Depriving Mice of Sleep also Deprives of Food.

Both sleep-wake behavior and circadian rhythms are tightly coupled to energy metabolism and food intake. Altered feeding times in mice are known to entrain clock gene rhythms in the brain and liver, and sleep-deprived humans tend to eat more and gain weight. Previous observations in mice showing that sleep deprivation (SD) changes clock gene expression might thus relate to altered food intake, and not to the loss of sleep per se. Whether SD affects food intake in the mouse and how this might affect clock gene expression is, however, unknown. We therefore quantified (i) the cortical expression of the clock genes Per1, Per2, Dbp, and Cry1 in mice that had access to food or not during a 6 h SD, and (ii) food intake during baseline, SD, and recovery sleep. We found that food deprivation did not modify the SD-incurred clock gene changes in the cortex. Moreover, we discovered that although food intake during SD did not differ from the baseline, mice lost weight and increased food intake during subsequent recovery. We conclude that SD is associated with food deprivation and that the resulting energy deficit might contribute to the effects of SD that are commonly interpreted as a response to sleep loss

Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

BACKGROUND/AIMS: Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms. METHODS: We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed. RESULTS: Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation. CONCLUSIONS/INTERPRETATION: Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes

Preoperative predictors of recurrent atrial fibrillation late after successful mitral valve reconstruction

Objective: Late outcome after mitral valve repair was examined to define preoperative predictors of recurrent atrial fibrillation late after successful mitral valve reconstruction. Methods: One hundred and eighty-nine patients, 112 with preoperative sinus rhythm and 72 with preoperative chronic or intermittent atrial fibrillation, were followed for 12.2±10 years after valve repair. Clinic, hemodynamic end echocardiographic data were entered into Cox-regression and Kaplan-Meyer analysis to assess predictors for recurrent atrial fibrillation late after successful mitral valve repair. Results: Univariate and multivariate predictors for recurrent atrial fibrillation late after successful mitral valve reconstruction were preoperative atrial fibrillation (P=0.0001), preoperative antiarrhythmic drug treatment (P=0.005), heart rate (P=0.01), left ventricular ejection fraction (P=0.01) and increased left ventricular posterior wall thickness (P=0.05). Patients>57.5 years with a mean pulmonary artery pressure ≥23mm Hg and a history of preoperative antiarrhythmic drug treatment had an odds ratio of 53.33 (95% confidence limits 6.12-464.54) for atrial fibrillation late after successful mitral valve repair. Conclusion: Older patients with a history of atrial fibrillation, antiarrhythmic treatment or an elevated pulmonary artery pressure may present atrial fibrillation late after successful mitral valve repair. They could be considered for combined mitral valve reconstruction and surgery for atrial fibrillation even though sinus rhythm is present preoperativel

Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast.

Rho-type GTPases control many cytoskeletal rearrangements, but their regulation remains poorly understood. Here, we show that in S. cerevisiae, activation of the CDK Cdc28-Cln2 at bud emergence triggers relocalization of Cdc24, the GEF for Cdc42, from the nucleus to the polarization site, where it is stably maintained by binding to the adaptor Bem1. Locally activated Cdc42 then polarizes the cytoskeleton in a manner dependent on its effectors Bni1 and the PAK-like kinase Cla4. In addition, Cla4 induces phosphorylation of Cdc24, leading to its dissociation from Bem1 at bud tips, thereby ending polarized bud growth in vivo. Our results thus suggest a dynamic temporal and spatial regulation of the Cdc42 module: Cdc28-Cln triggers actin polarization by activating Cdc42, which in turn restricts its own activation via a negative feedback loop acting on its GEF Cdc24

Conservative treatment of the aortic root in acute type A dissection

Objective: In acute type A dissection long-term results of conservative aortic root surgery were compared with the outcome of primary valve and/or root replacement. Methods: Between 1985 and 1995, 199 patients (mean age 59 years, 154 men) were operated on. The aortic root was involved in the dissection process and valve incompetence of varying degree was present without exception. Replacement of a proximal aortic segment was standard procedure in all patients. The aortic valve was preserved in 126 patients: commissural suture resuspension (12 patients), root reconstruction with GRF-glue (gelatine-resorcin-formaldehyde/glutaraldehyde-glue) (114 patients). Valve replacement was performed in 73 patients (50 composite grafts, 23 valve prostheses with separate supracoronary grafts). Preoperative risk factors (valve replacement vs. preservation): coronary artery disease (11 vs. 8%, NS), tamponade (18 vs. 17%, NS), unstable hemodynamics (22 vs. 15%, NS), renal failure (4 vs. 6%, NS), neurologic disorder (19 vs. 32%, NS). Results: The overall early mortality was 23.6% (47/199 patients) and increased after commissural suture resuspension compared with GRF-glue reconstruction (P=NS). Parameters of the early postoperative period did not differ between conservative treatment and root/valve replacement: low cardiac output, 34 versus 38% (P=NS); myocardial infarction, 10 versus 11% (P=NS); hemorrhage, 25 versus 23% (P=NS); duration of intensive care (P=NS). Survival was 61% after 8 years without difference between the two principal treatment groups (P=NS) and between the two conservative subgroups (P=NS). At 2 years, GRF-glue reconstruction had an increased freedom from reoperation on the aortic root (92 vs. 70%, P=0.0253) and event free survival (77 vs. 41%, P=0.0224) compared with suture resuspension. Commissural suture resuspension was an independent, significant predictor for reoperation (P=0.0221, relative risk=4.7130). Conclusion: Surgery for acute type A dissection still carries a considerable early risk. Preservation of the aortic root is safe in the absence of Marfan or annuloaortic ectasia, but a certain incidence of reoperations on the aortic valve and the aortic root has to be accepted. Root reconstruction using GRF-glue is the method of choice and is superior to suture resuspension, with a significantly better reoperation-free and event-free survival

CDK7 Mediates the Beta-Adrenergic Signaling in Thermogenic Brown and White Adipose Tissues.

Cyclin-dependent kinases (CDKs) are emerging regulators of adipose tissue metabolism. Here we aimed to explore the role of CDK7 in thermogenic fat. We found that CDK7 brown adipose tissue (BAT)-specific knockout mice (Cdk7 <sup>bKO</sup> ) have decreased BAT mass and impaired β3-adrenergic signaling and develop hypothermia upon cold exposure. We found that loss of CDK7 in BAT disrupts the induction of thermogenic genes in response to cold. However, Cdk7 <sup>bKO</sup> mice do not show systemic metabolic dysfunction. Increased expression of genes of the creatine metabolism compensates for the heat generation in the BAT of Cdk7 <sup>bKO</sup> mice in response to cold. Finally, we show that CDK7 is required for beta 3-adrenergic agonist-induced browning of white adipose tissue (WAT). Indeed, Cdk7 ablation in all adipose tissues (Cdk7 <sup>aKO</sup> ) has impaired browning in WAT. Together, our results demonstrate that CDK7 is an important mediator of beta-adrenergic signaling in thermogenic brown and beige fat

Association of Time of Day When Endovascular Therapy for Stroke Starts and Functional Outcome.

To investigate the association between EVT start time in acute ischemic stroke (AIS) and mid-term functional outcome. This retrospective cohort study included all AIS cases treated with EVT from two stroke center registries from January 2012 to December 2018. The primary outcome was the score on the modified Rankin Scale (mRS) and the utility-weighted mRS (uw-mRS) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention at a given EVT start time would lead to lower scores on the mRS (shift analysis). One thousand five hundred fifty-eight cases were equally allotted into twelve EVT-start-time periods. The primary outcome favored EVT start times in the morning at 08:00-10:20 and 10:20-11:34 (common odds ratio (OR), 0.53; 95% confidence interval (CI), 0.38 to 0.75; P<0.001; OR, 0.62; 95% CI, 0.44 to 0.87; P=0.006, respectively), while it disfavored EVT start times at the end of the working day at 15:55-17:15 and 18:55-20:55 (OR, 1.47; 95% CI, 1.03 to 2.09; P=0.034; OR, 1.49; 95% CI, 1.03 to 2.15; P=0.033). Symptom onset-to-EVT start time was significantly higher and use of IV t-PA significantly lower between 10:20-11:34 (P<0.004 and P=0.012, respectively). EVT for AIS in the morning leads to better mid-term functional outcome, while EVT at the end of the work day leads to poorer mid-term functional outcome. Neither difference in baseline factors, standard workflow and technical efficacy metrics could be identified as potential mediators of this effect

Hypothalamic CDK4 regulates thermogenesis by modulating sympathetic innervation of adipose tissues.

This study investigated the role of CDK4 in the oxidative metabolism of brown adipose tissue (BAT). BAT from Cdk4 <sup>-/-</sup> mice exhibited fewer lipids and increased mitochondrial volume and expression of canonical thermogenic genes, rendering these mice more resistant to cold exposure. Interestingly, these effects were not BAT cell-autonomous but rather driven by increased sympathetic innervation. In particular, the ventromedial hypothalamus (VMH) is known to modulate BAT activation via the sympathetic nervous system. We thus examined the effects of VMH neuron-specific Cdk4 deletion. These mice display increased sympathetic innervation and enhanced cold tolerance, similar to Cdk4 <sup>-/-</sup> mice, in addition to browning of scWAT. Overall, we provide evidence showing that CDK4 modulates thermogenesis by regulating sympathetic innervation of adipose tissue depots through hypothalamic nuclei, including the VMH. This demonstrates that CDK4 not only negatively regulates oxidative pathways, but also modulates the central regulation of metabolism through its action in the brain