A Drosophila \textit{Drosophila } model of myeloproliferative neoplasm reveals a feed-forward loop in the JAK pathway mediated by p38 MAPK signalling.

Myeloproliferative neoplasms (MPNs) of the Philadelphia-negative class comprise polycythaemia vera, essential thrombocythaemia and primary myelofibrosis (PMF). They are associated with aberrant numbers of myeloid lineage cells in the blood, and in the case of overt PMF, with development of myelofibrosis in the bone marrow and failure to produce normal blood cells. These diseases are usually caused by gain-of-function mutations in the kinase JAK2. Here, we use Drosophila to investigate the consequences of activation of the JAK2 orthologue in haematopoiesis. We have identified maturing haemocytes in the lymph gland, the major haematopoietic organ in the fly, as the cell population susceptible to induce hypertrophy upon targeted overexpression of JAK. We show that JAK activates a feed-forward loop, including the cytokine-like ligand Upd3 and its receptor, Domeless, which are required to induce lymph gland hypertrophy. Moreover, we present evidence that p38 MAPK signalling plays a key role in this process by inducing expression of the ligand Upd3. Interestingly, we also show that forced activation of the p38 MAPK pathway in maturing haemocytes suffices to generate hypertrophic organs and the appearance of melanotic tumours. Our results illustrate a novel pro-tumourigenic crosstalk between the p38 MAPK pathway and JAK signalling in a Drosophila model of MPNs. Based on the shared molecular mechanisms underlying MPNs in flies and humans, the interplay between Drosophila JAK and p38 signalling pathways unravelled in this work might have translational relevance for human MPNs.This work was supported by grants from the European Commission [ERC 294665] and Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) [2014 SRG-535] to A.R.N.; Ministerio de Economía y Competitividad (MINECO) [Government of Spain, SIGNAGROWTH-BFU2013-44485 and INTERGROWTH-BFU2016-77587-P] and FEDER ‘Una manera de hacer Europa’ to M.M.; the European Union Seventh Framework Programme [FP7/Marie Curie-Skłodowska Actions/COFUND/IRBPostPro 2.0 2013] and the European Molecular Biology Organization (EMBO) [ASTF 369-2016] to A.T.-F

Modelling of homogeneously catalyzed hemicelluloses hydrolysis in a laminar-flow reactor

Hydrolysis of hemicelluloses with acid catalysts yield different sugar monomers and oligomers, depending on the substrate as well as the process design. The hydrolysis kinetics are typically rather slow, which leads to requirements of long residence times, i.e. slow flow rates, in order to achieve adequate conversion. Hydrolysis experiments of two different polysaccharides – o-acetylgalactoglucomannan (GGM) and inulin - were conducted in an isothermal tubular continuous reactor in laboratory scale, working in the laminar flow regime. A dynamic mass balance-based reactor model was developed, including convection and molecular diffusion in axial and radial directions, as well as the self-accelerating kinetics of the reaction. The model gave a very satisfactory description of the experimental data. The behavior of the laminar flow reactor in the hemicellulose hydrolysis was further illustrated by numerical simulations

A novel anaerobic filter membrane bioreactor: prototype start-up and filtration assays

Anaerobic digestion allows efficient treatment of high loaded wastewater, and membrane technology allows obtaining high quality effluents with complete biomass retention. However, high biomass concentration interferes with membrane fouling. In the present work, a new bioreactor that integrates an attached biomass anaerobic culture on a fixed bed and a submerged membrane has been started up. The recirculation between the digestion and filtration chambers is coupled to the gas-lift effect of the bubbling employed for the scouring of the membranes, avoiding the use or electromechanical pumps that damage the suspended biomass. The support material retains the biomass in the digestion tank despite the downwards flow, avoiding the submerged membrane contacting with a high concentrated suspension. This novel system, called an anaerobic filter membrane bioreactor was immediately started up, achieving chemical oxygen demand (COD) removal efficiencies of 96% at an organic loading rate (OLR) of 7 kg COD/m3·d. In order to select filtration flux, specific gas demand and filtration cycle duration, the results of 15 short term assays, eight hours for each one, is presented for fluxes between 15.7 and 17.7 L/m2·h, cycle duration between 10 and 30 minutes, and three levels of scouring. It was checked that reversible and irreversible fouling were directly related when dTMP/dt > 2.5 mbar/min.The authors gratefully acknowledge financial support provided by TCUE 2015- 2017 cofounded by European Regional Development Fond (ERDF) and Junta de Castilla y León and the inestimable collaboration of Campofrio Frescos and Ecoalia

Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells

Breast cancer is the second leading cause of cancer-related death among women. Here we report a role for the protein kinase p38α in coordinating the DNA damage response and limiting chromosome instability during breast tumor progression, and identify the DNA repair regulator CtIP as a p38α substrate. Accordingly, decreased p38α signaling results in impaired ATR activation and homologous recombination repair, with concomitant increases in replication stress, DNA damage, and chromosome instability, leading to cancer cell death and tumor regression. Moreover, we show that pharmacological inhibition of p38α potentiates the effects of taxanes by boosting chromosome instability in murine models and patient-derived xenografts, suggesting the potential interest of combining p38α inhibitors with chemotherapeutic drugs that induce chromosome instability

Inhibition of p38 MAPK in the brain through nasal administration of p38 inhibitor loaded in chitosan nanocapsules

[Aim]: To determine whether a p38 MAPK inhibitor incorporated into nanoemulsion-based chitosan nanocapsules can reduce the activity of this kinase in the brain through their nasal administration in mice.[Materials & methods]: We selected the p38 MAPK inhibitor PH797804, an ATP-competitive inhibitor of p38α encapsulated in nanoemulsion-based chitosan nanocapsules. Biological effect was evaluated in microglial and neuronal cells in vitro and in ex vivo and in vivo systems, in a mouse model of Alzheimer’s disease.[Results]: Encapsulated inhibitor retains enzymatic inhibitory activity and tissue penetration capacity in vitro, ex vivo and in vivo.[Conclusion]: Nasal administration of chitosan nanocapsules can be an effective approach for brain-restricted reduction of p38 MAPK activity, thus reducing the side effects of systemic administration.Peer reviewe

Exploratory Longitudinal Study of Ocular Structural and Visual Functional Changes in Subjects at High Genetic Risk of Developing Alzheimer’s Disease

This article belongs to the Special Issue Neurodegenerative Diseases: Recent Advances and Future Perspectives. Received: 19 June 2023 ; Revised: 6 July 2023 ; Accepted: 12 July 2023 ; Published: 18 July 2023This study aimed to analyze the evolution of visual changes in cognitively healthy individuals at risk for Alzheimer’s disease (AD). Participants with a first-degree family history of AD (FH+) and carrying the Ε4+ allele for the ApoE gene (ApoE ε4+) underwent retinal thickness analysis using optical coherence tomography (OCT) and visual function assessments, including visual acuity (VA), contrast sensitivity (CS), color perception, perception digital tests, and visual field analysis. Structural analysis divided participants into FH+ ApoE ε4+ and FH− ApoE ε4− groups, while functional analysis further categorized them by age (40–60 years and over 60 years). Over the 27-month follow-up, the FH+ ApoE ε4+ group exhibited thickness changes in all inner retinal layers. Comparing this group to the FH− ApoE ε4− group at 27 months revealed progressing changes in the inner nuclear layer. In the FH+ ApoE ε4+ 40–60 years group, no progression of visual function changes was observed, but an increase in VA and CS was maintained at 3 and 12 cycles per degree, respectively, compared to the group without AD risk at 27 months. In conclusion, cognitively healthy individuals at risk for AD demonstrated progressive retinal structural changes over the 27-month follow-up, while functional changes remained stable.Ministerio de Economía y Competitividad (España)Instituto de Salud Carlos III (España)Ministerio de Ciencia e Innovación (España)Ministerio de Economía (España)Universidad Complutense de MadridUnidad Docente de Inmunología, Oftalmología y ORLDepto. de Inmunología, Oftalmología y ORLDepto. de MedicinaDepto. de Psicología Experimental, Procesos Cognitivos y LogopediaFac. de Óptica y OptometríaFac. de MedicinaTRUEpu