Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.     

Monkeypox: A New Threat?

The global vaccination programme against smallpox led to its successful eradication and averted millions of deaths. Monkeypox virus (MPXV) is a close relative of the Variola (smallpox) virus. Due to antigenic similarity, smallpox vaccines cross-protect against MPXV. However, over 70% of people living today were never vaccinated against smallpox. Symptoms of monkeypox (MPX) include fever, head- and muscle ache, lymphadenopathy and a characteristic rash that develops into papules, vesicles and pustules which eventually scab over and heal. MPX is less often fatal (case fatality rates range from <1% to up to 11%) than smallpox (up to 30%). MPXV is endemic in sub-Saharan Africa, infecting wild animals and causing zoonotic outbreaks. Exotic animal trade and international travel, combined with the increasing susceptibility of the human population due to halted vaccination, facilitated the spread of MPXV to new areas. The ongoing outbreak, with >10,000 cases in >50 countries between May and July 2022, shows that MPXV can significantly spread between people and may thus become a serious threat to public health with global consequences. Here, we summarize the current knowledge about this re-emerging virus, discuss available strategies to limit its spread and pathogenicity and evaluate its risk to the human population.     

Models and emerging trends of concurrent constraint programming

Concurrent Constraint Programming (CCP) has been used over the last two decades as an elegant and expressive model for concurrent systems. It models systems of agents communicating by posting and querying partial information, represented as constraints over the variables of the system. This covers a vast variety of systems as those arising in biological phenomena, reactive systems, net-centric computing and the advent of social networks and cloud computing. In this paper we survey the main applications, developments and current trends of CCP.     

保存平民记忆的博物馆

要证实哪个国家的博物馆的密度最高是很困难的,因为这在很大程度上取决于所使用的标准。然而,荷兰确实进入了世界前10名的行列。——荷兰博物馆学家彼得·冯·门斯奇     

采用单独碳化室压力调节系统减少焦炉排放

PROven(R)系统的开发为了减少焦炉的排放,过去已进行了多种技术的开发.但是从焦炉炉门、装料孔边缘等处逸散物的减少,已受到工艺技术的制约.一个基本的制约因素是,在集气总管内的压力和联接到总管的所有碳化室内的压力之间有着密不可分的关系.     

The Dynamic Emission Zone in Sandwich Polymer Light‐Emitting Electrochemical Cells

In light‐emitting electrochemical cells (LECs), the position of the emission zone (EZ) is not predefined via a multilayer architecture design, but governed by a complex motion of electrical and ionic charges. As a result of the evolution of doped charge transport layers that enclose a dynamic intrinsic region until steady state is reached, the EZ is often dynamic during turn‐on. For thick sandwich polymer LECs, a continuous change of the emission color provides a direct visual indication of a moving EZ. Results from an optical and electrical analysis indicate that the intrinsic zone is narrow at early times, but starts to widen during operation, notably well before the electrical device optimum is reached. Results from numerical simulations demonstrate that the only precondition for this event to occur is that the mobilities of anions (μ_a) and cations (μ_c) are not equal, and the direction of the EZ shift dictates μ_c > μ_a. Quantitative ion profiles reveal that the displacement of ions stops when the intrinsic zone stabilizes, confirming the relation between ion movement and EZ shift. Finally, simulations indicate that the experimental current peak for constant‐voltage operation is intrinsic and the subsequent decay does not result from degradation, as commonly stated.     

提高电池供电应用系统的电源效率

开关式电源的效率可以接近100％，但在低负载电流工作下其效率则会大幅下降，甚至低于线性稳压器。采用断续导电模式（DCM)再配合多种不同的操作模式，可以提高开关式电源的效率。