GAS6 and AXL Promote Insulin Resistance by Rewiring Insulin Signaling and Increasing Insulin Receptor Trafficking to Endosomes.

Growth arrest-specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL, and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood.

Vitamin K-dependent carboxylation in β-cells and diabetes.

Vitamin K is an essential micronutrient and a cofactor for the enzyme γ-glutamyl carboxylase, which adds a carboxyl group to specific glutamic acid residues in proteins transiting through the secretory pathway. Higher vitamin K intake has been linked to a reduced incidence of type 2 diabetes (T2D) in humans. Preclinical work suggests that this effect depends on the γ-carboxylation of specific proteins in β-cells, including endoplasmic reticulum Gla protein (ERGP), implicated in the control of intracellular Ca levels.

Single Functional Group Platform for Multistimuli Responsivities: Tertiary Amine for CO/pH/ROS-Triggered Cargo Release in Nanocarriers.

The design of multistimuli-responsive soft nanoparticles (NPs) often presents synthetic complexities and limited breadth in exploiting changes surrounding physiological environments. Nanocarriers that could collectively take advantage of several endogenous stimuli can offer a powerful tool in nanomedicine. Herein, we have capitalized on the chemical versatility of a single tertiary amine to construct miktoarm polymer-based nanocarriers that respond to dissolved CO, varied pH, reactive oxygen species (ROS), and ROS + CO.

Vitamin K-dependent carboxylation regulates Ca flux and adaptation to metabolic stress in β cells.

Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown.

Adcy9 Gene Inactivation Improves Cardiac Function After Myocardial Infarction in Mice.

Background: Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity.

Methods: Wild-type (WT) and Adcy9-inactivated (Adcy9) male mice, transgenic or not for human CETP (tgCETP), were subjected to MI by permanent left anterior descending coronary artery ligation and studied for 4 weeks.

COVID-19 vaccination, incidence, and mortality rates among indigenous populations compared to the general population in Brazil: Describing trends over time.

Background: Chronic social and health inequities faced by indigenous peoples in Brazil foretell the detrimental impact of COVID-19.

Methods: We use de-identified, publicly available data from the Ministry of Health from March/2020 - December/2021 to describe vaccination coverage, cumulative incidence, and cumulative mortality rates due to COVID-19 among indigenous peoples. We also compare vaccination coverage among indigenous peoples with that reported for older adults, who were simultaneously included as a priority group in the vaccination strategy.

MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries.

All five muscarinic receptors have important physiological roles. The endothelial M2 and M3 subtypes regulate arterial tone through direct coupling to Gq or Gi/o proteins. Yet, we lack selective pharmacological drugs to assess the respective contribution of muscarinic receptors to a given function.

OCA-B does not act as a transcriptional coactivator in T cells.

Pou2af1 encodes for OCA-B, a coactivator of OCT-1/2 transcription factors, which plays a key role in B-cell maturation. The function of OCA-B has also been studied in T cells, where T cells from Pou2af1 mice have impaired functions, such as cytokine production and T follicular helper (Tfh) differentiation. Arguably, some of these T-cell phenotypes may result from impaired T-B interactions, secondary to the well-documented B-cell defects in Pou2af1 mice.

ERK3-MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation.

The physiological functions and downstream effectors of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain to be characterized. We recently reported that mice expressing catalytically-inactive ERK3 (Mapk6 ) exhibit a reduced postnatal growth rate as compared to control mice. Here, we show that genetic inactivation of ERK3 impairs postnatal skeletal muscle growth and adult muscle regeneration after injury.

Unification of Treatments and Interventions for Tinnitus Patients (UNITI): a study protocol for a multi-center randomized clinical trial.

Background: Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients.

Colchicine reduces atherosclerotic plaque vulnerability in rabbits.

Background And Aims: The anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis.

Analysis of the Contribution of Proprotein Convertases to the Processing of FGF23.

Fibroblast growth factor 23 (FGF23) is a hormone secreted from fully differentiated osteoblasts and osteocytes that inhibits phosphate reabsorption by kidney proximal tubules. The full-length (i.e.

Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes.

High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin-deficient diabetes. We introduced the sclerostin-resistant Lrp5 mutation, associated with high bone mass, in mice carrying the Ins2 mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males.

Male but not female mice with severe osteogenesis imperfecta are partially protected from high-fat diet-induced obesity.

Previously we have shown that young mice with a dominant severe form of osteogenesis imperfecta (OI), caused by mutated collagen type I, exhibit an altered glucose/insulin metabolism and energy expenditure along with elevated levels of osteocalcin, a bone-derived hormone involved in the regulation of whole-body metabolism. This study aimed to examine the long-term effects of a western diet in these OI mice. Male and female OI mice and wild type littermates (WT) were fed a high-fat diet (HFD) or a matched low-fat diet (LFD) for 26 weeks.

Implications of a Soy-Based Diet for Animal Models.

The use of animal models in fundamental or pre-clinical research remains an absolute requirement for understanding human pathologies and developing new drugs. In order to transpose these results into clinical practice, many parameters must be taken into account to limit bias. Attention has recently been focused on the sex, age or even strain of each animal, but the impact of diet has been largely neglected.

Early nebivolol treatment is beneficial in myocardial infarction in rats partly through β3-adrenoceptor remodelling.

It remains unknown whether β-blockers are useful and safe in acute myocardial infarction (MI). Owing to its pharmacological profile and vasodilating action, nebivolol (N) is useful in MI. The aim of the present study was to assess in rat whether early nebivolol treatment could be beneficial in MI.

The half-life of the bone-derived hormone osteocalcin is regulated through -glycosylation in mice, but not in humans.

Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover -glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylation and endoproteolysis, two other PTMs regulating this hormone.

Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification.

In endochondral ossification, chondroblasts become embedded in their matrix and become chondrocytes, which are mature cells that continue to proliferate, eventually becoming hypertrophic. Hypertrophic chondrocytes produce cartilage that is then resorbed by osteoclasts prior to bone matrix replacement via osteoblasts. Although sexually dimorphic bone phenotypes have long been characterized, specific modulation of the growth plate during a critical window in sexual maturation has not been evaluated.

PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.

Background: The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear.

Overexpression of endothelial β -adrenergic receptor induces diastolic dysfunction in rats.

Aims: Diastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide ( NO) pathway.

Cadmium, lead and mercury in the blood of workers from recycling sorting facilities in São Paulo, Brazil.

Approximately 600,000 people work as recycling material collectors in Brazil and few studies evaluate the health risks involved in this occupation. The objective was to evaluate the blood levels of cadmium (Cd), lead (Pb) and mercury (Hg) among workers from recycling sorting facilities (RSF) in the metropolitan region of São Paulo, Brazil, compare the results with a non-occupationally exposed population, and identify factors associated with higher blood metal levels. Four RSF were selected and 226 collectors were examined for their blood metal levels and associated factors.

AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network.

Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells.