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High-entropy alloys (HEAs) have been around since 2004. The breakthroughs in this field led to several potential applications of these alloys as refractory, structural, functional, and biomedical materials. In this work, a short overview on the concept of high-entropy alloys is provided, as well as the theoretical design approach. The special focus of this review concerns one novel class of these alloys: biomedical high-entropy alloys. Here, a literature review on the potential high-entropy alloys for biomedical applications is presented. The characteristics that are required for these alloys to be used in biomedical-oriented applications, namely their mechanical and biocompatibility properties, are discussed and compared to commercially available Ti6Al4V. Different processing routes are also discussed.

Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.

Proneural transcription factors (TFs) such as Ascl1 function as master regulators of neurogenesis in vertebrates, being both necessary and sufficient for the activation of a full program of neuronal differentiation. Novel insights into the dynamics of Ascl1 expression at the cellular level, combined with the progressive characterization of its transcriptional program, have expanded the classical view of Ascl1 as a differentiation factor in neurogenesis. These advances resulted in a new model, whereby Ascl1 promotes sequentially the proliferation and differentiation of neural/stem progenitor cells. The multiple activities of Ascl1 are associated with the activation of distinct direct targets at progressive stages along the neuronal lineage. How this temporal pattern is established is poorly understood. Two modes of Ascl1 expression recently described (oscillatory vs. sustained) are likely to be of importance, together with additional mechanistic determinants such as the chromatin landscape and other transcriptional pathways. Here we revise these latest findings, and discuss their implications to the gene regulatory functions of Ascl1 during neurogenesis.

Proneural genes were initially identified in Drosophila , where pioneer work on these important regulators of neural development was performed, and from which the term proneural function was coined. Subsequently, their counterparts in vertebrates were identified, and their function in neural development extensively characterized. The function of proneural transcription factors in flies and vertebrates is, however, very distinct. In flies, proneural genes play an early role in neural induction, by endowing neural competence to ectodermal cells. In contrast, vertebrate proneural genes are expressed only after neural specification, in neural stem and progenitor cells, where they play key regulatory functions in quiescence, proliferation, and neuronal differentiation. An exception to this scenario is the Drosophila proneural gene asense , which has a late onset of expression in neural stem cells of the developing embryo and larvae, similar to its vertebrate counterparts. Although the role of Asense remains poorly investigated, its expression pattern is suggestive of functions more in line with those of vertebrate proneural genes. Here, we revise our current understanding of the multiple activities of Asense and of its closest vertebrate homologue Ascl1 in neural stem/progenitor cell biology, and discuss possible parallels between the two transcription factors in neurogenesis regulation.

Key Points Genetic studies in Drosophila and vertebrate models have provided evidence that a small number of 'proneural genes', which encode transcription factors of the basic helix–loop–helix (bHLH) class, are both necessary and sufficient to initiate the development of neuronal lineages and to promote the generation of progenitors that are committed to differentiation. Molecular analysis in Drosophila led to the isolation of four genes that regulate the early steps of neural development — achaete ( ac ), scute ( sc ), lethal of scute ( lsc ) and asense ( ase ). An additional proneural gene, atonal ( ato ), was identified in a screen to identify bHLH sequences related to that found in achaete-scute complex ( asc ) genes. Many genes that are related to asc and ato have been found in vertebrates. Proneural proteins bind DNA as heterodimeric complexes that are formed with ubiquitously expressed bHLH proteins, or E proteins, and most of them act as transcriptional activators. Mutation analysis in the mouse has so far established a clear proneural activity for only a few genes, namely Mash1 , Ngn1 and Ngn2 , and possibly Math1 and Math5 . However, these genes do not account for the selection of all neural progenitors, so it is likely that other genes with proneural activity remain to be identified. The mechanisms that underlie proneural function include: activation of the Notch signalling pathway, leading to the inhibition of proneural gene expression in adjacent cells; positive-feedback loops that maintain proneural gene expression; activation of neuronal-differentiation gene cascades that implement neuronal-differentiation programmes; inhibition of glial cell fates; and regulation of the cell cycle. In addition to their role in the initial selection and specification of neural progenitor cells, proneural proteins are also involved in neuronal-subtype specification. Future studies might reveal new roles for proneural genes that will help us to understand the coupling between proneural and subtype-differentiation programmes. Certain morphological, physiological and molecular characteristics are shared by all neurons. However, despite these similarities, neurons constitute the most diverse cell population of any organism. Recently, considerable attention has been focused on identifying the molecular mechanisms that underlie this cellular diversity. Parallel studies in Drosophila and vertebrates have revealed that proneural genes are key regulators of neurogenesis, coordinating the acquisition of a generic neuronal fate and of specific subtype identities that are appropriate for the location and time of neuronal generation. These studies reveal that, in spite of differences between invertebrate and vertebrate neural lineages, Drosophila and vertebrate proneural genes have remarkably similar roles.

Neuronal migration: neurogenin 2 acts via Rnd2 Proneural transcription factors, such as neurogenin 2, are thought to control the expression of many genes during brain development to promote both the differentiation of neurons and their migration to their final locations in the cerebral cortex. A new study reveals that overexpression of a single target of neurogenin 2, Rnd2, can restore the neuronal migration defects of Neuogenin2-depleted neurons. Rnd2 is thus an atypical member of the Rho family of small GTP-ases, which regulate actin cytoskeleton dynamics, with its activity regulated at the gene transcription level, rather than by the usual post-translational GTP/GDP cycle. A study reveals that overexpression of a single target of neurogenin 2, Rnd2 , can restore the neuronal migration defects of neurogenin 2-depleted neurons. Rnd2 is thus an atypical member of the Rho family of small GTP-ases, which regulate actin cytoskeleton dynamics, with its activity regulated at the gene transcription level, rather than by the usual post-translational GTP/GDP cycle. Motility is a universal property of newly generated neurons. How cell migration is coordinately regulated with other aspects of neuron production is not well understood. Here we show that the proneural protein neurogenin 2 (Neurog2), which controls neurogenesis in the embryonic cerebral cortex 1 , 2 , directly induces the expression of the small GTP-binding protein Rnd2 (ref. 3 ) in newly generated mouse cortical neurons before they initiate migration. Rnd2 silencing leads to a defect in radial migration of cortical neurons similar to that observed when the Neurog2 gene is deleted. Remarkably, restoring Rnd2 expression in Neurog2 -mutant neurons is sufficient to rescue their ability to migrate. Our results identify Rnd2 as a novel essential regulator of neuronal migration in the cerebral cortex and demonstrate that Rnd2 is a major effector of Neurog2 function in the promotion of migration. Thus, a proneural protein controls the complex cellular behaviour of cell migration through a remarkably direct pathway involving the transcriptional activation of a small GTP-binding protein.

In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers. During the formation of the brain, developing neurons are faced with a logistical problem. After newborn neurons form they must change in shape and move to their final location in the brain. Despite much speculation, little is known about these processes. Neurons mature via the activity of several pathways that control the activity, or expression, of the neuron’s genes. One way of controlling such gene expression is through proteins called transcription factors. At the same time, the developing neurons go through a process called polarization, where different regions of the cell develop different characteristics. However, it was not known how the maturation and polarization processes are linked, or how the developing neurons actively regulate polarization. By studying the developing mouse brain, Singh et al. found that a transcription factor called Zeb1 keeps neurons in a immature state, stopping them from becoming polarized. Further investigation revealed that Zeb1 does this by preventing the production of a group of proteins that helps to polarize the cells. The most common type of malignant brain tumour in children is called a medulloblastoma. Singh et al. analyzed the genes expressed in mice that have a type of medulloblastoma that results from the constant activity of a gene called Sonic Hedgehog in developing neurons. This revealed that these tumour cells contain abnormally high levels of Zeb1, and so do not take on a polarized form. However, artificially restoring other factors that encourage the cells to polarize caused the neurons to mature normally. Further investigation is now needed to find out whether the activity of the Sonic Hedgehog gene regulates Zeb1 activity, and to discover whether inhibiting Zeb1 could prevent brain tumours from developing.

The proneural factor Ascl1 controls multiple steps of neurogenesis in the embryonic brain, including progenitor division and neuronal migration. Here we show that Cenpj , also known as CPAP , a microcephaly gene, is a transcriptional target of Ascl1 in the embryonic cerebral cortex. We have characterized the role of Cenpj during cortical development by in utero electroporation knockdown and found that silencing Cenpj in the ventricular zone disrupts centrosome biogenesis and randomizes the cleavage plane orientation of radial glia progenitors. Moreover, we show that downregulation of Cenpj in post-mitotic neurons increases stable microtubules and leads to slower neuronal migration, abnormal centrosome position and aberrant neuronal morphology. Moreover, rescue experiments shows that Cenpj mediates the role of Ascl1 in centrosome biogenesis in progenitor cells and in microtubule dynamics in migrating neurons. These data provide insights into genetic pathways controlling cortical development and primary microcephaly observed in humans with mutations in Cenpj. The proneural factor Ascl1/Mash1 is an important regulator of embryonic neurogenesis. Here the authors identify that the microcephaly protein Cenpj/CPAP is essential for several microtubule-dependent steps in the neurogenic program driven by Ascl1 in the developing cerebral cortex.

Hybrid organic–inorganic perovskite materials have become one of the most studied classes of light‐harvesting materials due to their exceptional properties such as high light absorption, long carrier diffusion lengths, bandgap tuning and defect tolerance. Since 2009 that the scientific community has been working on improving the power conversion efficiency (PCE) of perovskite solar cell devices, reaching now an impressive value of 25.5%. Moreover, efficiencies over 18% are often reported by several authors. Since the efficiency goal is almost fulfilled, the scientific community is currently addressing five challenges, with the ultimate objective to make this technology competitive and turn it commercial; these challenges are cost, stability, upscaling, safety and environmental impact. Given the astonishing progresses reached during the past decade and the numerous research groups working to the same goal, it is a matter of time until commercial perovskite solar devices become a reality. In this review work, the most recent achievements regarding this purpose are put together and compared, so as to suggest the most suitable perovskite solar fabrication processes and materials to produce commercial devices. In this state‐of‐the‐art conception, the five criteria that a commercial perovskite solar device must fulfil are thoroughly addressed: efficiency, cost, stability, upscaling and environmental impact. Additionally, a holistic and critical analysis is made to the collected data and the most suitable materials and fabrication processes compatible with industrialization are proposed.

CERNBox is an innovative scientific collaboration platform, built using solely open-source components to meet the unique requirements of scientific workflows. Used at CERN for the last decade, the service satisfies the 35K users at CERN and seamlessly integrates with batch farms and Jupyter-based services. Powered by Reva, an open-source HTTP and gRPC server written in Go, CERNBox has demonstrated the provision of sync&share capabilities on top of multiple storage systems such as EOS and CephFS, as well as enabling federated sharing with other institutions. In this contribution, we present the evolution of CERNBox towards supporting the low-latency Windows applications use-cases at CERN. As we are migrating out of DFS, the legacy Windows storage provided by Microsoft, and commissioning Windows Workspaces powered by CephFS, we show how CERNBox provides a flexible software stack to seamlessly integrate the Windows-based community, which includes the Engineering sector of the Organization. We conclude by emphasizing the multiple synergies enabled by this approach. On one hand, Windows-based data-centric workflows can leverage the multiprotocol accesses (sync, web, SMB) provided by CERNBox. On the other hand, the widespread adoption of CephFS within the scientific community positions CERNBox as an out-of-the-box solution for implementing a scalable collaborative cloud storage service.