Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

Synthesis and stereochemistry of bis(dithiacrown ether) and dodecylthio substituted (E)-thiodesaurines

Reductive dimerization of dodecylthio substituted 1,2-dithiole-3-thiones 6a–b and trithion-dithiacrown ethers 10a–c with triethyl phosphite furnished bis- and tetrakis (dodecylthio), and bis(dithiacrown ether) substituted thiodesaurines (E)- 11a–b and (E)- 12a–c . The stereochemistry of bis(dithia[15]crown-5)-thiodesaurine (E)- 12b has been determined by X-ray crystallographic analysis.     

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Hydrogen storage properties of the pseudo binary laves phase (Sc1−xZrx)(Co1−yNiy)2 system

The (Sc_1−xZr_x)(Co_1−yNi_y)₂-H_z system has been studied using both experimental techniques and ab initio calculations. The material was synthesised through high temperature synthesis and characterised using powder XRD. Hydrogen absorption and desorption was studied in-situ using synchrotron radiation. Maximal storage capacity increased when Co replaced Ni and substitution of Sc for Zr increased the equilibrium pressure. Density functional based calculations reproduce the experimental trends in terms of cell parameters both for the non-hydrogenated systems as well as for the hydrogenated systems, and helped to quantitatively understand the observed hydrogen uptake properties.     

Output SNR analysis of integrated active noise control and noise reduction in hearing aids under a single speech source scenario

This paper analyses the output signal-to-noise ratio for a standard noise reduction scheme based on the multichannel Wiener filter and for an integrated active noise control and noise reduction scheme based on the filtered-X multichannel Wiener filter, both applied in a hearing aid framework that includes the effects of signal leakage through an open fitting and secondary path effects. In previous work, integrating noise reduction and active noise control has been shown to allow to compensate for effects of signal leakage and secondary path effects. These experimental results are now verified theoretically. The output signal-to-noise ratios are derived under a single speech source scenario. Theoretical results are then compared to simulations for a single noise source scenario and a multiple noise sources scenario.     

A combined multi-channel Wiener filter-based noise reduction and dynamic range compression in hearing aids

Noise reduction (NR) and dynamic range compression (DRC) are basic components in hearing aids, but generally these components are developed and evaluated independently of each other. Hearing aids typically use a serial concatenation of NR and DRC. However, the DRC in such a concatenation negatively affects the performance of the NR stage: the residual noise after NR receives more amplification compared to the speech, resulting in a signal-to-noise-ratio (SNR) degradation. The integration of NR and DRC has not received a lot of attention so far. In this paper, a multi-channel Wiener filter (MWF)-based approach is presented for speech and noise scenarios, where an MWF-based NR algorithm is combined with DRC. The proposed solution is based on modifying the MWF and the DRC to incorporate the conditional speech presence probability in order to avoid residual noise amplification. The goal is then to analyse any undesired interaction effects by means of objective measures. Experimental results indeed confirm that a serial concatenation of NR and DRC degrades the SNR improvement provided by the NR, whereas the combined approach proposed here shows less degradation of the SNR improvement at a low increase in distortion compared to a serial concatenation.     

IL-18 But Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r^−/−- but not Il-1r^−/− mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.