Palaeo–Basque and Palaeo–Sardininan: reconstruction and comparison.

Reconstruir substratos lingüísticos a partir de sus vestigios requiere una profunda competencia de las premisas metodológicas. En este trabajo se trata primeramente la discusión crítica de las deficiencias en la recostrucción del protovascuence para después refutar algunas conclusiones del lingüista J. Lakarra en su rechazo de cualquier conexión entre protovascuence y paleosardo. Se subraya la necesidad de reconocer la total equivalencia de las reglas de desarrollo fonológico, morfosintáctico y léxico en ambas lenguas con objeto de ofrecer una prueba incontestable de su origen común. Finalmente se objeta la total ausencia de datos toponímicos en el método de Lakarra, lo que dificulta la correcta comparación entre ambos protosistemas e impide al investigador vasco valorar el neto apoyo que dicho material ofrece para identificar la común evolución de protovascuence y paleosardo.Reconstruction of substrata residue demands a high level of competence in methodological linguistic premises. In this paper we first of all undertake a thorough discussion of the methodological flaws and weaknesses detected in the reconstruction of Palaeo–Basque. We then take issue with some misplaced conclusions drawn by the Basque linguist Joseba Lakarra when he dismisses any genealogical link between Basque and Palaeo–Sardinian. We make a powerful point for ascertaining a complete match of phonological, morphosyntactic and lexical diachronic rules between the two reconstructed languages, so as to provide compelling evidence of their common ancestral origin. Finally, we criticise the overall lack of toponymic data in Lakarra’s operational rules, which hampers a correct comparison between the two proto–systems and prevents the Basque scholar from assessing the telling support for evidence as to the common evolution of Paleo–Basque and Palaeo–Sardinian.Humanidade

Blocking IL-6 signaling prevents astrocyte-induced neurodegeneration in an iPSC-based model of Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive death of midbrain dopamine (DAn) neurons in the substantia nigra (SN). Since it has been proposed that patients with PD exhibit an overall proinflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing patients with PD and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared with controls. In particular, the proinflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes and was found to induce toxicity in DAn. Mechanistically, neuronal cell death was mediated by IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Blockage of IL-6R by the addition of the FDA-approved anti-IL-6R antibody, Tocilizumab, prevented PD neuronal death. SN neurons overexpressing IL-6R and reactive astrocytes expressing IL-6 were detected in postmortem brain tissue of patients at early stages of PD. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD and pave the way for the design of future therapeutics

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Protovascuence y Paleosardo: reconstrucción y comparación

Reconstruction of substrata residue demands a high level of competence in methodological linguistic premises. In this paper we first of all undertake a thorough discussion of the methodological flaws and weaknesses detected in the reconstruction of Palaeo–Basque. We then take issue with some misplaced conclusions drawn by the Basque linguist Joseba Lakarra when he dismisses any genealogical link between Basque and Palaeo–Sardinian. We make a powerful point for ascertaining a complete match of phonological, morphosyntactic and lexical diachronic rules between the two reconstructed languages, so as to provide compelling evidence of their common ancestral origin. Finally, we criticise the overall lack of toponymic data in Lakarra’s operational rules, which hampers a correct comparison between the two proto–systems and prevents the Basque scholar from assessing the telling support for evidence as to the common evolution of Paleo–Basque and Palaeo–Sardinian.Reconstruir substratos lingüísticos a partir de sus vestigios requiere una profunda competencia de las premisas metodológicas. En este trabajo se trata primeramente la discusión crítica de las deficiencias en la recostrucción del protovascuence para después refutar algunas conclusiones del lingüista J.Lakarra en su rechazo de cualquier conexión entre protovascuence y paleosardo. Se subraya la necesidad de reconocer la total equivalencia de las reglas de desarrollo fonológico, morfosintáctico y léxico en ambas lenguas con objeto de ofrecer una prueba incontestable de su origen común. Finalmente se objeta la total ausencia de datos toponímicos en el método de Lakarra, lo que dificulta la correcta comparación entre ambos protosistemas e impide al investigador vasco valorar el neto apoyo que dicho material ofrece para identificar la común evolución de protovascuence y paleosardo

La tipología lingüística del sardo.

Sin resume