Gigaxonin, mutated in Giant Axonal Neuropathy, interacts with TDP-43 and other RNA binding proteins.

Giant Axonal Neuropathy (GAN) is a neurodegenerative disease caused by loss-of-function mutations in the KLHL16 gene, encoding the cytoskeleton regulator gigaxonin. In the absence of functional gigaxonin, intermediate filament (IF) proteins accumulate in neurons and other cell types due to impaired turnover and transport. GAN neurons exhibit distended, swollen axons and distal axonal degeneration, but the mechanisms behind this selective neuronal vulnerability are unknown. Our objective was to identify novel gigaxonin interactors pertinent to GAN neurons. Unbiased proteomics revealed a statistically significant predominance of RNA-binding proteins (RBPs) within the soluble gigaxonin interactome and among differentially-expressed proteins in iPSC-neuron progenitors from a patient with classic GAN. Among the identified RBPs was TAR DNA-binding protein 43 (TDP-43), which associated with the gigaxonin protein and its mRNA transcript. TDP-43 co-localized within large axonal neurofilament IFs aggregates in iPSC-motor neurons derived from a GAN patient with the 'axonal CMT-plus' disease phenotype. Our results implicate RBP dysfunction as a potential underappreciated contributor to GAN-related neurodegeneration. Summary: This work reveals that the neurodegeneration-associated protein and cytoskeleton regulator gigaxonin and its mRNA associate with numerous RNA binding proteins. These findings shift understanding of normal gigaxonin function and provide insights into how disease-causing mutations in the gigaxonin-encoding gene ( KLHL16 ) may ignite a pathogenic cascade in neurons.

Stability dynamics of neurofilament and GFAP networks and protein fragments.

Neurofilaments (NFs) and GFAP are cytoskeletal intermediate filaments (IFs) that support cellular processes unfolding within the uniquely complex environments of neurons and astrocytes, respectively. This review highlights emerging concepts on the transitions between stable and destabilized IF networks in the nervous system. While self-association between transiently structured low-complexity IF domains promotes filament assembly, the opposing destabilizing actions of phosphorylation-mediated filament severing facilitate faster intracellular transport. Cellular proteases, including caspases and calpains, produce a variety of IF fragments, which may interact with N-degron and C-degron pathways of the protein degradation machinery. The rapid adoption of NF and GFAP-based clinical biomarker tests is contrasted with the lagging understanding of the dynamics between the native IF proteins and their fragments.

Calpain-mediated proteolysis of vimentin filaments is augmented in giant axonal neuropathy fibroblasts exposed to hypotonic stress.

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by loss-of-function mutations in the E3 ubiquitin ligase adaptor gigaxonin, which is encoded by the KLHL16 gene. Gigaxonin regulates the degradation of multiple intermediate filament (IF) proteins, including neurofilaments, GFAP, and vimentin, which aggregate in GAN patient cells. Understanding how IFs and their aggregates are processed under stress can reveal new GAN disease mechanisms and potential targets for therapy. Here we tested the hypothesis that hypotonic stress-induced vimentin proteolysis is impaired in GAN. In both GAN and control fibroblasts exposed to hypotonic stress, we observed time-dependent vimentin cleavage that resulted in two prominent ∼40-45 kDa fragments. However, vimentin proteolysis occurred more rapidly and extensively in GAN cells compared to unaffected controls as both fragments were generated earlier and at 4-6-fold higher levels. To test enzymatic involvement, we determined the expression levels and localization of the calcium-sensitive calpain proteases-1 and -2 and their endogenous inhibitor calpastatin. While the latter was not affected, the expression of both calpains was 2-fold higher in GAN cells compared to control cells. Moreover, pharmacologic inhibition of calpains with MDL-28170 or MG-132 attenuated vimentin cleavage. Imaging analysis revealed striking colocalization between large perinuclear vimentin aggregates and calpain-2 in GAN fibroblasts. This colocalization was dramatically altered by hypotonic stress, where selective breakdown of filaments over aggregates occurred rapidly in GAN cells and coincided with calpain-2 cytoplasmic redistribution. Finally, mass spectrometry-based proteomics revealed that phosphorylation at Ser-412, located at the junction between the central "rod" domain and C-terminal "tail" domain on vimentin, is involved in this stress response. Over-expression studies using phospho-deficient and phospho-mimic mutants revealed that Ser-412 is important for filament organization, solubility dynamics, and vimentin cleavage upon hypotonic stress exposure. Collectively, our work reveals that osmotic stress induces calpain- and proteasome-mediated vimentin degradation and IF network breakdown. These effects are significantly augmented in the presence of disease-causing KLHL16 mutations that alter intermediate filament organization. While the specific roles of calpain-generated vimentin IF fragments in GAN cells remain to be defined, this proteolytic pathway is translationally-relevant to GAN because maintaining osmotic homeostasis is critical for nervous system function.

Fabry-Pérot Phonon Polaritons in Boron Nitride Nanotube Resonators.

Phonon polaritons (PhPs) offer extreme confinement of optical fields and strong dispersion in the mid-infrared spectral region. To study the propagation and interference of PhPs in a 1-D system, we employ scattering scanning near-field optical microscopy (s-SNOM), analytical, and computational techniques to describe the resonance behavior observed in boron nitride nanotubes (BNNTs). In BNNTs of a sufficiently small length, the reflected standing waves from both terminals strongly interfere with one another, leading to large constructive enhancement at select wavelengths through the Fabry-Pérot interference. This 1-D nanoresonant behavior illustrates methods to increase and localize field strength at positions on a BNNT nanotube.

High COVID-19 Attack Rate Among Attendees at Events at a Church - Arkansas, March 2020.

On March 16, 2020, the day that national social distancing guidelines were released (1), the Arkansas Department of Health (ADH) was notified of two cases of coronavirus disease 2019 (COVID-19) from a rural county of approximately 25,000 persons; these cases were the first identified in this county. The two cases occurred in a husband and wife; the husband is the pastor at a local church (church A). The couple (the index cases) attended church-related events during March 6-8, and developed nonspecific respiratory symptoms and fever on March 10 (wife) and 11 (husband). Before his symptoms had developed, the husband attended a Bible study group on March 11. Including the index cases, 35 confirmed COVID-19 cases occurred among 92 (38%) persons who attended events held at church A during March 6-11; three patients died. The age-specific attack rates among persons aged ≤18 years, 19-64 years, and ≥65 years were 6.3%, 59.4%, and 50.0%, respectively. During contact tracing, at least 26 additional persons with confirmed COVID-19 cases were identified among community members who reported contact with church A attendees and likely were infected by them; one of the additional persons was hospitalized and subsequently died. This outbreak highlights the potential for widespread transmission of SARS-CoV-2, the virus that causes COVID-19, both at group gatherings during church events and within the broader community. These findings underscore the opportunity for faith-based organizations to prevent COVID-19 by following local authorities' guidance and the U.S. Government's Guidelines: Opening Up America Again (2) regarding modification of activities to prevent virus transmission during the COVID-19 pandemic.

Surface and Volume Phonon Polaritons in Boron Nitride Nanotubes.

Phonon polaritons (PhPs) are quasiparticles created by coupling of photons to polar lattice vibrations. Previously, PhPs have been observed as both surface and volume confined waves. The dispersion of the polariton depends strongly on the nature of the material. Volume polaritons show asymptotic behavior near the longitudinal optical phonon frequency of the material, whereas surface polaritons instead approach the surface phonon frequency. Boron nitride nanotubes (BNNTs) were found to exhibit the dispersion of volume modes below the surface phonon frequency. However, around and above the surface phonon frequency, the behavior becomes that of a surface wave with an amplified near-field response. These findings improve our understanding of photonics within BNNTs and suggest potential applications that take advantage of the high fields and density of states in that spectral region.

Recent Fast Food Consumption and Bisphenol A and Phthalates Exposures among the U.S. Population in NHANES, 2003-2010.

BACKGROUND: Phthalates and bisphenol A (BPA) are widely used industrial chemicals that may adversely impact human health. Human exposure is ubiquitous and can occur through diet, including consumption of processed or packaged food. OBJECTIVE: To examine associations between recent fast food intake and BPA and urinary metabolites of di(2-ethylhexyl) phthalate (ΣDEHPm) and diisononyl phthalate (DiNPm) among the U.S. METHODS: We combined data on 8,877 participants from the National Health and Nutrition Examination Survey (NHANES 2003-2010). Using 24-hr dietary recall data, we quantified: a) fast food intake [percent of total energy intake (TEI) from fast food]; b) fast food-derived fat intake (percent of TEI from fat in fast food); and c) fast food intake by food group (dairy, eggs, grains, meat, and other). We examined associations between dietary exposures and urinary chemical concentrations using multivariate linear regression. RESULTS: We observed evidence of a positive, dose-response relationship between fast food intake and exposure to phthalates (p-trend < 0.0001) but not BPA; participants with high consumption (≥ 34.9% TEI from fast food) had 23.8% (95% CI: 11.9%, 36.9%) and 39.0% (95% CI: 21.9%, 58.5%) higher levels of ΣDEHPm and DiNPm, respectively, than nonconsumers. Fast food-derived fat intake was also positively associated with ΣDEHPm and DiNPm (p-trend < 0.0001). After adjusting for other food groups, ΣDEHPm was associated with grain and other intake, and DiNPm was associated with meat and grain intake. CONCLUSION: Fast food may be a source of exposure to DEHP and DiNP. These results, if confirmed, could inform individual and regulatory exposure reduction strategies. CITATION: Zota AR, Phillips CA, Mitro SD. 2016. Recent fast food consumption and bisphenol A and phthalates exposures among the U.S. population in NHANES, 2003-2010. Environ Health Perspect 124:1521-1528; http://dx.doi.org/10.1289/ehp.1510803.

Aller vers le "cocobai": La reconstruction et les personnes handicapées en Haïti

Ce cahier de politique analyse le Plan dÆaction pour le relèvement et le développement national dÆHaïti du point de vue de lÆincapacité pour en identifier les lacunes et faire des recommandations quant aux solutions pour les combler à faible coût. Les recommandations formulées concernent les domaines de l'intégration des personnes handicapées, la santé, la justice, l'éducation, l'emploi et les édifices publics. De plus, il identifie en annexe les groupes locaux et internationaux existants qui tentent déjà de combler certaines de ces lacunes. Il s'agit de la version du cahier en français.

Reaching the "cocobai": Reconstruction and persons with disabilities in Haiti

Ce cahier de politique analyse le Plan dÆaction pour le relèvement et le développement national dÆHaïti du point de vue de lÆincapacité pour en identifier les lacunes et faire des recommandations quant aux solutions pour les combler à faible coût. Les recommandations formulées concernent les domaines de l'intégration des personnes handicapées, la santé, la justice, l'éducation, l'emploi et les édifices publics. De plus, il identifie en annexe les groupes locaux et internationaux existants qui tentent déjà de combler certaines de ces lacunes. Il s'agit de la version du cahier en anglais.