The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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Demonstration of Feeding Vehicle-Integrated Photovoltaic-Converted Energy into the High-Voltage On-Board Network of Practical Light Commercial Vehicles for Range Extension

The setting up of a practical electrically driven light commercial demonstration vehicle with integrated photovoltaics (PV) is reported. The demonstrator vehicle is equipped with 15 modules based on the crystalline Si/amorphous Si heterojunction technology. The nominal total peak power under standard testing conditions is 2180 Wp. Specifically, the PV-converted energy is fed into the high-voltage (HV; 400 V) board-net for a utilization of the large capacity of the HV battery and thus for direct range extension. The demonstrator vehicle is equipped with irradiation, wind, temperature, magnetic, and global positioning system sensors. Irradiation and temperature as well as the energy flows from modules, maximum power point trackers (MPPTs), low-voltage buffer battery to HV battery via DC/DC, and from the HV battery to the loads during an exemplarily test drive day (May 31, 2021) are monitored. The range extension obtained at this day on our test route (51° 59′ N, 9° 31′ E) was 36 km, the corresponding CO2 savings account for ≈2.3 kg. The chain efficiency of the electronic components from the input side of the MPPTs to the HV output side of the DC/DC was 68.6%, whereas the DC/DC itself has an average efficiency of 90%. © 2021 The Authors. Solar RRL published by Wiley-VCH Gmb

Distinct Occurrence of Proarrhythmic Afterdepolarizations in Atrial Versus Ventricular Cardiomyocytes: Implications for Translational Research on Atrial Arrhythmia

Background: Principal mechanisms of arrhythmia have been derived from ventricular but not atrial cardiomyocytes of animal models despite higher prevalence of atrial arrhythmia (e.g., atrial fibrillation). Due to significant ultrastructural and functional differences, a simple transfer of ventricular proneness toward arrhythmia to atrial arrhythmia is critical. The use of murine models in arrhythmia research is widespread, despite known translational limitations. We here directly compare atrial and ventricular mechanisms of arrhythmia to identify critical differences that should be considered in murine models for development of antiarrhythmic strategies for atrial arrhythmia.Methods and Results: Isolated murine atrial and ventricular myocytes were analyzed by wide field microscopy and subjected to a proarrhythmic protocol during patch-clamp experiments. As expected, the spindle shaped atrial myocytes showed decreased cell area and membrane capacitance compared to the rectangular shaped ventricular myocytes. Though delayed afterdepolarizations (DADs) could be evoked in a similar fraction of both cell types (80% of cells each), these led significantly more often to the occurrence of spontaneous action potentials (sAPs) in ventricular myocytes. Interestingly, numerous early afterdepolarizations (EADs) were observed in the majority of ventricular myocytes, but there was no EAD in any atrial myocyte (EADs per cell; atrial myocytes: 0 ± 0; n = 25/12 animals; ventricular myocytes: 1.5 [0–43]; n = 20/12 animals; p < 0.05). At the same time, the action potential duration to 90% decay (APD90) was unaltered and the APD50 even increased in atrial versus ventricular myocytes. However, the depolarizing L-type Ca2+ current (ICa) and Na+/Ca2+-exchanger inward current (INCX) were significantly smaller in atrial versus ventricular myocytes.Conclusion: In mice, atrial myocytes exhibit a substantially distinct occurrence of proarrhythmic afterdepolarizations compared to ventricular myocytes, since they are in a similar manner susceptible to DADs but interestingly seem to be protected against EADs and show less sAPs. Key factors in the generation of EADs like ICa and INCX were significantly reduced in atrial versus ventricular myocytes, which may offer a mechanistic explanation for the observed protection against EADs. These findings may be of relevance for current studies on atrial level in murine models to develop targeted strategies for the treatment of atrial arrhythmia

First report on an inotropic peptide activating tetrodotoxin-sensitive, "neuronal" sodium currents in the heart

Background— New therapeutic approaches to improve cardiac contractility without severe risk would improve the management of acute heart failure. Increasing systolic sodium influx can increase cardiac contractility, but most sodium channel activators have proarrhythmic effects that limit their clinical use. Here, we report the cardiac effects of a novel positive inotropic peptide isolated from the toxin of the Black Judean scorpion that activates neuronal tetrodotoxin-sensitive sodium channels. Methods and Results— All venoms and peptides were isolated from Black Judean Scorpions (Buthotus Hottentotta) caught in the Judean Desert. The full scorpion venom increased left ventricular function in sedated mice in vivo, prolonged ventricular repolarization, and provoked ventricular arrhythmias. An inotropic peptide (BjIP) isolated from the full venom by chromatography increased cardiac contractility but did neither provoke ventricular arrhythmias nor prolong cardiac repolarization. BjIP increased intracellular calcium in ventricular cardiomyocytes and prolonged inactivation of the cardiac sodium current. Low concentrations of tetrodotoxin (200 nmol/L) abolished the effect of BjIP on calcium transients and sodium current. BjIP did not alter the function of Nav 1.5 , but selectively activated the brain-type sodium channels Nav 1.6 or Nav 1.3 in cellular electrophysiological recordings obtained from rodent thalamic slices. Nav 1.3 (SCN3A) mRNA was detected in human and mouse heart tissue. Conclusions— Our pilot experiments suggest that selective activation of tetrodotoxin-sensitive neuronal sodium channels can safely increase cardiac contractility. As such, the peptide described here may become a lead compound for a new class of positive inotropic agents. </jats:sec

A descriptive analysis of relations between parents' self-reported smoking behavior and infants' daily exposure to environmental tobacco smoke

<p>Abstract</p> <p>Background</p> <p>The aims of the present study were to examine relations between parents' self-reported smoking behavior and infants' daily exposure to environmental tobacco smoke, as assessed by urinary cotinine-to-creatinine ratio (CCR), and to describe the CCR over seven days among infants at home.</p> <p>Methods</p> <p>A convenience sample of 27 households was drawn. Each household had to have at least one daily tobacco smoker and one child up to three years of age. Over a seven-day period, urine samples were obtained from the child daily. To examine relations between parents' self-reported smoking and infants' daily CCR, generalized estimating equation (GEE) analysis was used.</p> <p>Results</p> <p>The data revealed that infants from households with indoor smoking had higher CCRs than infants in households with outdoor smoking. CCRs were higher in girls than in boys. Older infants had lower CCRs than younger infants. Smoking outside the home versus inside the home, infant's gender, and infants' age accounted for 68% of the variance in CCR in a GEE data analysis model. No increase or decrease of CCR over time was found.</p> <p>Conclusion</p> <p>The findings suggest that parents' self-reported smoking indoors at home versus outdoors is predictive of CCR among infants three and younger. Higher CCR concentrations in girls' urine need further examination. Furthermore, significant fluctuations in daily CCR were not apparent in infants over a seven-day time period.</p

One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis

Objective: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Design: Retrospective study conducted between 1997 and 2004. Setting: University-affiliated paediatric intensive care unit (PICU). Patients and participants: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Interventions: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12h and 24h. To assess disease severity, PRISM score and selected laboratory parameters were determined. Measurements and main results: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24h after admission. Conclusions: Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24h. It might therefore increase risk of death

Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker

BACKGROUND: To evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies. METHODS: The Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up. RESULTS: Ep-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor. CONCLUSION: Our results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention