The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment

ModelFLOWs-app: data-driven post-processing and reduced order modelling tools

This article presents an innovative open-source software named ModelFLOWs-app, written in Python, which has been created and tested to generate precise and robust hybrid reduced order models (ROMs) fully data-driven. By integrating modal decomposition and deep learning methods in diverse ways, the software uncovers the fundamental patterns in dynamic systems. This acquired knowledge is then employed to enrich the comprehension of the underlying physics, reconstruct databases from limited measurements, and forecast the progression of system dynamics. These hybrid models combine experimental and numerical database, and serve as accurate alternatives to numerical simulations, effectively diminishing computational expenses, and also as tools for optimization and control. The ModelFLOWs-app software has demonstrated in a wide range of applications its great capability to develop reliable data-driven hybrid ROMs, highlighting its potential in understanding complex non-linear dynamical systems and offering valuable insights into various applications. This article presents the mathematical background, review some examples of applications and introduces a short tutorial of ModelFLOWs-app

Premiers résultats concernant le site des Jardins de Saint-Benoît (Saint-Laurent-de-la-Cabrerisse, Aude), pôle religieux et funéraire des Corbières

Un projet immobilier est à l’origine de la découverte et de la fouille du site des Jardins de Saint-Benoît à Saint-Laurent-de-la-Cabrerisse (Aude). Il a livré un vaste cimetière, enserrant les vestiges d’une église à chevet plat. Les sépultures étudiées, de formes et d’architectures variées, témoignent de la longue durée de fonctionnement du pôle funéraire. En effet, celui-ci semble apparaître avant la fin du VIIIe siècle et perdurer jusqu’au bas Moyen Âge, période durant laquelle l’église est presque entièrement démantelée et le cimetière abandonné. La genèse du site souffre de nombreuses lacunes documentaires. Bien qu’il soit fait mention d’une fondation monastique sur le territoire de la commune (Sancti Laurentii), le bâtiment mis au jour pourrait également correspondre à l’église Saint-Benoît ou à un autre édifice cultuel, dont aucune mention ne nous serait parvenue. De même, ses modalités d’abandon demeurent incertaines. On peut toutefois évoquer le rôle éventuel de l’épidémie de peste noire de la seconde moitié du XIVe siècle, qui est la cause attestée du décès de plusieurs individus

A new methodology to estimate the steady-state permeability of roast and ground coffee in packed beds

AbstractIn an espresso-style extraction hot water (90±5°C) is driven through a coffee packed bed by a pressure gradient to extract soluble material from the coffee matrix. Permeability is a key parameter affecting extraction as it determines the flow rate through the bed and hence brewing and residence time. This may alter bed-to-cup mass transfer and therefore impact brew quality.In this work a methodology that will allow estimation of the permeability of coffee packed beds in steady-state was developed. Fitting measured flow rate – pressure drop data to Darcy’s law resulted in permeability values in the range of 10−13–10−14m2. Disagreement between the experimental and theoretical permeability, as estimated from dry measurements of particle size distribution and Kozeny–Carman equation, was found. Bed consolidation may have a larger effect on the packing structure than the mere decrease in bed bulk porosity. The Kozeny–Carman equation, corrected with a porosity-dependent tortuosity according to a power law, gave a good fit of the data

Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Acknowledgements We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016. Conflict of Interest statement. None declared. Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.Peer reviewedPublisher PD

A Ras GTPase associated protein is involved in the phototropic and circadian photobiology responses in fungi

[EN] Light is an environmental signal perceived by most eukaryotic organisms and that can have major impacts on their growth and development. The MadC protein in the fungus Phycomyces blakesleeanus (Mucoromycotina) has been postulated to form part of the photosensory input for phototropism of the fruiting body sporangiophores, but the madC gene has remained unidentified since the 1960s when madC mutants were first isolated. In this study the madC gene was identified by positional cloning. All madC mutant strains contain loss-of-function point mutations within a gene predicted to encode a GTPase activating protein (GAP) for Ras. The madC gene complements the Saccharomyces cerevisiae Ras-GAP ira1 mutant and the encoded MadC protein interacts with P. blakesleeanus Ras homologs in yeast two-hybrid assays, indicating that MadC is a regulator of Ras signaling. Deletion of the homolog in the filamentous ascomycete Neurospora crassa affects the circadian clock output, yielding a pattern of asexual conidiation similar to a ras-1 mutant that is used in circadian studies in N. crassa. Thus, MadC is unlikely to be a photosensor, yet is a fundamental link in the photoresponses from blue light perceived by the conserved White Collar complex with Ras signaling in two distantly-related filamentous fungal species

Uses for humanised mouse models in precision medicine for neurodegenerative disease

Neurodegenerative disease encompasses a wide range of disorders afflicting the central and peripheral nervous systems and is a major unmet biomedical need of our time. There are very limited treatments, and no cures, for most of these diseases, including Alzheimer’s Disease, Parkinson's Disease, Huntington Disease, and Motor Neuron Diseases. Mouse and other animal models provide hope by analysing them to understand pathogenic mechanisms, to identify drug targets, and to develop gene therapies and stem cell therapies. However, despite many decades of research, virtually no new treatments have reached the clinic. Increasingly, it is apparent that human heterogeneity within clinically defined neurodegenerative disorders, and between patients with the same genetic mutations, significantly impacts disease presentation and, potentially, therapeutic efficacy. Therefore, stratifying patients according to genetics, lifestyle, disease presentation, ethnicity, and other parameters may hold the key to bringing effective therapies from the bench to the clinic. Here, we discuss genetic and cellular humanised mouse models, and how they help in defining the genetic and environmental parameters associated with neurodegenerative disease, and so help in developing effective precision medicine strategies for future healthcare

Characterization of the Temperature-Sensitive Mutations un-7 and png-1 in Neurospora crassa

The model filamentous fungus Neurospora crassa has been studied for over fifty years and many temperature-sensitive mutants have been generated. While most of these have been mapped genetically, many remain anonymous. The mutation in the N. crassa temperature-sensitive lethal mutant un-7 was identified by a complementation based approach as being in the open reading frame designated NCU00651 on linkage group I. Other mutations in this gene have been identified that lead to a temperature-sensitive morphological phenotype called png-1. The mutations underlying un-7 result in a serine to phenylalanine change at position 273 and an isoleucine to valine change at position 390, while the mutation in png-1 was found to result in a serine to leucine change at position 279 although there were other conservative changes in this allele. The overall morphology of the strain carrying the un-7 mutation is compared to strains carrying the png-1 mutation and these mutations are evaluated in the context of other temperature-sensitive mutants in Neurospora

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues, given the link between ALS-frontotemporal dementia and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations