Multicomponent flow on curved surfaces: A vielbein lattice Boltzmann approach

We develop and implement a novel finite difference lattice Boltzmann scheme to study multicomponent flows on curved surfaces, coupling the continuity and Navier-Stokes equations with the Cahn-Hilliard equation to track the evolution of the binary fluid interfaces. The standard lattice Boltzmann method relies on regular Cartesian grids, which makes it generally unsuitable to study flow problems on curved surfaces. To alleviate this limitation, we use a vielbein formalism to write down the Boltzmann equation on an arbitrary geometry, and solve the evolution of the fluid distribution functions using a finite difference method. Focussing on the torus geometry as an example of a curved surface, we demonstrate drift motions of fluid droplets and stripes embedded on the surface of such geometries. Interestingly, they migrate in opposite directions: fluid droplets to the outer side while fluid stripes to the inner side of the torus. For the latter we demonstrate that the global minimum configuration is unique for small stripe widths, but it becomes bistable for large stripe widths. Our simulations are also in agreement with analytical predictions for the Laplace pressure of the fluid stripes, and their damped oscillatory motion as they approach equilibrium configurations, capturing the corresponding decay timescale and oscillation frequency. Finally, we simulate the coarsening dynamics of phase separating binary fluids in the hydrodynamics and diffusive regimes for tori of various shapes, and compare the results against those for a flat two-dimensional surface. Our finite difference lattice Boltzmann scheme can be extended to other surfaces and coupled to other dynamical equations, opening up a vast range of applications involving complex flows on curved geometries

Multicomponent flow on curved surfaces : A vielbein lattice Boltzmann approach

We develop and implement a novel finite difference lattice Boltzmann scheme to study multicomponent flows on curved surfaces, coupling the continuity and Navier-Stokes equations with the Cahn-Hilliard equation to track the evolution of the binary fluid interfaces. The standard lattice Boltzmann method relies on regular Cartesian grids, which makes it generally unsuitable to study flow problems on curved surfaces. To alleviate this limitation, we use a vielbein formalism to write down the Boltzmann equation on an arbitrary geometry, and solve the evolution of the fluid distribution functions using a finite difference method. Focussing on the torus geometry as an example of a curved surface, we demonstrate drift motions of fluid droplets and stripes embedded on the surface of such geometries. Interestingly, they migrate in opposite directions: fluid droplets to the outer side while fluid stripes to the inner side of the torus. For the latter we demonstrate that the global minimum configuration is unique for small stripe widths, but it becomes bistable for large stripe widths. Our simulations are also in agreement with analytical predictions for the Laplace pressure of the fluid stripes, and their damped oscillatory motion as they approach equilibrium configurations, capturing the corresponding decay timescale and oscillation frequency. Finally, we simulate the coarsening dynamics of phase separating binary fluids in the hydrodynamics and diffusive regimes for tori of various shapes, and compare the results against those for a flat two-dimensional surface. Our finite difference lattice Boltzmann scheme can be extended to other surfaces and coupled to other dynamical equations, opening up a vast range of applications involving complex flows on curved geometries

Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and “tether” regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca2+from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed

Short-lived AUF1 p42-binding mRNAs of RANKL and BCL6 have two distinct instability elements each.

Regulation of mRNA stability by RNA-protein interactions contributes significantly to quantitative aspects of gene expression. We have identified potential mRNA targets of the AU-rich element binding protein AUF1. Myc-tagged AUF1 p42 was induced in mouse NIH/3T3 cells and RNA-protein complexes isolated using anti-myc tag antibody beads. Bound mRNAs were analyzed with Affymetrix microarrays. We have identified 508 potential target mRNAs that were at least 3-fold enriched compared to control cells without myc-AUF1. 22.3% of the enriched mRNAs had an AU-rich cluster in the ARED Organism database, against 16.3% of non-enriched control mRNAs. The enrichment towards AU-rich elements was also visible by AREScore with an average value of 5.2 in the enriched mRNAs versus 4.2 in the control group. Yet, numerous mRNAs were enriched without a high ARE score. The enrichment of tetrameric and pentameric sequences suggests a broad AUF1 p42-binding spectrum at short U-rich sequences flanked by A or G. Still, some enriched mRNAs were highly unstable, as those of TNFSF11 (known as RANKL), KLF10, HES1, CCNT2, SMAD6, and BCL6. We have mapped some of the instability determinants. HES1 mRNA appeared to have a coding region determinant. Detailed analysis of the RANKL and BCL6 3'UTR revealed for both that full instability required two elements, which are conserved in evolution. In RANKL mRNA both elements are AU-rich and separated by 30 bases, while in BCL6 mRNA one is AU-rich and 60 bases from a non AU-rich element that potentially forms a stem-loop structure

Poisson-Boltzmann for oppositely charged bodies: an explicit derivation

The interaction between charged bodies in an ionic solution is a general problem in colloid physics and becomes a central topic in the study of biological systems where the electrostatic interaction between proteins, nucleic acids, membranes is involved. This problem is often described starting from the simple one-dimensional model of two parallel charged plates. Several different approaches to this problem exist, focusing on different features. In many cases, an intuitive expression of the pressure exerted on the plates is proposed, which includes an electrostatic plus an osmotic contribution. We present an explicit and self-consistent derivation of this formula for the general case of any charge densities on the plates and any salt solution, obtained in the framework of the Poisson-Boltzmann theory. We also show that, depending on external constraints, the correct thermodynamic potential can differ from the usual PB free energy. The resulting expression predicts, for asymmetric, oppositely charged plates, the existence of a non trivial equilibrium position with the plates separated by a finite distance. It is therefore crucial, in order to study the kinetic stability of the corresponding energy minimum, to obtain its explicit dependence on the plates charge densities and on the ion concentration. An analytic expression for the position and value of the corresponding energy minimum has been derived in 1975 by Ohshima [Ohshima H., Colloid and Polymer Sci. 253, 150-157 (1975)] but, surprisingly, this important result seems to be overlooked today. We retrieve the expressions obtained by Ohshima in a simpler formalism, more familiar to the physics community, and give a physical interpretation of the observed behavior.Comment: 11 pages, 7 figures, submitted to Molecular Physic

ALS/FTD‐associated FUS activates GSK‐3β to disrupt the VAPB–PTPIP51 interaction and ER–mitochondria associations

Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD

Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects

This is the final version. Available on open access from BMC via the DOI in this recordData availability: The datasets used and/or analysed during the current study are available from the corresponding authors on reasonable request.Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.Medical Research Council (MRC)Alzheimer’s Disease SocietyAlzheimer’s Research U

A single cell high content assay detects mitochondrial dysfunction in iPSC-derived neurons with mutations in SNCA

Mitochondrial dysfunction is implicated in many neurodegenerative diseases including Parkinson's disease (PD). Induced pluripotent stem cells (iPSCs) provide a unique cell model for studying neurological diseases. We have established a high-content assay that can simultaneously measure mitochondrial function, morphology and cell viability in iPSC-derived dopaminergic neurons. iPSCs from PD patients with mutations in SNCA and unaffected controls were differentiated into dopaminergic neurons, seeded in 384-well plates and stained with the mitochondrial membrane potential dependent dye TMRM, alongside Hoechst-33342 and Calcein-AM. Images were acquired using an automated confocal screening microscope and single cells were analysed using automated image analysis software. PD neurons displayed reduced mitochondrial membrane potential and altered mitochondrial morphology compared to control neurons. This assay demonstrates that high content screening techniques can be applied to the analysis of mitochondria in iPSC-derived neurons. This technique could form part of a drug discovery platform to test potential new therapeutics for PD and other neurodegenerative diseases

The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are mediated by “tethering proteins” that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-associated protein B (VAPB) and the mitochondrial membrane protein, protein tyrosine phosphatase interacting protein-51 (PTPIP51), interact to form one such tether. Recently, damage to ER-mitochondria signaling involving disruption of the VAPB-PTPIP51 tethers has been linked to the pathogenic process in Parkinson’s disease, fronto-temporal dementia (FTD) and related amyotrophic lateral sclerosis (ALS). Loss of neuronal synaptic function is a key feature of Parkinson’s disease and FTD/ALS but the roles that ER-mitochondria signaling and the VAPB-PTPIP51 tethers play in synaptic function are not known. Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. Moreover, siRNA loss of VAPB or PTPIP51 perturbs synaptic function and dendritic spine morphology. Our results reveal a new role for the VAPB-PTPIP51 tethers in neurons and suggest that damage to ER-mitochondria signaling contributes to synaptic dysfunction in Parkinson’s disease and FTD/ALS

Surgery and COVID-19: Balancing the nosocomial risk a french academic center experience during the epidemic peak

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