee an escalation of such novel treatments. Market forecasts predict exponential growth in such advanced medicinal products during the next decade, with a pragmatic innovation for medicine into a more advanced biomedical version, enlarging the portfolio for treating a wide range of congenital and acute conditions. However, all these promising and fascinating therapeutic possibilities cannot gain a solid and recognized role in established medical practice without rigid and harmonized manufacturing strategies. The implementation of strategies according to guidelines and directives compiled by Regulatory Agencies, in conformity to (European) Pharmacopoeia and for Good Manufacturing Practice -conforming production of such products, represent critical steps required to translate perinatal technologies into effective therapeutic approaches. During the past 5 years, a panel of European experts and developers, gathered under the umbrella of the COST Sprint Action, supported by the European Cooperation in Science and Technology action, had the opportunity to revise and summarize experience and recommendations for a fruitful and proficient generation of perinatal biomedical products. In order to facilitate the creation and potential commercialization of perinatal bioengineered and advanced pharmaceutical products and technologies, such a collection of data and recommendations is described and discussed here.Graphical Abstract

A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer1–3; however, much less is known about how pre-malignant or early invasive tumours evade immune detection. Here, to understand this process in early colorectal cancers (CRCs), we investigated how naive colon cancer organoids that were engineered in vitro to harbour Apc-null, KrasG12Dand Trp53-null (AKP) mutations adapted to the in vivo native colonic environment. Comprehensive transcriptomic and chromatin analyses revealed that the endoderm-specifying transcription factor SOX17 became strongly upregulated in vivo. Notably, whereas SOX17 loss did not affect AKP organoid propagation in vitro, its loss markedly reduced the ability of AKP tumours to persist in vivo. The small fraction of SOX17-null tumours that grew displayed notable interferon-γ (IFNγ)-producing effector-like CD8+T cell infiltrates in contrast to the immune-suppressive microenvironment in wild-type counterparts. Mechanistically, in both endogenous Apc-null pre-malignant adenomas and transplanted organoid-derived AKP CRCs, SOX17 suppresses the ability of tumour cells to sense and respond to IFNγ, preventing anti-tumour T cell responses. Finally, SOX17 engages a fetal intestinal programme that drives differentiation away from LGR5+tumour cells to produce immune-evasive LGR5−tumour cells with lower expression of major histocompatibility complex class I (MHC-I). We propose that SOX17 is a transcription factor that is engaged during the early steps of colon cancer to orchestrate an immune-evasive programme that permits CRC initiation and progression.

The Becalm project is an open and low-cost solution for the remote monitoring of respiratory support therapies like the ones used in COVID-19 patients. Becalm combines a decision-making system based on Case-Based Reasoning with a low-cost, non-invasive mask that enables the remote monitoring, detection, and explanation of risk situations for respiratory patients. This paper first describes the mask and the sensors that allow remote monitoring. Then, it describes the intelligent decision-making system that detects anomalies and raises early warnings. This detection is based on the comparison of cases that represent patients using a set of static variables plus the dynamic vector of the patient time series from sensors. Finally, personalized visual reports are created to explain the causes of the warning, data patterns, and patient context to the healthcare professional. To evaluate the case-based early-warning system, we use a synthetic data generator that simulates patients' clinical evolution from the physiological features and factors described in healthcare literature. This generation process has been verified with a real dataset and allows the validation of the reasoning system with noisy and incomplete data, threshold values, and life/death situations. The evaluation demonstrates promising results and good accuracy (0.91) for the proposed low-cost solution to monitor respiratory patients.

The centre of the Milky Way Galaxy hosts a black hole with a solar mass of about 4 million (Sagittarius A*(Sgr A)) that is very quiescent at present with a luminosity many orders of magnitude below those of active galactic nuclei1. Reflection of X-rays from Sgr A*by dense gas in the Galactic Centre region offers a means to study its past flaring activity on timescales of hundreds and thousands of years2. The shape of the X-ray continuum and the strong fluorescent iron line observed from giant molecular clouds in the vicinity of Sgr A*are consistent with the reflection scenario3–5. If this interpretation is correct, the reflected continuum emission should be polarized6. Here we report observations of polarized X-ray emission in the direction of the molecular clouds in the Galactic Centre using the Imaging X-ray Polarimetry Explorer. We measure a polarization degree of 31% ± 11%, and a polarization angle of −48° ± 11°. The polarization angle is consistent with Sgr A*being the primary source of the emission, and the polarization degree implies that some 200 years ago, the X-ray luminosity of Sgr A*was briefly comparable to that of a Seyfert galaxy.

Study design: Descriptive study with cross-sectional data collection. Objectives: To analyse and compare the 3D kinematics and kinetics of thorax, elbow and wrist, and the spatio-temporal parameters during swing-through gait (SG) and reciprocal gait (RG). Setting: Hospital Nacional de Parapléjicos in Toledo, Spain. Methods: An instrumented biomechanical analysis of the upper body of 15 adults with an incomplete lumbar or thoracic spinal cord injury was performed using a marker motion capture system and load cell crutches. Five walks of each gait pattern were analysed. Results: The elbow was in flexion, valgus and pronation and the wrist was in extension and ulnar deviation in both SG and RG. Their kinematic patterns were quite similar, except in elbow valgus and wrist extension in which statistically significant differences were observed. In the thorax prevailed flexion movement in SG and rotation movement in RG. The reaction forces in the elbow and the wrist were notably higher in SG than in RG, but the joint moments were similar in both gait patterns. Conclusions: SG showed greater demands and RG showed higher requirements on trunk motor control. In addition, SG could increase the probability of back and neck pain. Therefore RG should be recommended, whenever possible, in incomplete spinal cord injured people.

Cationic complex coacervates are contemplated for various medical applications controlling carrier or release processes. Here, lower Mwpoly(allylamine hydrochloride) (15 kg/mol) and (hydrogen)phosphate as cross-linking units were chosen to facilitate a sufficient coacervation and subsequently a controllable phosphate release, essential for consecutive mineralization reactions. In addition, the rheological characteristics of the obtained coacervates were assessed, exhibiting a pronounced liquid character, which enables beneficial properties toward remineralization applications such as high wettability and moldability. In light of our results, macroscopic hydrogels are considered for the first time as an ion source for the mineralization of crystalline calcium phosphate phases, representing an entirely new class of preceding mineralization species for potential applications in dentistry and osteology.

Food processing has been hypothesised to play a role in cancer development; however, data from large-scale epidemiological studies are scarce. This study investigated the association between dietary intake according to amount of food processing and risk of cancer at 25 anatomical sites using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Objective: Wireless power transfer (WPT) is used as an alternative to batteries to accomplish miniaturization in electronic medical implants. However, established WPT methods require bulky parts within the implant or cumbersome external systems, hindering minimally invasive deployments and the development of networks of implants. As an alternative, we propose a WPT approach based on volume conduction of high frequency (HF) current bursts. These currents are applied through external electrodes and are collected by the implants through two electrodes at their opposite ends. This approach avoids bulky components, enabling the development of flexible threadlike implants. Methods: We study in humans if HF (6.78 MHz) current bursts complying with safety standards and applied through two textile electrodes strapped around a limb can provide substantial powers from pairs of implanted electrodes. Results: Time averaged electric powers obtained from needle electrodes (diameter = 0.4 mm, length = 3 mm, separation = 30 mm) inserted into arms and lower legs of five healthy participants were 5.9 ± 0.7 mW and 2.4 ± 0.3 mW respectively. We also characterize the coupling between the external system and the implants using personalized two-port impedance models generated from medical images. Conclusions: The results demonstrate that innocuous and imperceptible HF current bursts that flow through the tissues by volume conduction can be used to wirelessly power threadlike implants. Significance: This is the first time that WPT based on volume conduction is demonstrated in humans. This method overcomes the limitations of existing WPT methods in terms of minimal invasiveness and usability.

Understanding the fundamental physicochemical processes that occur during the hydration of cementitious materials is essential for developing alternative binders that enable the partial substitution of Portland cement (PC), lowering the carbon footprint associated with the cement industry. Magnesium-silicate-hydrate (M-S-H) stands as a potential alternative binder; however, its inferior mechanical properties attributed to its nanostructure, and the high-water demand for curing, hinder the application of MgO-based cement as PC surrogate. A potential strategy to tackle these major drawbacks is based on controlling M-S-H formation from the early stages, building the properties and nanostructure of this binding phase from its basic building units. The present work provides insights into M-S-H nucleation and early growth gathered by combining titration experiments with electrospray ionization mass spectrometry, analytical ultracentrifugation, and transmission electron microscopy. We evidenced a nonclassical multistep pathway where a highly complex mixture of defined hydrated magnesium (sodium)-silicate oligomeric species exists in solution prior nucleation. Our results suggest that these entities aggregate, yielding an ill-defined M-S-H precursor phase (depleted in Mg compared to the final product) which later transforms into a denser M-S-H interconnected network (Mg:Si ratio ca. 1) with a more defined sheet-like structure that still retains its poorly crystalline character. The identification of oligomeric silicates species prior nucleation is of great importance for developing means to regulate M-S-H (and potentially other hydrous silicates) formation by using a bottom-up approach. This work reveals that, during the hydration process of cementitious materials, the stages prior to the formation of hydrated solids cannot be disregarded, as they could open new avenues for engineering the properties of the final materials.

Higher dietary calcium consumption is associated with lower colorectal cancer (CRC) risk. However, little data are available on the association between circulating calcium concentrations and CRC risk.

The field of tumour dormancy, originally defined as a clinical phenomenon of late recurrence after a long, apparently disease-free period, has seen significant advances that now allow us to think about monitoring and targeting dormant tumour cells to prevent relapse. In this Viewpoint article, we asked experts to share their views on the steps that are needed to translate dormancy research into the clinic.