Quantized Hall conductance is a generic feature of two-dimensional electronic systems with broken time reversal symmetry. In the quantum anomalous Hall state recently discovered in magnetic ...topological insulators, time reversal symmetry is believed to be broken by long-range ferromagnetic order, with quantized resistance observed even at zero external magnetic field. We use scanning nanoSQUID (nano-superconducting quantum interference device) magnetic imaging to provide a direct visualization of the dynamics of the quantum phase transition between the two anomalous Hall plateaus in a Cr-doped (Bi,Sb)2Te3 thin film. Contrary to naive expectations based on macroscopic magnetometry, our measurements reveal a superparamagnetic state formed by weakly interacting magnetic domains with a characteristic size of a few tens of nanometers. The magnetic phase transition occurs through random reversals of these local moments, which drive the electronic Hall plateau transition. Surprisingly, we find that the electronic system can, in turn, drive the dynamics of the magnetic system, revealing a subtle interplay between the two coupled quantum phase transitions.
Borrelia spirochetes are the causative agents of Lyme borreliosis (LB) and relapsing fever (RF). Despite the steady rise in infections and the identification of new species causing human illness over ...the last decade, isolation of borreliae in culture has become increasingly rare. A modified Barbour-Stoenner-Kelly (BSK) media formulation, BSK-R, was developed for isolation of the emerging RF pathogen, Borrelia miyamotoi. BSK-R is a diluted BSK-II derivative supplemented with Lebovitz's L-15, mouse and fetal calf serum. Decreasing the concentration of CMRL 1066 and other components was essential for growth of North American B. miyamotoi. Sixteen B. miyamotoi isolates, originating from Ixodes scapularis ticks, rodent and human blood collected in the eastern and upper midwestern United States, were isolated and propagated to densities > 10
spirochetes/mL. Growth of five other RF and ten different LB borreliae readily occurred in BSK-R. Additionally, primary culture recovery of 20 isolates of Borrelia hermsii, Borrelia turicatae, Borrelia burgdorferi and Borrelia mayonii was achieved in BSK-R using whole blood from infected patients. These data indicate this broadly encompassing borreliae media can aid in in vitro culture recovery of RF and LB spirochetes, including the direct isolation of new and emerging human pathogens.
Autophagy is important for protein and organelle quality control. Growing evidence demonstrates that autophagy is tightly controlled by transcriptional mechanisms, including repression by zinc finger ...containing KRAB and SCAN domains 3 (ZKSCAN3). We hypothesize that cardiomyocyte‐specific ZKSCAN3 knockout (Z3K) disrupts autophagy activation and repression balance and exacerbates cardiac pressure‐overload‐induced remodeling following transverse aortic constriction (TAC). Indeed, Z3K mice had an enhanced mortality compared to control (Con) mice following TAC. Z3K‐TAC mice that survived exhibited a lower body weight compared to Z3K‐Sham. Although both Con and Z3K mice exhibited cardiac hypertrophy after TAC, Z3K mice exhibited TAC‐induced increase of left ventricular posterior wall thickness at end diastole (LVPWd). Conversely, Con‐TAC mice exhibited decreases in PWT%, fractional shortening (FS%), and ejection fraction (EF%). Autophagy genes (Tfeb, Lc3b, and Ctsd) were decreased by the loss of ZKSCAN3. TAC suppressed Zkscan3, Tfeb, Lc3b, and Ctsd in Con mice, but not in Z3K. The Myh6/Myh7 ratio, which is related to cardiac remodeling, was decreased by the loss of ZKSCAN3. Although Ppargc1a mRNA and citrate synthase activities were decreased by TAC in both genotypes, mitochondrial electron transport chain activity did not change. Bi‐variant analyses show that while in Con‐Sham, the levels of autophagy and cardiac remodeling mRNAs form a strong correlation network, such was disrupted in Con‐TAC, Z3K‐Sham, and Z3K‐TAC. Ppargc1a also forms different links in Con‐sham, Con‐TAC, Z3K‐Sham, and Z3K‐TAC. We conclude that ZKSCAN3 in cardiomyocytes reprograms autophagy and cardiac remodeling gene transcription, and their relationships with mitochondrial activities in response to TAC‐induced pressure overload.
Our study demonstrated that ZKSCAN3 level is significantly decreased, along with TFEB, in response to pressure overload. We then generated cardiomyocyte‐specific ZKSCAN3 knockout (Z3K) mice, and found that Z3K mice had an enhanced mortality compared to control (Con) mice following TAC, and those that survived exhibited a lower body weight. Significant changes of transcription landscapes were found in Z3K mice after sham surgery.
The endoplasmic reticulum (ER) Ca(2+) sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca(2+) entry pathways and ...maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout ((cr)STIM1-KO) mouse. In cardiomyocytes isolated from (cr)STIM1-KO mice, STIM1 expression was reduced by ∼92% with no change in the expression of related store-operated Ca(2+) entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that (cr)STIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in (cr)STIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in (cr)STIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in (cr)STIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function.
Aim
Cardiac arrhythmias and sudden deaths have diurnal rhythms in humans. The underlying mechanisms are unknown. Mice with cardiomyocyte‐specific disruption of the molecular clock genes have lower ...heart rate than control. Because changes in the QT interval on the electrocardiogram is a clinically used marker of risk of arrhythmias, we sought to test if the biological rhythms of QT intervals are dependent on heart rate and if this dependency is changed when the molecular clock is disrupted.
Methods
We implanted radio transmitters in male mice with cardiomyocyte‐specific Bmal1 knockout (CBK) and in control mice and recorded 24‐h ECGs under diurnal and circadian conditions. We obtained left ventricular monophasic action potentials during pacing in hearts ex vivo.
Results
Both RR and QT intervals were longer in conscious CBK than control mice (RR: 117 ± 7 vs 110 ± 9 ms, P < .05; and QT: 53 ± 4 vs 48 ± 2 ms, P < .05). The prolonged QT interval was independent of the slow heart rate in CBK mice. The QT interval exhibited diurnal and circadian rhythms in both CBK and control mice. The action potential duration was longer in CBK than in control mice, indicating slower repolarization. Action potential alternans occurred at lower pacing rate in hearts from CBK than control mice (12 ± 3 vs 16 ± 2 Hz, respectively, P < .05).
Conclusion
The bradycardic CBK mice have prolonged ventricular repolarization independent of the heart rate. Diurnal and circadian rhythms in repolarization are preserved in CBK mice and are not a consequence of the 24‐h rhythm in heart rate. Arrhythmia vulnerability appears to be increased when the cardiac clock is disrupted.
Maintaining a balance of ω-6 and ω-3 fatty acids is essential for cardiac health. Current ω-6 and ω-3 fatty acids in the American diet have shifted from the ideal ratio of 2:1 to almost 20:1; while ...there is a body of evidence that suggests the negative impact of such a shift in younger organisms, the underlying age-related metabolic signaling in response to the excess influx of ω-6 fatty acids is incompletely understood. In the present study, young (6 mo old) and aging (≥18 mo old) mice were fed for 2 mo with a ω-6-enriched diet. Excess intake of ω-6 enrichment decreased the total lean mass and increased nighttime carbohydrate utilization, with higher levels of cardiac cytokines indicating low-grade chronic inflammation. Dobutamine-induced stress tests displayed an increase in PR interval, a sign of an atrioventricular defect in ω-6-fed aging mice. Excess ω-6 fatty acid intake in aging mice showed decreased 12-lipoxygenase with a concomitant increase in 15-lipoxygenase levels, resulting in the generation of 15( S)-hydroxyeicosatetraenoic acid, whereas cyclooxygenase-1 and -2 generated prostaglandin E
, leukotriene B
and thromboxane B
. Furthermore, excessive ω-6 fatty acids led to dysregulated nuclear erythroid 2-related factor 2/antioxidant-responsive element in aging mice. Moreover, ω-6 fatty acid-mediated changes were profound in aging mice with respect to the eicosanoid profile while minimal changes were observed in the size and shape of cardiomyocytes. These findings provide compelling evidence that surplus consumption of ω-6 fatty acids, coupled with insufficient intake of ω-3 fatty acids, is linked to abnormal changes in ECG. These manifestations contribute to functional deficiencies and expansion of the inflammatory mediator milieu during later stages of aging. NEW & NOTEWORTHY Aging has a profound impact on the metabolism of fatty acids to maintain heart function. The excess influx of ω-6 fatty acids in aging perturbed electrocardiography with marked signs of inflammation and a dysregulated oxidative-redox balance. Thus, the quality and quantity of fatty acids determine the cardiac pathology and energy utilization in aging.
Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast growth factor 21 (FGF21) secretion. However, FGF21 is only a ...partial mediator of metabolic actions ensuing from glucagon receptor (GCGR) activation, prompting us to search for additional pathways. Intriguingly, chronic GCGR agonism increases plasma bile acid levels. We hypothesized that GCGR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole-body and liver-specific FXR-knockout (
) mice. Chronic GCGR agonist (IUB288) administration in diet-induced obese (DIO)
,
and
whole-body or liver-specific knockout (
) mice failed to reduce body weight when compared with wild-type (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not
mice. GCGR agonism increased
Cpalmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from
mice. Our data clearly demonstrate that control of whole-body energy expenditure by GCGR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GCGR agonism in the therapy of metabolic disorders.
Background. Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. Methods. We conducted 2 parallel, randomized, double-blind, ...active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged ⩾18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). Results. A total of 1867 patients were randomized and received ⩾1 dose of study medication. In the clinically evaluable population, at 7–14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, −2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, −1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, −0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. Conclusions. Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.
Myocardial gene expression and metabolism fluctuate over the course of the day in association with changes in energy supply and demand. Time-of-day-dependent oscillations in myocardial processes have ...been linked to the intrinsic cardiomyocyte circadian clock. Triiodothyronine (T3) is an important modulator of heart metabolism and function. Recently, our group has reported time-of-day-dependent rhythms in cardiac T3 sensitivity, as well as, T3-mediated acute alterations on core clock components. Hypo and hyperthyroidism are the second most prevalent endocrine disease worldwide. Considering the importance of the cardiomyocyte circadian clock and T3 to cardiac physiology, the aim of this study was to investigate the consequences of chronic hypo and hyperthyroidism on 24-h rhythms of circadian clock genes in the heart. Hypo and hyperthyroidism was induced in rats by thyroidectomy (Tx) and i.p. injections of supraphysiological dose of T3, respectively. Here we report alterations in mRNA levels of the major core clock components (Bmal1, Per2, Nr1d1, and Rora) for both experimental conditions (with the exception of Per2 during hyperthyroid condition). Oscillations in mRNA levels of key glucose and fatty-acid metabolism genes known to be clock controlled (Pdk4, Ucp3, Acot1, and Cd36) were equally affected by the experimental conditions, especially during the hypothyroid state. These findings suggest that chronic alterations in thyroid status significantly impacts 24-h rhythms in circadian clock and metabolic genes in the heart. Whether these perturbations contribute toward the pathogenesis of cardiac dysfunction associated with hypo and hyperthyroidism requires further elucidation.
An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac ...metabolism also fluctuates across the 24‐hours day, in association with diurnal sleep‐wake and fasting‐feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day‐night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet‐induced obesity disrupts cardiac “diurnal metabolic flexibility”, which is normalized by time‐of‐day‐restricted feeding. Chronic high fat feeding (20‐wk)‐induced obesity in mice, abolished diurnal rhythms in whole body metabolic flexibility, and increased markers of adverse cardiac remodeling (hypertrophy, fibrosis, and steatosis). RNAseq analysis revealed that 24‐hours rhythms in the cardiac transcriptome were dramatically altered during obesity; only 22% of rhythmic transcripts in control hearts were unaffected by obesity. However, day‐night differences in cardiac substrate oxidation were essentially identical in control and high fat fed mice. In contrast, day‐night differences in both cardiac triglyceride synthesis and lipidome were abolished during obesity. Next, a subset of obese mice (induced by 18‐wks ad libitum high fat feeding) were allowed access to the high fat diet only during the 12‐hours dark (active) phase, for a 2‐wk period. Dark phase restricted feeding partially restored whole body metabolic flexibility, as well as day‐night differences in cardiac triglyceride synthesis and lipidome. Moreover, this intervention partially reversed adverse cardiac remodeling in obese mice. Collectively, these studies reveal diurnal metabolic inflexibility of the heart during obesity specifically for nonoxidative lipid metabolism (but not for substrate oxidation), and that restricting food intake to the active period partially reverses obesity‐induced cardiac lipid metabolism abnormalities and adverse remodeling of the heart.
PDF
