Building a modular and multi-cellular virtual twin of the synovial joint in Rheumatoid Arthritis.

Rheumatoid arthritis is a complex disease marked by joint pain, stiffness, swelling, and chronic synovitis, arising from the dysregulated interaction between synoviocytes and immune cells. Its unclear etiology makes finding a cure challenging. The concept of digital twins, used in engineering, can be applied to healthcare to improve diagnosis and treatment for complex diseases like rheumatoid arthritis.

A simplified method for theoretical sum frequency generation spectroscopy calculation and interpretation: The "pop model".

Existing methods to compute theoretical spectra are restricted to the use of time-correlation functions evaluated from accurate atomistic molecular dynamics simulations, often at the ab initio level. The molecular interpretation of the computed spectra requires additional steps to deconvolve the spectroscopic contributions from local water and surface structural populations at the interface. The lack of a standard procedure to do this often hampers rationalization.

Predictive power of deleterious single amino acid changes to infer on AAV2 and AAV2-13 capsids fitness.

Adeno-associated virus (AAV) is the most widely used vector for gene transfer. A major limitation of capsid engineering is the incomplete understanding of the consequences of multiple amino acid variations on AAV capsid stability resulting in high frequency of non-viable capsids. In this context, the study of natural AAV variants can provide valuable insights into capsid regions that exhibit greater tolerance to mutations.

Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.

Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins.

Large-scale computational modelling of the M1 and M2 synovial macrophages in rheumatoid arthritis.

Macrophages play an essential role in rheumatoid arthritis. Depending on their phenotype (M1 or M2), they can play a role in the initiation or resolution of inflammation. The M1/M2 ratio in rheumatoid arthritis is higher than in healthy controls.

Rapid correction of hyperglycemia: A necessity but at what price? A brief report of a patient living with type 1 diabetes.

Background: The correction and control of chronic hyperglycemia are the management goals of patients living with diabetes. Chronic hyperglycemia is the main factor inducing diabetes-related complications. However, in certain situations, the rapid and intense correction of chronic hyperglycemia can paradoxically favor the onset of microvascular complications.

FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage.

PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an RNA-binding protein, is specifically directed to PAR through its RNA recognition motif (RRM) to increase PAR synthesis by PARP-1 in HeLa cells after genotoxic stress. Using a structural approach, we also identify specific residues located in the FUS RRM, which can be PARylated by PARP-1 to control the level of PAR synthesis.

A guide for developing comprehensive systems biology maps of disease mechanisms: planning, construction and maintenance.

As a conceptual model of disease mechanisms, a disease map integrates available knowledge and is applied for data interpretation, predictions and hypothesis generation. It is possible to model disease mechanisms on different levels of granularity and adjust the approach to the goals of a particular project. This rich environment together with requirements for high-quality network reconstruction makes it challenging for new curators and groups to be quickly introduced to the development methods.

Evaluation of diversity indices to estimate clonal dominance in gene therapy studies.

In cell and gene therapy, achieving the stable engraftment of an abundant and highly polyclonal population of gene-corrected cells is one of the key factors to ensure the successful and safe treatment of patients. Because integrative vectors have been associated with possible risks of insertional mutagenesis leading to clonal dominance, monitoring the relative abundance of individual vector insertion sites in patients' blood cells has become an important safety assessment, particularly in hematopoietic stem cell-based therapies. Clinical studies often express clonal diversity using various metrics.

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.

Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients.

Algorithmic Graph Theory, Reinforcement Learning and Game Theory in MD Simulations: From 3D Structures to Topological 2D-Molecular Graphs (2D-MolGraphs) and Vice Versa.

This paper reviews graph-theory-based methods that were recently developed in our group for post-processing molecular dynamics trajectories. We show that the use of algorithmic graph theory not only provides a direct and fast methodology to identify conformers sampled over time but also allows to follow the interconversions between the conformers through graphs of transitions in time. Examples of gas phase molecules and inhomogeneous aqueous solid interfaces are presented to demonstrate the power of topological 2D graphs and their versatility for post-processing molecular dynamics trajectories.

Efficacy, pharmacokinetics, and safety in the mouse and primate retina of dual AAV vectors for Usher syndrome type 1B.

Gene therapy of Usher syndrome type 1B (USH1B) due to mutations in the large () gene is limited by the packaging capacity of adeno-associated viral (AAV) vectors. To overcome this, we have previously developed dual AAV8 vectors which encode human (dual AAV8.).

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders.

Lessons learned from decades-long practice in the transplantation of hematopoietic stem and progenitor cells (HSPCs) to treat severe inherited disorders or cancer, have set the stage for the current gene therapies using autologous gene-modified hematopoietic stem and progenitor cells that have treated so far, hundreds of patients with monogenic disorders. With increased knowledge of hematopoietic stem and progenitor cell biology, improved modalities for patient conditioning and with the emergence of new gene editing technologies, a new era of hematopoietic stem and progenitor cell-based gene therapies is poised to emerge. Gene editing has the potential to restore physiological expression of a mutated gene, or to insert a functional gene in a precise locus with reduced off-target activity and toxicity.

A Flashforward Look into Solutions for Fruit and Vegetable Production.

One of the most important challenges facing current and future generations is how climate change and continuous population growth adversely affect food security. To address this, the food system needs a complete transformation where more is produced in non-optimal and space-limited areas while reducing negative environmental impacts. Fruits and vegetables, essential for human health, are high-value-added crops, which are grown in both greenhouses and open field environments.

Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities.

Obligate sexual reproduction of a homothallic fungus closely related to the pathogenic species complex.

. Fungi are enigmatic organisms that flourish in soil, on decaying plants, or during infection of animals or plants. Growing in myriad forms, from single-celled yeast to multicellular molds and mushrooms, fungi have also evolved a variety of strategies to reproduce.

Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome.

A common feature of diverse brain disorders is the alteration of GABA-mediated inhibition because of aberrant, intracellular chloride homeostasis induced by changes in the expression and/or function of chloride transporters. Notably, pharmacological inhibition of the chloride importer NKCC1 is able to rescue brain-related core deficits in animal models of these pathologies and in some human clinical studies. Here, we show that reducing NKCC1 expression by RNA interference in the Ts65Dn mouse model of Down syndrome (DS) restores intracellular chloride concentration, efficacy of gamma-aminobutyric acid (GABA)-mediated inhibition, and neuronal network dynamics in vitro and ex vivo.

Validity of Hololens Augmented Reality Head Mounted Display for Measuring Gait Parameters in Healthy Adults and Children with Cerebral Palsy.

Serious games are a promising approach to improve gait rehabilitation for people with gait disorders. Combined with wearable augmented reality headset, serious games for gait rehabilitation in a clinical setting can be envisaged, allowing to evolve in a real environment and provide fun and feedback to enhance patient's motivation. This requires a method to obtain accurate information on the spatiotemporal gait parameters of the playing patient.

The Carbon Footprint of Marathon Runners: Training and Racing.

Unlabelled: Marathon running leaves a significant carbon footprint regarding CO emissions; for example, 37 percent of New York Marathon participants travel internationally to New York. The aim of this study is to estimate the CO footprint of a person training and competing in a marathon; we will also propose methods to minimize the CO footprint because of transportation. In addition, we also examine the influence of food practices and hygiene on training and racing a marathon.

Correction of β-thalassemia by CRISPR/Cas9 editing of the α-globin locus in human hematopoietic stem cells.

β-thalassemias (β-thal) are a group of blood disorders caused by mutations in the β-globin gene (HBB) cluster. β-globin associates with α-globin to form adult hemoglobin (HbA, α2β2), the main oxygen-carrier in erythrocytes. When β-globin chains are absent or limiting, free α-globins precipitate and damage cell membranes, causing hemolysis and ineffective erythropoiesis.

Chromatin phosphoproteomics unravels a function for AT-hook motif nuclear localized protein AHL13 in PAMP-triggered immunity.

In many eukaryotic systems during immune responses, mitogen-activated protein kinases (MAPKs) link cytoplasmic signaling to chromatin events by targeting transcription factors, chromatin remodeling complexes, and the RNA polymerase machinery. So far, knowledge on these events is scarce in plants and no attempts have been made to focus on phosphorylation events of chromatin-associated proteins. Here we carried out chromatin phosphoproteomics upon elicitor-induced activation of The events in WT were compared with those in , , and mutant plants to decipher specific MAPK targets.