Synergistic effect on cardiac energetics by targeting the creatine kinase system: in vivo application of high-resolution P-CMRS in the mouse.

Background: Phosphorus cardiovascular magnetic resonance spectroscopy (P-CMRS) has emerged as an important tool for the preclinical assessment of myocardial energetics in vivo. However, the high rate and diminutive size of the mouse heart is a challenge, resulting in low resolution and poor signal-to-noise. Here we describe a refined high-resolution P-CMRS technique and apply it to a novel double transgenic mouse (dTg) with elevated myocardial creatine and creatine kinase (CK) activity.

ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells.

Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like F-actin.

Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes.

The type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. Listeria monocytogenes (Lm), a facultative intracellular foodborne pathogen, can exploit the type I IFN response as part of their pathogenic strategy, but the molecular mechanisms involved remain unclear. Here we show that type I IFN suppresses the antibacterial activity of phagocytes to promote systemic Lm infection.

Subtle Role for Adenylate Kinase 1 in Maintaining Normal Basal Contractile Function and Metabolism in the Murine Heart.

Aims: Adenylate kinase 1 (AK1) catalyses the reaction 2ADP ↔ ATP + AMP, extracting extra energy under metabolic stress and promoting energetic homeostasis. We hypothesised that increased AK1 activity would have negligible effects at rest, but protect against ischaemia/reperfusion (I/R) injury.

Methods And Results: Cardiac-specific AK1 overexpressing mice (AK1-OE) had 31% higher AK1 activity ( = 0.

First presentation of LPIN1 acute rhabdomyolysis in adolescence and adulthood.

LPIN1 mutations are a known common cause of autosomal recessive, recurrent and life-threatening acute rhabdomyolysis of childhood-onset. The first episode of rhabdomyolysis usually happens in nearly all cases before the age of 5 and death is observed in 1/3 of patients. Here we present two cases of acute rhabdomyolysis with a milder phenotype caused by LPIN1 mutation presenting in adolescence (11 years old) and adulthood (40 years old) after Parvovirus infection and metabolic stress, respectively.

Labeling Acidic Compartments of Neutrophils with Cresyl Violet.

We introduce the acidotropic marker cresyl violet to stain acidic granules in live neutrophils. Cresyl violet is less phototoxic, more photostable, and more cost-effective than other commercially available acidotropic markers. Additionally, it does not photoconvert to fluorescent species of a different color, a limitation of other commonly used acidotropic markers.

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .

Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%).

Dynamic Podosome-Like Structures in Nascent Phagosomes Are Coordinated by Phosphoinositides.

Phagocytosis, the engulfment of particulate matter, requires the coordinated polymerization of F-actin; however, the nature and dynamics of the F-actin structures generated during the process are incompletely defined. Using super-resolution microscopy, we observed the formation of podosome-like structures during Fc receptor-mediated phagocytosis. Unlike conventional podosomes, these structures are short lived and vectorial, expanding radially from the sites where phagocytic targets are initially engaged.

Fractal Analysis of Right Ventricular Trabeculae in Pulmonary Hypertension.

Purpose To measure right ventricular (RV) trabecular complexity by its fractal dimension (FD) in healthy subjects and patients with pulmonary hypertension (PH) and to assess its relationship with hemodynamic and functional parameters and future cardiovascular events. Materials and Methods This retrospective study used data acquired from May 2004 to October 2013 in 256 patients with newly diagnosed PH who underwent cardiac MRI, right-sided heart catheterization, and 6-minute walk distance testing, with median follow-up of 4.0 years.

Over-expression of mitochondrial creatine kinase in the murine heart improves functional recovery and protects against injury following ischaemia-reperfusion.

Aims: Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of ATP at times of high demand. We hypothesized that elevating MtCK would be beneficial in ischaemia-reperfusion (I/R) injury.

Methods And Results: Mice were created over-expressing the sarcomeric MtCK gene with αMHC promoter at the Rosa26 locus (MtCK-OE) and compared with wild-type (WT) littermates.

Increasing creatine kinase activity protects against hypoxia / reoxygenation injury but not against anthracycline toxicity in vitro.

The creatine kinase (CK) phosphagen system is fundamental to cellular energy homeostasis. Cardiomyocytes express three CK isoforms, namely the mitochondrial sarcomeric CKMT2 and the cytoplasmic CKM and CKB. We hypothesized that augmenting CK in vitro would preserve cell viability and function and sought to determine efficacy of the various isoforms.

Cresyl violet: a superior fluorescent lysosomal marker.

We have characterized cresyl violet as a membrane-permeant fluorophore that localizes to lysosomes and acidic vacuoles of budding yeast, Drosophila, human, murine and canine cells. An acidotropic weak base, cresyl violet is shown to be virtually insensitive to physiological alkali and divalent cations. Because of its unique spectral properties, it can be used in combination with green, red and far-red fluorophores, is less susceptible to photobleaching than alternative acidotropic probes, and does not undergo photoconversion.

Diffusion Barriers, Mechanical Forces, and the Biophysics of Phagocytosis.

Phagocytes recognize and eliminate pathogens, alert other tissues of impending threats, and provide a link between innate and adaptive immunity. They also maintain tissue homeostasis, consuming dead cells without causing alarm. The receptor engagement, signal transduction, and cytoskeletal rearrangements underlying phagocytosis are paradigmatic of other immune responses and bear similarities to macropinocytosis and cell migration.

Meta-Analysis of Serum Insulin-Like Growth Factor 1 in Alzheimer's Disease.

Insulin-like growth factor 1 (IGF-1) serum levels have been reported to be altered in Alzheimer's disease patients, and it was suggested that the changes in IGF-1 serum level may play a role in disease pathology and progression. However, this notion remained controversial due to conflicting findings. We conducted a meta-analysis to determine the relationship between IGF-1 serum levels and Alzheimer's disease.

The position of lysosomes within the cell determines their luminal pH.

We examined the luminal pH of individual lysosomes using quantitative ratiometric fluorescence microscopy and report an unappreciated heterogeneity: peripheral lysosomes are less acidic than juxtanuclear ones despite their comparable buffering capacity. An increased passive (leak) permeability to protons, together with reduced vacuolar H(+)-adenosine triphosphatase (V-ATPase) activity, accounts for the reduced acidifying ability of peripheral lysosomes. The altered composition of peripheral lysosomes is due, at least in part, to more limited access to material exported by the biosynthetic pathway.

The significance of mitral and tricuspid valve systolic lateral annular velocities in the diagnosis of acute pulmonary embolism in patients with chronic heart failure.

Introduction: The diagnosis of acute pulmonary embolism (APE) in patients with chronic heart failure (CHF) remains a difficult task, despite the refinement of imaging techniques. The goal of this study was to assess the value of measuring tricuspid and mitral valve systolic annular velocities in CHF patients with suspected PE by tissue Doppler imaging (TDI).

Material And Methods: The study included 75 patients with previously diagnosed CHF, admitted due to resting dyspnea, with a maximum tricuspid regurgitation pressure gradient (TRPG) of ≥ 35 mm Hg and positive D-dimer assay.

A role for thioredoxin-interacting protein (Txnip) in cellular creatine homeostasis.

Creatine is important for energy metabolism, yet excitable cells such as cardiomyocytes do not synthesize creatine and rely on uptake via a specific membrane creatine transporter (CrT; SLC6A8). This process is tightly controlled with downregulation of CrT upon continued exposure to high creatine via mechanisms that are poorly understood. Our aim was to identify candidate endogenous CrT inhibitors.

Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction.

Aims: Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury.

Chronic creatine kinase deficiency eventually leads to congestive heart failure, but severity is dependent on genetic background, gender and age.

The creatine kinase (CK) energy transport and buffering system supports cardiac function at times of high demand and is impaired in the failing heart. Mice deficient in muscle- and mitochondrial-CK (M/Mt-CK(-/-)) have previously been described, but exhibit an unexpectedly mild phenotype of compensated left ventricular (LV) hypertrophy. We hypothesised that heart failure would develop with age and performed echocardiography and LV haemodynamics at 1 year.