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.     

Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models

Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics.     

Verifying Global Minima for L 2 Minimization Problems in Multiple View Geometry

We consider the least-squares (L2) minimization problems in multiple view geometry for triangulation, homography, camera resectioning and structure-and-motion with known rotation, or known plane. Although optimal algorithms have been given for these problems under an L-infinity cost function, finding optimal least-squares solutions to these problems is difficult, since the cost functions are not convex, and in the worst case may have multiple minima. Iterative methods can be used to find a good solution, but this may be a local minimum. This paper provides a method for verifying whether a local-minimum solution is globally optimal, by providing a simple and rapid test involving the Hessian of the cost function. The basic idea is that by showing that the cost function is convex in a restricted but large enough neighbourhood, a sufficient condition for global optimality is obtained. The method is tested on numerous problem instances of real data sets. In the vast majority of cases we are able to verify that the solutions are optimal, in particular, for small to medium-scale problems.     

Only connect

It is supposedly easier to connect with other human beings in the era of ubiquitous technology. Connecting requires action and an element of risk taking in a context of dynamic uncertainty and incomplete information. The article explores what is involved in developing sustainable connections. We reflect on the context of “Socially Useful Artificial Intelligence”, the focus of the first article in issue 1.1.1987 of AI & Society, and explore subsequent research in a changing world. The arguments are illustrated through an account of the development of the Penny University, from a London coffee house to a potential international virtual institution.     

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.