Complex patterns of spontaneous initiations and terminations of reentrant circulation in a loop of cardiac tissue

A two-component model is developed that consists of a discrete loop of cardiac cells that circulates action potentials together with a cardiac pacing mechanism. Physiological properties of cells such as restitutions of refractoriness and of conduction velocity are given via experimentally measured functions. The dynamics of circulating pulses and their interactions with the pacer are regulated by two threshold relations. Patterns of spontaneous initiations and terminations of reentry (SITR) generated by this system are studied through numerical simulations and analytical observations. These patterns can be regular or irregular; causes of irregularities are identified as the threshold bistability of reentrant circulation (T-bistability) and in some cases, also phase-resetting interactions with the pacer.Comment: 27 pages, 10 figures, 61 references; A version of this paper (same results) is to appear in the Journal of Theoretical Biology; arXiv V2 adds helpful commments to facilitate reading and corrects minor errors in presentatio

A dynamical model of lipoprotein metabolism

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Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by & UDelta;24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRa deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRa-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.Metabolic health: pathophysiological trajectories and therap

Prevalence of Frailty in European Emergency Departments (FEED): an international flash mob study

Introduction Current emergency care systems are not optimized to respond to multiple and complex problems associated with frailty. Services may require reconfiguration to effectively deliver comprehensive frailty care, yet its prevalence and variation are poorly understood. This study primarily determined the prevalence of frailty among older people attending emergency care. Methods This cross-sectional study used a flash mob approach to collect observational European emergency care data over a 24-h period (04 July 2023). Sites were identified through the European Task Force for Geriatric Emergency Medicine collaboration and social media. Data were collected for all individuals aged 65 + who attended emergency care, and for all adults aged 18 + at a subset of sites. Variables included demographics, Clinical Frailty Scale (CFS), vital signs, and disposition. European and national frailty prevalence was determined with proportions with each CFS level and with dichotomized CFS 5 + (mild or more severe frailty). Results Sixty-two sites in fourteen European countries recruited five thousand seven hundred eighty-five individuals. 40% of 3479 older people had at least mild frailty, with countries ranging from 26 to 51%. They had median age 77 (IQR, 13) years and 53% were female. Across 22 sites observing all adult attenders, older people living with frailty comprised 14%. Conclusion 40% of older people using European emergency care had CFS 5 + . Frailty prevalence varied widely among European care systems. These differences likely reflected entrance selection and provide windows of opportunity for system configuration and workforce planning

Studies of non-isothermal flow in saturated and partially saturated porous media

Physical and numerical experiments have been performed to investigate the behavior of nonisothermal flow in two-dimensional saturated and partially saturated porous media. The physical experiments were performed to identify non-isothermal flow fields and temperature distributions in fully saturated, half-saturated, and residually saturated two-dimensional porous media with bottom heating and top cooling. Two counter-rotating liquid-phase convective cells were observed to develop in the saturated regions of all three cases. Gas-phase convection was also evidenced in the unsaturated regions of the partially saturated experiments. TOUGH2 numerical simulations of the saturated case were found to be strongly dependent on the assumed boundary conditions of the physical system. Models including heat losses through the boundaries of the test cell produced temperature and flow fields that were in better agreement with the observed temperature and flow fields than models that assumed insulated boundary conditions. A sensitivity analysis also showed that a reduction of the bulk permeability of the porous media in the numerical simulations depressed the effects of convection, flattening the temperature profiles across the test cell

Phosphorylation of histone H3 is functionally linked to retinoic acid receptor β promoter activation

Ligand-dependent transcriptional activation of retinoic acid receptors (RARs) is a multistep process culminating in the formation of a multimeric co-activator complex on regulated promoters. Several co-activator complexes harbor an acetyl transferase activity, which is required for retinoid-induced transcription of reporter genes. Using murine P19 embryonal carcinoma cells, we examined the relationship between histone post-translational modifications and activation of the endogenous RARβ2 promoter, which is under the control of a canonical retinoic acid response element and rapidly induced upon retinoid treatment. While histones H3 and H4 were constitutively acetylated at this promoter, retinoid agonists induced a rapid phosphorylation at Ser10 of histone H3. A retinoid antagonist, whose activity was independent of co-repressor binding to RAR, could oppose this agonist-induced H3 phosphorylation. Since such post-translational modifications were not observed at several other promoters, we conclude that histone H3 phosphorylation may be a molecular signature of the activated, retinoid-controlled mRARβ2 gene promoter