Physics-informed neural networks for transformed geometries and manifolds

Physics-informed neural networks (PINNs) effectively embed physical principles into machine learning, but often struggle with complex or alternating geometries. We propose a novel method for integrating geometric transformations within PINNs to robustly accommodate geometric variations. Our method incorporates a diffeomorphism as a mapping of a reference domain and adapts the derivative computation of the physics-informed loss function. This generalizes the applicability of PINNs not only to smoothly deformed domains, but also to lower-dimensional manifolds and allows for direct shape optimization while training the network. We demonstrate the effectivity of our approach on several problems: (i) Eikonal equation on Archimedean spiral, (ii) Poisson problem on surface manifold, (iii) Incompressible Stokes flow in deformed tube, and (iv) Shape optimization with Laplace operator. Through these examples, we demonstrate the enhanced flexibility over traditional PINNs, especially under geometric variations. The proposed framework presents an outlook for training deep neural operators over parametrized geometries, paving the way for advanced modeling with PDEs on complex geometries in science and engineering

Flow in Porous Media with Fractures of Varying Aperture

We study single-phase flow in a fractured porous medium at a macroscopic scale that allows to model fractures individually. The flow is governed by Darcy's law in both fractures and porous matrix. We derive a new mixed-dimensional model, where fractures are represented by $(n-1)$-dimensional interfaces between $n$-dimensional subdomains for $n\ge 2$. In particular, we suggest a generalization of the model in [22] by accounting for asymmetric fractures with spatially varying aperture. Thus, the new model is particularly convenient for the description of surface roughness or for modeling curvilinear or winding fractures. The wellposedness of the new model is proven under appropriate conditions. Further, we formulate a discontinuous Galerkin discretization of the new model and validate the model by performing two- and three-dimensional numerical experiments

Variants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration

Reduced Basal Autophagy and Impaired Mitochondrial Dynamics Due to Loss of Parkinson's Disease-Associated Protein DJ-1

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease

Infeccions urinàries en mascotes i bacteris multiresistents : estat de la qüestió a Espanya

Molts dels bacteris que causen infecció del tracte urinari (ITU) en persones i animals de companyia ofereixen resistència a un o varis antibiòtics, fet que suposa un repte per a la medicina veterinària i un problema de salut pública. Per orientar els veterinaris en l'ús més apropiat d'antibiòtics, un estudi liderat per investigadores del Departament de Sanitat i Anatomia Animal de la UAB ha actualitzat les dades sobre els bacteris multiresistents detectats en gossos i gats amb ITU a Espanya. Les autores donen suport a les pautes de tractament aplicades avui dia, tot i que reservant els antibiòtics d'ús crític en humans només per al tractament dels casos més greus, i recomanen extremar pràctiques d'higiene i prevenció per minimitzar la transmissió bacteriana entre mascotes i humans.Muchas de las bacterias que causan infección del tracto urinario (ITU) en personas y animales de compañía ofrecen resistencia a uno o varios antibióticos, lo que supone un reto para la medicina veterinaria y un problema de salud pública. Para orientar a los veterinarios en el uso más apropiado de antibióticos, un estudio liderado por investigadoras del Departamento de Sanidad y Anatomía Animal de la UAB ha actualizado los datos sobre las bacterias multirresistentes detectadas en perros y gatos con ITU en España. Las autoras apoyan las pautas de tratamiento aplicadas hoy día, aunque reservando los antibióticos de uso crítico en humanos sólo para el tratamiento de los casos más graves, y recomiendan extremar prácticas de higiene y prevención para minimizar la transmisión bacteriana entre mascotas y humanos

Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD

Aldehyde dehydrogenase 2 in the spotlight: The link between mitochondria and neurodegeneration

Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity.Fil: Deza Ponzio, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Herrera, Macarena Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Bellini, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Virgolini, Miriam Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentin

DJ-1 Null Dopaminergic Neuronal Cells Exhibit Defects in Mitochondrial Function and Structure: Involvement of Mitochondrial Complex I Assembly

DJ-1 is a Parkinson's disease-associated gene whose protein product has a protective role in cellular homeostasis by removing cytosolic reactive oxygen species and maintaining mitochondrial function. However, it is not clear how DJ-1 regulates mitochondrial function and why mitochondrial dysfunction is induced by DJ-1 deficiency. In a previous study we showed that DJ-1 null dopaminergic neuronal cells exhibit defective mitochondrial respiratory chain complex I activity. In the present article we investigated the role of DJ-1 in complex I formation by using blue native-polyacrylamide gel electrophoresis and 2-dimensional gel analysis to assess native complex status. On the basis of these experiments, we concluded that DJ-1 null cells have a defect in the assembly of complex I. Concomitant with abnormal complex I formation, DJ-1 null cells show defective supercomplex formation. It is known that aberrant formation of the supercomplex impairs the flow of electrons through the channels between respiratory chain complexes, resulting in mitochondrial dysfunction. We took two approaches to study these mitochondrial defects. The first approach assessed the structural defect by using both confocal microscopy with MitoTracker staining and electron microscopy. The second approach assessed the functional defect by measuring ATP production, O2 consumption, and mitochondrial membrane potential. Finally, we showed that the assembly defect as well as the structural and functional abnormalities in DJ-1 null cells could be reversed by adenovirus-mediated overexpression of DJ-1, demonstrating the specificity of DJ-1 on these mitochondrial properties. These mitochondrial defects induced by DJ-1mutation may be a pathological mechanism for the degeneration of dopaminergic neurons in Parkinson's disease