RYR1 mutations are a common cause of congenital myopathies with central nuclei.

OBJECTIVE: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. METHODS: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. RESULTS: The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. INTERPRETATION: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.

Analysis, modeling and optimal control of COVID-19 outbreak with three forms of infection in Democratic Republic of the Congo.

This paper deals with modeling and simulation of the novel coronavirus in which the infectious individuals are divided into three subgroups representing three forms of infection. The rigorous analysis of the mathematical model is provided. We provide also a rigorous derivation of the basic reproduction number R 0 . For R 0 < 1 , we prove that the Disease Free Equilibium (DFE) is Globally Asymptotically Stable (GAS), thus COVID-19 extincts; whereas for R 0 > 1 , we found the co-existing phenomena under some assumptions and parametric values. Elasticity indices for R 0 with respect to different parameters are calculated with baseline parameter values estimated. We also prove that a transcritical bifurcation occurs at R 0 = 1 . Taking into account the control strategies like screening, treatment and isolation (social distancing measures), we present the optimal control problem of minimizing the cost due to the application of these measures. By reducing the values of some parameters, such as death rates (representing a management effort for all categories of people) and recovered rates (representing the action of reduction in transmission, improved screening, treatment for individuals diagnosed positive to COVID-19 and the implementation of barrier measures limiting contamination for undiagnosed individuals), it appears that after 140 - 170 days, the peak of the pandemic is reached and shows that by continuing with this strategy, COVID-19 could be eliminated in the population.

Analysis of a model of gambiense sleeping sickness in humans and cattle.

Human African Trypanosomiasis (HAT) and Nagana in cattle, commonly called sleeping sickness, is caused by trypanosome protozoa transmitted by bites of infected tsetse flies. We present a deterministic model for the transmission of HAT caused by Trypanosoma brucei gambiense between human hosts, cattle hosts and tsetse flies. The model takes into account the growth of the tsetse fly, from its larval stage to the adult stage. Disease in the tsetse fly population is modeled by three compartments, and both the human and cattle populations are modeled by four compartments incorporating the two stages of HAT. We provide a rigorous derivation of the basic reproduction number R0. For R0 < 1, the disease free equilibrium is globally asymptotically stable, thus HAT dies out; whereas (assuming no return to susceptibility) for R0 >1, HAT persists. Elasticity indices for R0 with respect to different parameters are calculated with baseline parameter values appropriate for HAT in West Africa; indicating parameters that are important for control strategies to bring R0 below 1. Numerical simulations with R0 > 1 show values for the infected populations at the endemic equilibrium, and indicate that with certain parameter values, HAT could not persist in the human population in the absence of cattle.