RANKL Inhibition Reduces Cardiac Hypertrophy in Mice and Possibly in Children with Duchenne Muscular Dystrophy.

Cardiomyopathy has become one of the leading causes of death in patients with Duchenne muscular dystrophy (DMD). We recently reported that the inhibition of the interaction between the receptor activator of nuclear factor κB ligand (RANKL) and receptor activator of nuclear factor κB (RANK) significantly improves muscle and bone functions in dystrophin-deficient mice. RANKL and RANK are also expressed in cardiac muscle.

Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a multifactorial disorder diagnosed through the assessment of amyloid-beta (Aβ) and tau protein depositions. Filamin A (FLNA) could be a key partner of both Aβ and tau pathological processes and may be an important contributor to AD progression. The main aim of this study was to describe the differences in FLNA levels across clinicopathologic groups.

The inflammatory response, a mixed blessing for muscle homeostasis and plasticity.

Skeletal muscle makes up almost half the body weight of heathy individuals and is involved in several vital functions, including breathing, thermogenesis, metabolism, and locomotion. Skeletal muscle exhibits enormous plasticity with its capacity to adapt to stimuli such as changes in mechanical loading, nutritional interventions, or environmental factors (oxidative stress, inflammation, and endocrine changes). Satellite cells and timely recruited inflammatory cells are key actors in muscle homeostasis, injury, and repair processes.

The Roles of RANK/RANKL/OPG in Cardiac, Skeletal, and Smooth Muscles in Health and Disease.

Although their physiology and functions are very different, bones, skeletal and smooth muscles, as well as the heart have the same embryonic origin. Skeletal muscles and bones interact with each other to enable breathing, kinesis, and the maintenance of posture. Often, muscle and bone tissues degenerate synchronously under various conditions such as cancers, space travel, aging, prolonged bed rest, and neuromuscular diseases.

RALDH Activity Induced by Bacterial/Fungal Pathogens in CD16 Monocyte-Derived Dendritic Cells Boosts HIV Infection and Outgrowth in CD4 T Cells.

HIV reservoirs persist in gut-homing CD4 T cells of people living with HIV and receiving antiretroviral therapy, but the antigenic specificity of such reservoirs remains poorly documented. The imprinting for gut homing is mediated by retinoic acid (RA), a vitamin A-derived metabolite produced by dendritic cells (DCs) exhibiting RA-synthesizing (RALDH) activity. RALDH activity in DCs can be induced by TLR2 ligands, such as bacterial peptidoglycans and fungal zymosan.

Testing the efficacy of a human full-length OPG-Fc analog in a severe model of cardiotoxin-induced skeletal muscle injury and repair.

Although receptor-activator of nuclear factor κB (RANK), its ligand RANKL, and osteoprotegerin (OPG), which are members of the tumor necrosis factor (TNF) superfamily, were first discovered in bone cells, they are also expressed in other cells, including skeletal muscle. We previously showed that the RANK/RANKL/OPG pathway is involved in the physiopathology of Duchenne muscular dystrophy and that a mouse full-length OPG-Fc (mFL-OPG-Fc) treatment is superior to muscle-specific RANK deletion in protecting dystrophic muscles. Although mFL-OPG-Fc has a beneficial effect in the context of muscular dystrophy, the function of human FL-OPG-Fc (hFL-OPG-Fc) during muscle repair is not yet known.

Orthopedist involvement in the management of clinical activities: a case study.

Background: The rapid shift in hospital governance in the past few years suggests greater orthopedist involvement in management roles, would have wide-reaching benefits for the efficiency and effectiveness of healthcare delivery. This paper analyzes the dynamics of orthopedist involvement in the management of clinical activities for three orthopedic care pathways, by examining orthopedists' level of involvement, describing the implications of such involvement, and indicating the main responses of other healthcare workers to such orthopedist involvement.

Methods: We selected four contrasting cases according to their level of governance in a Canadian university hospital center.

Tetrahydrobiopterin Improves Recognition Memory in the Triple-Transgenic Mouse Model of Alzheimer's Disease, Without Altering Amyloid-β and Tau Pathologies.

Background: Alzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized.

Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice.

Bone and muscle are tightly coupled and form a functional unit under normal conditions. The receptor-activator of nuclear factor κB/receptor-activator of nuclear factor κB ligand/osteoprotegerin (RANK/RANKL/OPG) triad plays a crucial role in bone remodeling. RANKL inhibition by OPG prevents osteoporosis.

Detection of S-100β Protein in Plasma and Urine After a Mild Traumatic Brain Injury.

This study assessed whether S-100β protein could be measured in urine when detectable in plasma after a mild traumatic brain injury (mTBI). Clinical data, plasma and urine samples were collected for the 46 adult patients prospectively enrolled in the emergency department (ED) of a Level 1 trauma center. S-100β protein concentrations were analysed using ELISA.

An anti-RANKL treatment reduces muscle inflammation and dysfunction and strengthens bone in dystrophic mice.

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy which leads to progressive muscle degeneration and inflammation. The receptor activator of nuclear factor NF-κB ligand (RANKL) and its receptor (RANK), which are expressed in bone and skeletal and cardiac muscles, form a signaling network upstream from nuclear factor-kappa B (NF-κB). We thus hypothesized that prolonged silencing RANKL/RANK signaling would significantly improve DMD.

Proteomic markers of low and high fertility bovine spermatozoa separated by Percoll gradient.

In the context of artificial insemination, male fertility is defined as the ability to produce functional spermatozoa able to withstand cryopreservation. We hypothesized that interindividual variations in fertility depend on the proportion of the fully functional sperm population contained in the insemination dose. The objective of this study was to identify protein markers of the fully functional sperm subpopulation.

The toxin MPTP generates similar cognitive and locomotor deficits in hTau and tau knock-out mice.

Parkinson's disease (PD) is characterized by motor deficits, although cognitive disturbances are frequent and have been noted early in the disease. The main pathological characteristics of PD are the loss of dopaminergic neurons and the presence of aggregated α-synuclein in Lewy bodies of surviving cells. Studies have also documented the presence of other proteins within Lewy bodies, particularly tau, a microtubule-associated protein implicated in a wide range of neurodegenerative diseases, including Alzheimer's disease (AD).

[Brain insulin signaling and Tau: impact for Alzheimer's disease and Tauopathies].

Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive deficits and neuropathological lesions such as Tau aggregates and amyloid plaques, but also associated with metabolic and neuroendocrine abnormalities, such as impairment of cerebral insulin. However, the origin of these symptoms and their relationship to pathology and cognitive disorders remain poorly understood. Insulin is a hormone involved in the control of peripheral and central energy homeostasis, and insulin-resistant state has been linked to increased risk of dementia.

Communities of Phytoplankton Viruses across the Transition Zone of the St. Lawrence Estuary.

The St. Lawrence hydrographic system includes freshwater, brackish, and marine habitats, and is the largest waterway in North America by volume. The food-webs in these habitats are ultimately dependent on phytoplankton.

Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5 mice exhibits activated dendritic cells and intrinsic inflammation.

Targeting the Muscle-Bone Unit: Filling Two Needs with One Deed in the Treatment of Duchenne Muscular Dystrophy.

Purpose Of Review: In Duchenne muscular dystrophy (DMD), the progressive skeletal and cardiac muscle dysfunction and degeneration is accompanied by low bone mineral density and bone fragility. Glucocorticoids, which remain the standard of care for patients with DMD, increase the risk of developing osteoporosis. The scope of this review emphasizes the mutual cohesion and common signaling pathways between bone and skeletal muscle in DMD.

Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors.

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors.

Utrophin haploinsufficiency does not worsen the functional performance, resistance to eccentric contractions and force production of dystrophic mice.

The lack of dystrophin in Duchenne muscular dystrophy (DMD) compromises the integrity and function of muscle fibers. Skeletal muscles, except the diaphragm, do not undergo progressive degeneration in adult mdx mice due to compensatory mechanisms, including structural protein upregulation. New mouse models, including utrophin haploinsufficient mdx (mdx/utrn+/-) mice, may better recapitulate DMD.

Genetic deletion of muscle RANK or selective inhibition of RANKL is not as effective as full-length OPG-fc in mitigating muscular dystrophy.

Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology.

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood.

Osteoprotegerin and β-Agonists Mitigate Muscular Dystrophy in Slow- and Fast-Twitch Skeletal Muscles.

Our recent work showed that daily injections of osteoprotegerin (OPG)-immunoglobulin fragment complex (OPG-Fc) completely restore the function of fast-twitch extensor digitorum longus muscles in dystrophic mdx mice, a murine model of Duchenne muscular dystrophy. However, despite marked improvements, OPG-Fc was not as effective in preventing the loss of function of slow-twitch soleus and diaphragm muscles. Because β-agonists enhance the function of slow- and fast-twitch dystrophic muscles and because their use is limited by their adverse effects on bone and cardiac tissues, we hypothesized that OPG-Fc, a bone and skeletal muscle protector, acts synergistically with β-agonists and potentiates their positive effects on skeletal muscles.

Old age potentiates cold-induced tau phosphorylation: linking thermoregulatory deficit with Alzheimer's disease.

Thermoregulatory deficits coincide with a rise in the incidence of Alzheimer's disease (AD) in old age. Lower body temperature increases tau phosphorylation, a neuropathological hallmark of AD. To determine whether old age potentiates cold-induced tau phosphorylation, we compared the effects of cold exposure (4 °C, 24 hours) in 6- and 18-month-old mice.

Tau hyperphosphorylation in the brain of ob/ob mice is due to hypothermia: Importance of thermoregulation in linking diabetes and Alzheimer's disease.

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM.