CFTR corrector C17 is effective in muscular dystrophy, in vivo proof of concept in LGMDR3.

Limb-girdle muscular dystrophy R3 (LGMDR3) is caused by mutations in the SGCA gene coding for α-sarcoglycan (SG). Together with β- γ- and δ-SG, α-SG forms a tetramer embedded in the dystrophin associated protein complex crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded, even though potentially functional α-SG.

Effects of Mild Excitotoxic Stimulus on Mitochondria Ca Handling in Hippocampal Cultures of a Mouse Model of Alzheimer's Disease.

In Alzheimer's disease (AD), the molecular mechanisms involved in the neurodegeneration are still incompletely defined, though this aspect is crucial for a better understanding of the malady and for devising effective therapies. Mitochondrial dysfunctions and altered Ca signaling have long been implicated in AD, though it is debated whether these events occur early in the course of the pathology, or whether they develop at late stages of the disease and represent consequences of different alterations. Mitochondria are central to many aspects of cellular metabolism providing energy, lipids, reactive oxygen species, signaling molecules for cellular quality control, and actively shaping intracellular Ca signaling, modulating the intensity and duration of the signal itself.

Common and unique structural plasticity after left and right hemisphere stroke.

Strokes to the left and right hemisphere lead to distinctive behavioral profiles. Are left and right hemisphere strokes (LHS and RHS) associated with distinct or common poststroke neuroplasticity patterns? Understanding this issue would reveal hemispheric neuroplasticity mechanisms in response to brain damage. To this end, we investigated poststroke structural changes (2 weeks to 3 months post-onset) using longitudinal MRI data from 69 LHS and 55 RHS patients and 31 demographic-matched healthy control participants.

PERM1 interacts with the MICOS-MIB complex to connect the mitochondria and sarcolemma via ankyrin B.

Skeletal muscle subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria subpopulations have distinct metabolic activity and sensitivity, though the mechanisms that localize SSM to peripheral areas of muscle fibers are poorly understood. A protein interaction study and complexome profiling identifies PERM1 interacts with the MICOS-MIB complex. Ablation of Perm1 in mice reduces muscle force, decreases mitochondrial membrane potential and complex I activity, and reduces the numbers of SSM in skeletal muscle.

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging.

Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a 'rewired' metabolic circuitry has been shown to accelerate or delay biological aging.

Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration.

Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms.

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease.

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets).

The secret life of predictive brains: what's spontaneous activity for?

Brains at rest generate dynamical activity that is highly structured in space and time. We suggest that spontaneous activity, as in rest or dreaming, underlies top-down dynamics of generative models. During active tasks, generative models provide top-down predictive signals for perception, cognition, and action.

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to microbial infections, cellular stress, and tissue damage, yet failure to control this mechanism can lead to autoimmune diseases. Several monogenic and multifactorial autoimmune diseases have been associated with type-I interferons and interferon-stimulated genes (ISGs) induced by deregulated recognition of self-DNA.

MYOD modified mRNA drives direct on-chip programming of human pluripotent stem cells into skeletal myocytes.

Drug screening and disease modelling for skeletal muscle related pathologies would strongly benefit from the integration of myogenic cells derived from human pluripotent stem cells within miniaturized cell culture devices, such as microfluidic platform. Here, we identified the optimal culture conditions that allow direct differentiation of human pluripotent stem cells in myogenic cells within microfluidic devices. Myogenic cells are efficiently derived from both human embryonic (hESC) or induced pluripotent stem cells (hiPSC) in eleven days by combining small molecules and non-integrating modified mRNA (mmRNA) encoding for the master myogenic transcription factor MYOD.

Covalent functionalization of decellularized tissues accelerates endothelialization.

In the field of tissue regeneration, the lack of a stable endothelial lining may affect the hemocompatibility of both synthetic and biological replacements. These drawbacks might be prevented by specific biomaterial functionalization to induce selective endothelial cell (EC) adhesion. Decellularized bovine pericardia and porcine aortas were selectively functionalized with a REDV tetrapeptide at 10 M and 10 M working concentrations.

Estrogen Receptor Functions and Pathways at the Vascular Immune Interface.

Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of the MAP kinase signaling cascade. Membrane localizations of ERs are generally associated with rapid, non-genomic effects while nuclear localizations are associated with nuclear activities/transcriptional modulation of target genes.

NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.

Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3.

Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans.

Key Points: Few days of unloading are sufficient to induce a decline of skeletal muscle mass and function; notably, contractile force is lost at a faster rate than muscle mass. The reasons behind this disproportionate loss of muscle force are still poorly understood. We provide strong evidence of two mechanisms only hypothesized until now for the rapid muscle force loss in only 10 days of bed rest.

Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction.

Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking. Defective complex III is associated with a highly variable clinical spectrum. We show that pyocyanin, a bacterial redox cycler, can replace the redox functions of complex III, acting as an electron shunt.

Temporal modes of hub synchronization at rest.

The brain is a dynamic system that generates a broad repertoire of perceptual, motor, and cognitive states by the integration and segregation of different functional domains represented in large-scale brain networks. However, the fundamental mechanisms underlying brain network integration remain elusive. Here, for the first time to our knowledge, we found that in the resting state the brain visits few synchronization modes defined as clusters of temporally aligned functional hubs.

Clinical efficacy and safety of angiogenesis inhibitors: sex differences and current challenges.

Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects.

Identification of highest neurotoxic amyloid-β plaque type showing reduced contact with astrocytes.

Amyloid-β (Aβ) plaques are strongly associated with the development of Alzheimer's disease (AD). However, it remains unclear how morphological differences in Aβ plaques determine the pathogenesis of Aβ. Here, we categorized Aβ plaques into four types based on the macroscopic features of the dense core, and found that the Aβ-plaque subtype containing a larger dense core showed the strongest association with neuritic dystrophy.

Live Mitochondrial or Cytosolic Calcium Imaging Using Genetically-encoded Cameleon Indicator in Mammalian Cells.

Calcium (Ca) imaging aims at investigating the dynamic changes in live cells of its concentration ([Ca]) in different pathophysiological conditions. Ca is an ubiquitous and versatile intracellular signal that modulates a large variety of cellular functions thanks to a cell type-specific toolkit and a complex subcellular compartmentalization. Many Ca sensors are presently available (chemical and genetically encoded) that can be specifically targeted to different cellular compartments.

FGF21: a promising therapeutic agent for alcoholic cardiomyopathy?.

The metabolic regulator fibroblast growth factor 21 (FGF21) has been reported as a cardioprotective factor regulating cardiac remodeling in several cardiac diseases. In a recent issue of The Journal of Pathology, Ferrer-Curriu, Guitart-Mampel et al investigated FGF21 in alcoholic cardiomyopathy (ACM). They showed that FGF21 deficiency aggravates alcohol-induced cardiac damage and dysfunction by exacerbating mitochondrial alterations, oxidative stress, and lipid metabolic dysregulation, suggesting FGF21 as a promising therapeutic agent in ACM.