Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth

The heterotetrameric architecture of the epithelial sodium channel (ENaC).

The epithelial sodium channel (ENaC) is a key element for the maintenance of sodium balance and the regulation of blood pressure. Three homologous ENaC subunits (alpha, beta and gamma) assemble to form a highly Na+-selective channel. However, the subunit stoichiometry of ENaC has not yet been solved. Quantitative analysis of cell surface expression of ENaC alpha, beta and gamma subunits shows that they assemble according to a fixed stoichiometry, with alpha ENaC as the most abundant subunit. Functional assays based on differential sensitivities to channel blockers elicited by mutations tagging each alpha, beta and gamma subunit are consistent with a four subunit stoichiometry composed of two alpha, one beta and one gamma. Expression of concatameric cDNA constructs made of different combinations of ENaC subunits confirmed the four subunit channel stoichiometry and showed that the arrangement of the subunits around the channel pore consists of two alpha subunits separated by beta and gamma subunits

Stacked graphene nanoplatelet paper sensor for protein detection

Carbon-based sensors have shown great potential to revolutionize protein diagnostic tools, including the ability to detect pathogens and biomarkers. Many different microdevices have been fabricated using carbon nanotubes and graphene nanoplatelets. However, creating devices on the nanoscale can be difficult and expensive. Stacked graphene nanoparticle composites (hereafter called graphene paper) are a convenient and novel technology that has not been previously reported as a carbon-based sensor platform. Graphene paper is inexpensive and available on a macroscale, making device construction simple. Additional advantages include that paper composition and additives can be manipulated to increase the sensitivity and eventually the selectivity of proteins. We have created a microdevice sensor that detects proteins in solution by measuring the surface electrical resistivity of graphene/cellulose composite paper as a function of protein concentration. Four different proteins were tested for their ability to change the surface resistivity of the graphene paper and there was a clear correlation between the molecular weight of the protein and the equilibrium dissociation constant calculated by fitting the protein adsorption data to the Langmuir isotherm model. This result implies that the dissociation constant is likely a function of the size of the protein. © 2013 Elsevier B.V

The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin

Huntington's disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini. By virtue of its N-terminal polyQ domain, HTT has an intrinsically disordered amino terminus. In studies employing immortalized cells, primary neurons and a knock-in (KI) mouse model of HD, we tested the effect of Ube2W deficiency on mHTT levels, aggregation and neurotoxicity. In cultured cells, deficiency of Ube2W activity markedly decreases mHTT aggregate formation and increases the level of soluble monomers, while reducing mHTT-induced cytotoxicity. Consistent with this result, the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. This study sheds light on the potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in this polyQ neurodegenerative disease

Associations Among Hip Structure, Bone Mineral Density, and Strength Vary With External Bone Size in White Women

ABSTRACT Bone mineral density (BMD) is heavily relied upon to reflect structural changes affecting hip strength and fracture risk. Strong correlations between BMD and strength are needed to provide confidence that structural changes are reflected in BMD and, in turn, strength. This study investigated how variation in bone structure gives rise to variation in BMD and strength and tested whether these associations differ with external bone size. Cadaveric proximal femurs (n = 30, White women, 36–89+ years) were imaged using nanocomputed tomography (nano‐CT) and loaded in a sideways fall configuration to assess bone strength and brittleness. Bone voxels within the nano‐CT images were projected onto a plane to create pseudo dual‐energy X‐ray absorptiometry (pseudo‐DXA) images consistent with a clinical DXA scan. A validation study using 19 samples confirmed pseudo‐DXA measures correlated significantly with those measured from a commercially available DXA system, including bone mineral content (BMC) (R2 = 0.95), area (R2 = 0.58), and BMD (R2 = 0.92). BMD–strength associations were conducted using multivariate linear regression analyses with the samples divided into narrow and wide groups by pseudo‐DXA area. Nearly 80% of the variation in strength was explained by age, body weight, and pseudo‐DXA BMD for the narrow subgroup. Including additional structural or density distribution information in regression models only modestly improved the correlations. In contrast, age, body weight, and pseudo‐DXA BMD explained only half of the variation in strength for the wide subgroup. Including bone density distribution or structural details did not improve the correlations, but including post‐yield deflection (PYD), a measure of bone material brittleness, did increase the coefficient of determination to more than 70% for the wide subgroup. This outcome suggested material level effects play an important role in the strength of wide femoral necks. Thus, the associations among structure, BMD, and strength differed with external bone size, providing evidence that structure–function relationships may be improved by judiciously sorting study cohorts into subgroups. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research