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.     

Graphene nanoplatelets composite membranes for thermal comfort enhancement in performance textiles

The advent of 2D nanostructured materials as advanced fillers for polymer matrix composites has opened the doors to a plethora of new industrial applications requiring both electric and thermal management. Unique properties, in fact, can arise from accurate selection and processing of 2D fillers and their matrix. Here, we report an innovative family of nanocomposite membranes based on polyurethane (PU) and graphene nanoplatelets (GNPs), designed to improve thermal comfort in functional textiles. GNP particles were thoroughly characterized (through Raman, atomic force microscopy, high-resolution TEM, scanning electron microscope), and showed high crystallinity (I_D/I_G = 0.127), low thickness (D50 < 6–8 layers), and high lateral dimensions (D50 ≈ 3 μm). When GNPs were loaded (up to 10% wt/wt) into the PU matrix, their homogeneous dispersion resulted in an increase of the in-plane thermal conductivity of composite membranes up to 471%. The thermal dissipation of membranes, alone or coupled with cotton fabric, was further evaluated by means of an ad hoc system designed to simulate a human forearm. The results obtained provide a new strategy for the preparation of membranes suitable for technical textiles, with improved thermal comfort.     

Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties

KCND3 encodes the voltage-gated potassium channel K_V4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K_V4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the K_V4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K_V4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K_V4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.     

SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.     

Prediction and optimization of electroplated Ni-based coating composition and thickness using central composite design and artificial neural network

Journal of Applied Electrochemistry - The choice of the electroplating conditions of Ni-based alloys has always been a serious research question. In this study, an artificial neural network based...     

Spectral characterization of periglacial surfaces and geomorphological units in the Arctic Lena Delta using field spectrometry and remote sensing

Important environmental parameters in arctic periglacial landscapes (i.e. permafrost temperature, active-layer depth, soil moisture, precipitation, vegetation cover) will very likely change in a warming climate. The thawing of permafrost, especially, might cause massive landscape changes due to thermokarst and an enhanced release of greenhouse gasses from the large amounts of carbon stored in frozen deposits, resulting in positive climate-warming feedback. For the identification, mapping, and quantification of such changes on various scales up to the entire circum-Arctic, remote sensing and spatial data analysis are essential tools. In this study an extensive field-work dataset including spectral surface properties, vegetation, soils, and geomorphology was acquired in the largest Arctic delta formed by a single river, the Siberian Lena River Delta. A portable field spectrometer (ASD FieldSpec Pro FR®) was used for spectral surveys of terrain surfaces, and optical satellite data (Landsat Enhanced Thematic Mapper (ETM+), CHRIS-Proba) were used for the characterization, manual mapping, and automatic classification of typical periglacial land-cover units in the Lena Delta. Qualitative data from soils, vegetation, soil moisture, and relief units were correlated with the field-spectral data and catalogued for a wide variety of surface types. The wide range of micro- and meso-scale variations of periglacial surface features in the delta results in distinctive spectral characteristics for different land-cover units. The three main delta terraces could also be spectrally separated and characterized. The present dataset provides a basis for further spectral data acquisitions in the Lena Delta and for comparisons with periglacial surfaces from other regions.     

Are moods motivational states? A study on effort-related cardiovascular response.

Based on the mood-behavior-model (Gendolla, 2000), this study tested the idea that moods only have effects on effort mobilization in settings that directly call for this and in which people can thus use their moods as task-relevant information. Fifty university students were randomly assigned to a 2 (Mood: negative vs. positive) × 2 (Memorizing: intentional vs. incidental) × 2 (Time: mood induction vs. task performance) mixed model design. Effort mobilization was operationalized as systolic blood pressure (SBP) reactivity. As expected, in the intentional-memorizing condition, SBP reactivity was stronger in a negative mood than in a positive mood. Mood had no impact in the incidental-memorizing condition, which did not call for effort mobilization. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An Equal-Order DG Method for the Incompressible Navier-Stokes Equations

We introduce and analyze a discontinuous Galerkin method for the incompressible Navier-Stokes equations that is based on finite element spaces of the same polynomial order for the approximation of the velocity and the pressure. Stability of this equal-order approach is ensured by a pressure stabilization term. A simple element-by-element post-processing procedure is used to provide globally divergence-free velocity approximations. For small data, we prove the existence and uniqueness of discrete solutions and carry out an error analysis of the method. A series of numerical results are presented that validate our theoretical findings.     

Tuneable Heterodyne Infrared Spectrometer for atmospheric and astronomical studies

The transportable setup of the Cologne Tuneable Heterodyne Infrared Spectrometer (THIS) is presented. Frequency tuneability over a wide range provided by the use of tuneable diode lasers as local oscillators (LO) allows a variety of molecules in the mid-infrared to be observed. Longtime integration, which is essential for astronomical observations, is possible owing to tight frequency control of the LO with optical feedback from an external cavity. THIS is developed to fly on the Stratospheric Observatory for Infrared Astronomy beginning in 2006 but can also be used on different types of ground-based telescopes.