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Abstract Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigate the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for diHSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we show that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice have enhanced fibrosis, RORA agonists rescue multi-organ fibrosis in in vivo models. Notably, RORA expression correlates negatively with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, important for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.

Abstract Deltas are deposits directly accumulated by land‐generated gravity flows in a standing body of water. The paradigm of deltaic sedimentation has dramatically changed during recent years, from the popular very simplified ternary models of marine littoral deltas towards more realistic and comprehensive models, considering the importance of sediment‐laden river discharges. Ternary delta models were designed for clean rivers, where a stream flow drags the sediments. Depending on the basin dynamics, these littoral deposits can be modified, forming tidal‐dominated, wave‐dominated or fluvial‐dominated littoral deltas. In recent years, a new classification of delta systems was proposed, based on contrasting the salinity of the receiving water body with the bulk density of the incoming fluvial discharge. Rivers are highly dynamic systems, and their discharges can be very variable in terms of flow duration and sediment concentration. Additionally, the salinity of the receiving water body can exhibit significant variability, especially in closed lakes and epicontinental seas, ranging from freshwater to brines. This scenario allows the distinction of three major delta categories (hypopycnal, homopycnal and hyperpycnal deltas) which can be in turn subdivided, defining seven delta types. Hypopycnal deltas form when the bulk density of the incoming flow is lower than the density of the water in the basin, allowing the definition of three delta types, corresponding to hypersaline littoral deltas, marine littoral deltas and brackish littoral deltas. Homopycnal deltas form when the bulk density of the incoming flow is similar to the density of the water in the basin, defining a delta type termed homopycnal littoral deltas. Hyperpycnal deltas form when the bulk density of the incoming flow is higher than the density of the water in the basin, allowing the definition of three categories termed hyperpycnal littoral deltas, hyperpycnal subaqueous deltas and hyperpycnal fan deltas.

Summary: Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases’ progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH. Methods: We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples. Findings: Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840–0.979) for screening MASH. Interpretation: Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses. Funding: The project leading to these results has received funding from ‘la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

This 1:30,000 scale geological map describes Oxia Planum, Mars, the landing site for the ExoMars Rosalind Franklin rover mission. The map represents our current understanding of bedrock units and their relationships prior to Rosalind Franklin’s exploration of this location. The map details 15 bedrock units organised into 6 groups and 7 textural and surficial units. The bedrock units were identified using visible and near-infrared remote sensing datasets. The objectives of this map are (i) to identify where the most astrobiologically relevant rocks are likely to be found, (ii) to show where hypotheses about their geological context (within Oxia Planum and in the wider geological history of Mars) can be tested, (iii) to inform both the long-term (hundreds of metres to ∼1 km) and the short-term (tens of metres) activity planning for rover exploration, and (iv) to allow the samples analysed by the rover to be interpreted within their regional geological context.

Introduction: Nonalcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease (MASLD), is an escalating health concern linked to obesity and type 2 diabetes. Despite liver biopsy being the gold standard, its invasiveness underscores the need for noninvasive diagnostic methods. Methods: A cross-sectional study was performed to assess MASLD using the noninvasive OWLiver® serum lipidomics test in a cohort of 117 patients with severe obesity undergoing bariatric surgery, comparing outcomes with liver biopsy. Exclusions (n = 24) included insufficient data, liver disease etiology other than MASLD, corticosteroid treatment, excessive alcohol consumption, low glomerular filtration rate, and declination to participate. Comprehensive laboratory tests, demographic assessments, and liver biopsies were performed. Serum metabolites were analyzed using OWLiver®, a serum lipidomic test that discriminates between healthy liver, steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and MASH with fibrosis ≥2 by means of three algorithms run sequentially. Results: Liver biopsy revealed a MASLD prevalence of 95.7%, with MASH present in 28.2% of cases. OWLiver® demonstrated a tendency to diagnose more severe cases. Body mass index (BMI), rather than the presence of type 2 diabetes, emerged as the sole independent factor linked to the probability of concordance. Therefore, the all-population concordance of 63.2% between OWLiver® and liver biopsy notably raised to 77.1% in patients with a BMI

Cleanrooms are controlled environments where the number of airborne particles is reduced to a level defined by an International Organization for Standardization (ISO) standard. These facilities have applications in different fields, such as the electronic, pharmaceutical, and healthcare sectors, and are also necessary for the assembly, testing and handling of space hardware. Cleanrooms are expensive to build and maintain and require the permanent designation of infrastructures and dedicated spaces within a building. Once built, clean rooms cannot be used for any other purpose, as contamination is a significant risk. The restricted access to these facilities limits the process of designing, testing, and calibrating instruments developed by academic institutions, small companies, and space startups. Here we present a Commercial Off-The-Shelf (COTS) procedure for building and maintaining a highly controlled ISO class 5 cleanroom, according to ISO14644 standards. We provide a detailed explanation of how to design, develop and operate a portable, modular, and cost-effective ISO class 5 cleanroom that can be used for the usual workflow of development, integration, test procedures and planetary protection associated with the design of instrumentation for planetary exploration.

Abstract The Perseverance rover has collected seven oriented samples of sedimentary rocks, all likely older than the oldest signs of widespread life on Earth, at the exposed base of the western fan in Jezero crater, Mars. The samples include a sulfate‐ and clay‐bearing mudstone and sandstone, a fluvial sandstone from a stratigraphically low position at the fan front, and a carbonate‐bearing sandstone deposited above the sulfate‐bearing strata. All samples contain aqueously precipitated materials and most or all were aqueously deposited. Although the rover instruments have not confidently detected organic matter in the rocks from the fan front, the much more sensitive terrestrial instruments will still be able to search for remnants of prebiotic chemistries and past life, and study Mars's past habitability in the samples returned to Earth. The hydrated, sulfate‐bearing mudstone has the highest potential to preserve organic matter and biosignatures, whereas the carbonate‐bearing sandstones can be used to constrain when and for how long Jezero crater contained liquid water. Returned sample science analyses of sulfate, carbonate, clay, phosphate and igneous minerals as well as trace metals and volatiles that are present in the samples acquired at the fan front would provide transformative insights into past habitable environments on Mars, the evolution of its magnetic field, atmosphere and climate and the past and present cycling of atmospheric and crustal water, sulfur and carbon.

Ozone plays a key role in both atmospheric chemistry and UV absorption in planetary atmospheres. On Mars, upper-tropospheric ozone has been widely characterized by space-based instruments. However, surface ozone remains poorly characterized, hindered by the limited sensitivity of orbiters to the lowest scale height of the atmosphere and challenges in delivering payloads to the surface of Mars, which have prevented, to date, the measurement of ozone from the surface of Mars. Systematic measurements from the Martian surface could advance our knowledge of the atmospheric chemistry and habitability potential of this planet. NASA’s Mars 2020 mission includes the first ozone detector deployed on the Martian surface, which is based on discrete photometric observations in the ultraviolet band, a simple technology that could obtain the first insights into total ozone abundance in preparation for more sophisticated measurement techniques. This paper describes the Mars 2020 ozone detector and its retrieval algorithm, including its performance under different sources of uncertainty and the potential application of the retrieval algorithm on other missions, such as NASA’s Mars Science Laboratory. Pre-landing simulations using the UVISMART radiative transfer model suggest that the retrieval is robust and that it can deal with common issues affecting surface operations in Martian missions, although the expected low ozone abundance and instrument uncertainties could challenge its characterization in tropical latitudes of the planet. Other space missions will potentially include sensors of similar technology.

Abstract Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL–based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.

In recent years there has been a strong expansion of photovoltaic (PV) distributed generation systems. A high PV penetration level can cause uncertainty in the operation and management processes carried out by electric utilities, since most meters register the net load, i.e., the actual load minus the power generated by the PV systems behind the meter. The goal of this paper was to analyze the difference in the net load forecasting error achieved by models using or not using behind-the-meter PV generation data. The PV plant is connected to the lower voltage side of the power substation, representing a penetration level of more than 35% of the total load. The study shows that the best forecasting results are obtained with an indirect approach using two forecasting models, one for the total load and the other for the PV generation. However, the difference with respect to the results obtained with a unique net load forecasting model is almost negligible, which may be of special interest for power system distributors or other agents who do not have access to behind-the-meter generation data.

Abstract DNA is an incontrovertible biosignature whose sequencing aids in species identification, genome functionality, and evolutionary relationships. To study life within the rocks of Earth and Mars, we demonstrate, in an ISO5 clean room, a procedure based on nanopore technology that correctly identifies organisms at picogram levels of DNA without amplification. Our study with E. coli and S. cerevisiae DNA samples showed that MinION sequencer (Oxford Nanopore Technologies) can unequivocally detect and characterise microbes with as little as 2 pg of input with just 50 active nanopores. This result is an excellent advancement in sensitivity, immediately applicable to investigating low biomass samples. This value is also at the level of possible background contamination associated with the reagents and the environment. Cultivation of natural and heat-treated Martian analogue (MMS-2) regolith samples, exposed to atmospheric water vapour or in increasing water concentrations, led to the extraction of 600–1000 pg of DNA from 500 mg of soil. Applying the low detectability technology enabled through MinION sequencer for a natural low biomass setting, we characterised the dry MMS-2 and found few soil-related organisms and airborne contaminants. The picogram detection level and the procedure presented here, may be of interest for the future Mars sample Return program, and the life research and planetary protection studies that will be implemented through the sample safety assessment.

Many natural and artificial liquid environments, such as rivers, oceans, lakes, water storage tanks, aquariums, and urban water distribution systems, are difficult to access. As a result, technology is needed to enable autonomous liquid sampling to monitor water quality and ecosystems. Existing in situ sample acquisition and handling systems for liquid environments are currently limited to a single use and are semi-autonomous, relying on an operator. Liquid sampling systems should be robust and light and withstand long-term operation in remote locations. The system components involved in liquid sampling should be sterilisable to ensure reusability. Here, we introduce a prototype of a liquid sampler that can be used in various liquid environments and may be valuable for the scientific characterisation of different natural, remote, and planetary settings. The Autonomous Planetary Liquid Sampler (APLS) is equipped with pre-programmed, fully autonomous extraction, cleaning, and sterilisation functionalities. It can operate in temperatures between −10 °C and 60 °C and pressure of up to 0.24 MPa (~24 m depth below mean sea level on Earth). As part of the control experiment, we demonstrate its safe and robust autonomous operation in a laboratory environment using a liquid media with Bacillus subtilis. A typical sampling procedure required 28 s to extract 250 mL of liquid, 5 s to fill the MilliQ water, 25 s for circulation within the system for cleaning and disposal, and 200 s to raise the system temperature from ~30 °C ambient laboratory temperature to 150 °C. The temperature is then maintained for another 3.2 h to sterilise the critical parts, allowing a setup reset for a new experiment. In the future, the liquid sampler will be combined with various existing analytical instruments to characterise the liquid solution and enable the autonomous, systematic monitoring of liquid environments on Earth.

Extensive carbonate precipitation has occurred on Mars. To gain insight into the carbonation mechanisms and formation processes under ancient Martian aqueous conditions, we examine the precipitation of carbonates resulting from atmospheric carbon fixation, focusing on interactions between various brines and silicate and perchlorate solutions in alkaline environments. The micro-scale morphology and composition of the resulting precipitates are analysed using ESEM micrographs, EDX chemical compositional analysis, X-ray diffraction, and micro-Raman spectroscopy. Our findings indicate a significant atmospheric carbonation process involving chlorate and sulphate brines reacting with alkaline perchlorate solutions, leading to the precipitation of calcium carbonate polymorphs, including vaterite, aragonite, and calcite, as well as other carbonates like siderite (iron carbonate) and zaratite (nickel carbonate). Some precipitates exhibit biomorphic structures (such as globular spherical aggregates, fine branched tubes, and flower-like morphologies) that should not be mistaken for fossils. These experiments demonstrate that various precipitates can form simultaneously in a single reaction vessel while being exposed to different micro-scale pH conditions. We propose that systematic laboratory studies of such precipitate reactions should be conducted in preparation for the analysis of the Mars Sample Return collection on Earth, aiding in the interpretation of carbonate presence in natural brine-rock carbonation processes under Martian conditions while also helping to distinguish potential biosignatures from purely geochemical processes.

An intense and long-lasting Saharan dust outbreak crossed the Iberian Peninsula (IP) from the southwest (SW) to the northeast (NE) from 25 March until 7 April 2021. This work aims to assess the optical and mass contribution of both fine and coarse dust particles along their transport. Five Iberian lidar stations were monitoring the transport and evolution of the Saharan dust particles, i.e. El Arenosillo/Huelva, Granada, Torrejón/Madrid and Barcelona in Spain, and Évora in Portugal. The particular meteorological conditions determined the aerosol scenario along the overall dust event, differing in the first part of the event (25–31 March), in which the strongest dust incidence occurred on 29–31 March at the south and central stations and 1 April at Barcelona, from the second one (1–7 April). The use of the two-step POLIPHON algorithm showed the relevance of using polarized lidar measurements for separating the aerosol properties of dust fine and coarse particles as an added value. Both the fine dust (Df) and coarse dust (Dc) components of the total particle backscatter coefficient (total dust, DD = Dc + Df) were separately derived. The dust plume was well-mixed with height and no significant differences were found in the vertical structure of both the Dc and Df particle backscatter coefficients. From the beginning of the dust outbreak until 1 April, the vertical Df / DD mass ratio was nearly constant in time at each station and also in altitude with values of ∼ 10 %. Moreover, the mean dust optical depth at 532 nm was decreasing along that dust pathway, reporting values from SW to NE stations of 0.34 at El Arenosillo/Huelva, 0.28 at Granada, 0.20 at Évora, 0.28 at Torrejón/Madrid, and 0.14 at Barcelona, although its Df / DD ratio remained almost constant (28 %–30 %). A similar pattern was found for the total dust mass loading and its Df / DD ratio, i.e. mostly decreasing mean mass values were reported, being constant in its Df / DD ratio (∼ 10 %) along the SW–NE dust pathway. In addition, the episode-mean centre-of-mass height increased with latitude overall, showing a high variability, being greater than 0.5 km at the southern sites (El Arenosillo/Huelva, Granada, Évora) and ∼ 1.0 km at Torrejón/Madrid and Barcelona. However, despite the relatively high intensity of the dust intrusion, the expected ageing of the dust particles was hardly observed, by taking into account the minor changes found in the contribution and properties of the coarse and fine dust particles. This is on the basis that the IP is relatively close to the Saharan dust sources and then, under certain dust transport conditions, any potential ageing processes in the dust particles remained unappreciated. The following must be highlighted: the different relative contribution of the fine dust particles to the total dust found for their optical properties (∼ 30 %) associated with the radiative effect of dust, with respect to that for the mass features (∼ 10 %) linked to air quality issues, along the overall dust event by crossing the IP.

Background and Objectives: Modern classification and categorization of individuals’ health requires personalized variables such as nutrition, physical activity, lifestyle, and medical data through advanced analysis and clustering methods involving machine learning tools. The objective of this project was to categorize Mediterranean dwellers’ health factors and design metabotypes to provide personalized well-being in order to develop professional implementation tools in addition to characterizing nutritional and lifestyle features in such populations. Materials and Methods: A two-phase observational study was conducted by the Pharmacists Council to identify Spanish nutritional and lifestyle characteristics. Adults over 18 years of age completed questionnaires on general lifestyle habits, dietary patterns (FFQ, MEDAS-17 p), physical activity (IPAQ), quality of life (SF-12), and validated well-being indices (LS7, MEDLIFE, HHS, MHL). Subsequently, exploratory factor, clustering, and random forest analysis methods were conducted to objectively define the metabotypes considering population determinants. Results: A total of 46.4% of the sample (n = 5496) had moderate-to-high adherence to the Mediterranean diet (>8 points), while 71% of the participants declared that they had moderate physical activity. Almost half of the volunteers had a good self-perception of health (49.9%). Regarding lifestyle index, population LS7 showed a fair cardiovascular health status (7.9 ± 1.7), as well as moderate quality of life by MEDLIFE (9.3 ± 2.6) and MHL scores (2.4 ± 0.8). In addition, five metabotype models were developed based on 26 variables: Westernized Millennial (28.6%), healthy (25.1%), active Mediterranean (16.5%), dysmetabolic/pre-morbid (11.5%), and metabolically vulnerable/pro-morbid (18.3%). Conclusions: The support of tools related to precision nutrition and lifestyle integrates well-being characteristics and contributes to reducing the impact of unhealthy lifestyle habits with practical implications for primary care. Combining lifestyle, metabolic, and quality of life traits will facilitate personalized precision interventions and the implementation of targeted public health policies.

During aging, skeletal muscle undergoes a loss of mass, strength and function, encompassed in the biological process termed sarcopenia. Given demographic aging, it is essential to comprehend the molecular determinants resulting in age-related sarcopenia. Here we studied the role of the mitophagy adaptor BNIP3 in mitochondrial homeostasis and muscle during aging. Our findings reveal that BNIP3 orchestrates mitochondrial and lysosomal function to mitigate muscle inflammation and atrophy during aging.

IntroductionIndividuals with type 2 diabetes (T2D) should be considered a susceptible group for pulmonary dysfunction. So, we aimed to evaluate the sensation of breathlessness in this population by administering two well-validated questionnaires.MethodsThis is a crosssectional study with 592 people without known respiratory disease (353 with T2D) who answered the modified Medical Research Council (mMRC) questionnaire. In addition, 47% also responded to the St George Respiratory Questionnaire, a specific instrument designed to be applied to patients with obstructive airway disease.ResultsPatients with T2D showed a higher mMRC score in comparison to the control group [1.0 (0.0 – 4.0) vs. 0.0 (0.0 – 4.0), p

The NASA Mars 2020 Perseverance Rover Mission has collected samples of rock, regolith, and atmosphere within the Noachian-aged Jezero Crater, once the site of a delta-lake system with a high potential for habitability and biosignature preservation. Between sols 109 and 1,088 of the mission, 27 sample tubes have been sealed, including witness tubes. Each sealed sample tube has been collected along with detailed documentation provided by the Perseverance instrument payload, preserving geological and environmental context. Samples representative of the stratigraphy within each of four campaigns have been collected: samples from the Crater Floor Campaign represent a suite of potentially petrogenetically related igneous rocks displaying variable degrees of aqueous alteration; samples from the Fan Front record fluvial to deltaic sediments formed by the transport and deposition of materials from the Jezero watershed; regolith samples from the Fan Front preserve material possibly representative of global dust as well as diverse, locally derived clasts; Upper Fan samples record the latest stages of aqueous activity within Jezero; and samples from the Margin Campaign preserve lacustrine, littoral, or possibly igneous processes that may have occurred early in the history of the crater. Along with anticipated samples from the older rocks within the rim of Jezero Crater, Perseverance promises to deliver a suite of samples preserving a diversity of formation environments and ages. Upon return to Earth and analysis in terrestrial laboratories, these samples would address longstanding questions pertaining to the geologic evolution of Mars, its habitability, and the potential for life outside the Earth. [ABSTRACT FROM AUTHOR]