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Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.

Commercial fisheries have increased in all the world’s oceans with diverse unintended impacts on marine ecosystems. As a result of resource overlap, interactions between cetaceans and fisheries are a common occurrence and, in many cases, can give rise to significant conservation issues. Research on the distribution and types of such interactions is important for efficient management. In this study, we describe the behaviors of two whale species: sperm whales (Physeter macrocephalus) and northern bottlenose whales (Hyperoodon ampullatus), interacting with benthic trawlers fishing off the eastern Grand Banks of the western North Atlantic in 2007. Whale interactions were only observed when vessels were targeting Greenland halibut (Reinhardtius hippoglossoides) in deep-water fishing areas and were most common during net hauling. Sperm whales and northern bottlenose whales appeared to engage in feeding behavior close to the surface during hauling, especially during the latter stages, suggesting they targeted fish escapees rather than discards. Using photo-identification methods, seven individual sperm whales were identified with multiple resights of six individuals being recorded over an almost two month period. The maximum distance between two resights was 234 km, suggesting individual sperm whales were repeatedly targeting and even following fishing vessels over multiple days and between fishing areas. By contrast, there were no photographic resights of individual northern bottlenose whales within this study, or with substantial photo-identification catalogues from other adjacent high density areas, suggesting that individuals of this species may be less likely to follow vessels or move between areas. This study documents the earliest confirmed records of northern bottlenose whales in this remote region. These interactions and high encounter rates may indicate that adjacent populations are recovering from the previous century of commercial whaling. Our study provides new insights and details on whale-fisheries interactions, which can inform future research and help managers understand the real and perceived impacts of depredation behaviour on fisheries and whales.

Abstract The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial‐based separation is a promising high‐throughput, marker‐free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine‐tunable cut‐off value of 9 μm and a separation range of 2 μm. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut‐off value and better separation results than the state of the art.

Recently, the appeal of Hybrid Energy Storage Systems (HESSs) has been growing in multiple application fields, such as charging stations, grid services, and microgrids. HESSs consist of an integration of two or more single Energy Storage Systems (ESSs) to combine the benefits of each ESS and improve the overall system performance, e.g., efficiency and lifespan. Most recent studies on HESS mainly focus on power management and coupling between the different ESSs without a particular interest in a specific type of ESS. Over the last decades, Redox-Flow Batteries (RFBs) have received significant attention due to their attractive features, especially for stationary storage applications, and hybridization can improve certain characteristics with respect to short-term duration and peak power availability. Presented in this paper is a comprehensive overview of the main concepts of HESSs based on RFBs. Starting with a brief description and a specification of the Key Performance Indicators (KPIs) of common electrochemical storage technologies suitable for hybridization with RFBs, HESS are classified based on battery-oriented and application-oriented KPIs. Furthermore, an optimal coupling architecture of HESS comprising the combination of an RFB and a Supercapacitor (SC) is proposed and evaluated via numerical simulation. Finally, an in-depth study of Energy Management Systems (EMS) is conducted. The general structure of an EMS as well as possible application scenarios are provided to identify commonly used control and optimization parameters. Therefore, the differentiation in system-oriented and application-oriented parameters is applied to literature data. Afterwards, state-of-the-art EMS optimization techniques are discussed. As an optimal EMS is characterized by the prediction of the system’s future behavior and the use of the suitable control technique, a detailed analysis of the previous implemented EMS prediction algorithms and control techniques is carried out. The study summarizes the key aspects and challenges of the electrical hybridization of RFBs and thus gives future perspectives on newly needed optimization and control algorithms for management systems.

This article proposes a novel methodology for estimating metallurgical copper recovery, a critical feature in mining project evaluations. The complexity of modeling this nonadditive variable using geostatistical methods due to low sampling density, strong heterotopic relationships with other measurements, and nonlinearity is highlighted. As an alternative, a copula-based conditional quantile regression method is proposed, which does not rely on linearity or additivity assumptions and can fit any statistical distribution. The proposed methodology was evaluated using geochemical log data and metallurgical testing from a simulated block model of a porphyry copper deposit. A highly heterotopic sample was prepared for copper recovery, sampled at 10% with respect to other variables. A copula-based nonparametric dependence model was constructed from the sample data using a kernel smoothing method, followed by the application of a conditional quantile regression for the estimation of copper recovery with chalcocite content as secondary variable, which turned out to be the most related. The accuracy of the method was evaluated using the remaining 90% of the data not included in the model. The new methodology was compared to cokriging placed under the same conditions, using performance metrics RMSE, MAE, MAPE, and R2. The results show that the proposed methodology reproduces the spatial variability of the secondary variable without the need for a variogram model and improves all evaluation metrics compared to the geostatistical method. [ABSTRACT FROM AUTHOR]

The definition of geostatistical domains is a stage in the estimation of mineral resources, in which a sample resulting from a mining exploration process is divided into zones that show homogeneity or minimal variation in the main element of interest or mineral grade, having geological and spatial meaning. Its importance lies in the fact that the quality of the estimation techniques, and therefore, the correct quantification of the mineral resource, will improve in geostatistically stationary areas. The present study seeks to define geostatistical domains of estimation for a mineral grade, using a non-traditional approach based on the k-prototype clustering algorithm. This algorithm is based on the k-means paradigm of unsupervised machine learning, but it is exempt from the one-time restriction on numeric data. The latter is especially convenient, as it allows the incorporation of categorical variables such as geological attributes in the grouping. The case study corresponds to a hydrothermal gold deposit of high sulfidation, located in the southern zone of Peru, where estimation domains are defined from a historical record of data recovered from 131 diamond drill holes and 37 trenches. The characteristics directly involved were the gold grade (Au), silver grade (Ag), type of hydrothermal alteration, and type of mineralization. The results obtained showed that clustering with k-prototypes is an efficient approach and can be used as an alternative or complement to the traditional methodology.

There is an exponential increase in electric vehicles on the road that need a follow up in terms of warranty. The proposed state of warranty (SOW) is a metastate that qualitatively describes the warranty fulfillment level of an electric vehicle. All the relevant warranty information is synthesized in a single merit while maintaining the level of detail through the qualitative substates. The developed SOW is calculated with a rule-based logic of an expert system that evaluates the quantitative value of three substates: the remaining warranty, the remaining health and the remaining useful warranty. The SOW provides a synthesized and user-friendly description of the warranty fulfillment state while providing quantitative detailed information of the most relevant features of each of the different maintenance methodologies.

Para aquellos que venimos transitando por la universidad pública desde hace décadas resulta inocultable una clara tendencia en la mayoría de nuestras instituciones a repensar sus sentidos, sus misiones, sus funciones, en suma: su deber ser. En estos tiempos y estos contextos en que se visibilizan con absoluta claridad las profundas desigualdades, estas tendencias a construir nuevos significados adquieren una relevancia particular. Entendemos que las universidades públicas en el ejercicio de su autonomía y como integrantes del Estado, deben asumir un papel protagónico con un aporte que contribuya a garantizar derechos, en particular, de los sectores subalternizados. Ese posicionamiento crítico resulta ineludible para consolidar el compromiso social de nuestras instituciones de educación superior. Esta imperiosa intención transformadora cuenta con antecedentes valiosos. En este sentido advertimos que tanto en Argentina como en algunos de los países de la Región se reproducen desde hace algunos años tendencias a consolidar, sistematizar, institucionalizar procesos de articulación emancipadora en sus relaciones con el territorio, las organizaciones y movimientos sociales, muchas de ellas, a través de procesos de curricularización en sus diferentes acepciones. Estas experiencias, disímiles por cierto, encuentran la necesidad de afincarse, de institucionalizarse a través de diversas conformaciones que en algunos casos confluyen en Prácticas Sociales Educativas o denominaciones similares, con formatos distintos, singulares, pero con sentidos también diferentes. Es por eso que nos proponemos desplegar, analizar, visibilizar algunas de las características salientes de estos procesos, las normativas sus singularidades, similitudes, la multiplicidad de sus sentidos, en suma sus metáforas.

The exponential growth of digitalisation and the continuous increase in sustainability needs are currently reshaping the European manufacturing industry through its entire value chain. Industrial sectors have undergone significant changes globally in recent years, and they will continue to face this deep transformation. The manufacturing sectors, more specifically, companies, need to develop a relevant strategy that can support their organisation to handle the upcoming future technological developments and sustainability requirements properly. In order to implement the strategy effectively and achieve an adequate digital and green transformation, their main focus should be the development of a multi-skilled workforce. This competent workforce can only be built by foreseeing the changes in the needed skills for the manufacturing industry and then updating the skills of the current workforce accordingly. As an answer to this need, we developed an automated skill database for the manufacturing industry, particularly transversal occupations of this sector related to the industrial symbiosis (IS) and energy efficiency (EE). Differently from the conventional ones, the generated database incorporated not only the current but also the future skill needs for each profile. During the development of the future skills for each occupation in the database, we identified the foreseen skill needs for the manufacturing industry through detailed desk research. Therefore, this paper presents a valuable perspective on the subject. Our work aimed to fill the gap for a database specifically developed for the manufacturing industry, which provides the end-users with data about the new skills requirements resulting from industrial changes and sustainability needs. We believe that companies, education and training institutions and policymakers can make use of the generated database as a complementary tool for developing their training programmes or strategy roadmaps to cover the emerging changes in each individual industrial sector.

Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, neutropenia, and skeletal abnormalities. Biallelic mutations in SBDS, which encodes a ribosome maturation factor, are found in 90% of SDS cases. Sbds–/– mice are embryonic lethal. Using CRISPR/Cas9 editing, we created sbds-deficient zebrafish strains. Sbds protein levels progressively decreased and became undetectable at 10 days postfertilization (dpf). Polysome analysis revealed decreased 80S ribosomes. Homozygous mutant fish developed normally until 15 dpf. Mutant fish subsequently had stunted growth and showed signs of atrophy in pancreas, liver, and intestine. In addition, neutropenia occurred by 5 dpf. Upregulation of tp53 mRNA did not occur until 10 dpf, and inhibition of proliferation correlated with death by 21 dpf. Transcriptome analysis showed tp53 activation through upregulation of genes involved in cell cycle arrest, cdkn1a and ccng1, and apoptosis, puma and mdm2. However, elimination of Tp53 function did not prevent lethality. Because of growth retardation and atrophy of intestinal epithelia, we studied the effects of starvation on WT fish. Starved WT fish showed intestinal atrophy, zymogen granule loss, and tp53 upregulation — similar to the mutant phenotype. In addition, there was reduction in neutral lipid storage and ribosomal protein amount, similar to the mutant phenotype. Thus, loss of Sbds in zebrafish phenocopies much of the human disease and is associated with growth arrest and tissue atrophy, particularly of the gastrointestinal system, at the larval stage. A variety of stress responses, some associated with Tp53, contribute to pathophysiology of SDS.

Summary: Neutrophils are the shortest‐lived blood cells, which requires a prodigious degree of proliferation and differentiation to sustain physiologically sufficient numbers and be poised to respond quickly to infectious emergencies. More than 107 neutrophils are produced every minute in an adult bone marrow—a process that is tightly regulated by a small group of cytokines and chemical mediators and dependent on nutrients and energy. Like granulocyte colony‐stimulating factor, the primary growth factor for granulopoiesis, they stimulate signalling pathways, some affecting metabolism. Nutrient or energy deficiency stresses the survival, proliferation, and differentiation of neutrophils and their precursors. Thus, it is not surprising that monogenic disorders related to metabolism exist that result in neutropenia. Among these are pathogenic mutations in HAX1, G6PC3, SLC37A4, TAFAZZIN, SBDS, EFL1 and the mitochondrial disorders. These mutations perturb carbohydrate, lipid and/or protein metabolism. We hypothesize that metabolic disturbances may drive the pathogenesis of a subset of inherited neutropenias just as defects in DNA damage response do in Fanconi anaemia, telomere maintenance in dyskeratosis congenita and ribosome formation in Diamond–Blackfan anaemia. Greater understanding of metabolic pathways in granulopoiesis will identify points of vulnerability in production and may point to new strategies for the treatment of neutropenias. [ABSTRACT FROM AUTHOR]

Summary: Shwachman–Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman–Bodian–Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183‐184TA>CT nonsense mutation. Several translational readthrough‐inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full‐length SBDS protein synthesis in SDS‐derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS‐derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full‐length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation. [ABSTRACT FROM AUTHOR]

En la última década, el campo de la Extensión Universitaria adquirió una mayor densidad en el sistema universitario, con legitimidad creciente y avances en tópicos particulares (curricularización, convocatorias a proyectos, integralidad de funciones, etc.). Ello no estuvo exento de ciertos obstáculos en cuanto a condiciones presupuestarias y de acreditación académica, entre otras cuestiones. La evaluación adquiere relevancia en tanto elemento composicional permanente del proceso extensionista. Desde una mirada reflexiva y dialógica, que también supone un desarrollo propositivo y movilizador, se comparten las experiencias recogidas sobre dicha praxis evaluativa en la perspectiva de la extensión crítica. Así, los interrogantes compartidos son propuestos como vectores que interpelan y convocan a la acción transformadora hacia el interior del propio ámbito universitario.

Inherited bone marrow failure syndromes are experiments of nature characterized by impaired hematopoiesis with cancer and leukemia predisposition. The mutations associated with inherited bone marrow failure syndromes affect fundamental cellular pathways, such as DNA repair, telomere maintenance, or proteostasis. How these disturbed pathways fail to produce sufficient blood cells and lead to leukemogenesis are not understood. The rarity of inherited cytopenias, the paucity of affected primary human hematopoietic cells, and the sometime inadequacy of murine or induced pluripotential stem cell models mean it is difficult to acquire a greater understanding of them. Zebrafish offer a model organism to study gene functions. As vertebrates, zebrafish share with humans many orthologous genes involved in blood disorders. As a model organism, zebrafish provide advantages that include rapid development of transparent embryos, high fecundity (providing large numbers of mutant and normal siblings), and a large collection of mutant and transgenic lines useful for investigating the blood system and other tissues during development. Importantly, recent advances in genomic editing in zebrafish can speedily validate the new genes or novel variants discovered in clinical investigation as causes for marrow failure. Here we review zebrafish as a model organism that phenocopies Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, and severe congenital neutropenia. Two important insights, provided by modeling inherited cytopenias in zebrafish, widen understanding of ribosome biogenesis and TP53 in mediating marrow failure and non-hematologic defects. They suggest that TP53-independent pathways contribute to marrow failure. In addition, zebrafish provide an attractive model organism for drug development.

A unified evaluation framework for stochastic tools is developed in this paper. Firstly, we provide a set of already existing quantitative and qualitative metrics that rate the relevant aspects of the performance of a stochastic prognosis algorithm. Secondly, we provide innovative guidelines to detect and minimize the effect of side aspects that interact on the algorithms’ performance. Those aspects are related with the input uncertainty (the uncertainty on the data and the prior knowledge), the parametrization method and the uncertainty propagation method. The proposed evaluation framework is contextualized on a Lithium-ion battery Remaining Useful Life prognosis problem. As an example, a Particle Filter is evaluated. On this example, two different data sets taken from NCA aged batteries and two semi-empirical aging models available in the literature fed up the Particle Filter under evaluation. The obtained results show that the proposed framework gives enough details to take decisions about the viability of the chosen algorithm.

The growth of the renewable energy industry is happening at a swift pace pushed, by the emergence of Industry 4.0. Smart technologies like artificial intelligence (AI), Big Data, the Internet of Things (IoT), Digital Twin (DT), etc. enable companies within the sector of renewable energies to drastically improve their operations. In this sectoral context, where upgraded sustainability standards also play a vital role, it is necessary to fulfil the human capital requirements of the imminent technological advances. This article aims to determine the current skills of the renewable energy industry workforce and to predict the upcoming skill requirements linked to a digital transition by creating a unified database that contains both types of skills. This will serve as a tool for renewable energy businesses, education centers, and policymakers to plan the training itinerary necessary to close the skills gap, as part of the sectoral strategy to achieve a competent future workforce.