Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice

The amino acid sequence of amyloid precursor protein (APP) is highly conserved, and age-related Abeta aggregates have been described in a variety of vertebrate animals, with the notable exception of mice and rats. Three amino acid substitutions distinguish mouse and human Abeta that might contribute to their differing properties in vivo. To examine the amyloidogenic potential of mouse Abeta, we studied several lines of transgenic mice overexpressing wild-type mouse amyloid precursor protein (moAPP) either alone or in conjunction with mutant PS1 (PS1dE9). Neither overexpression of moAPP alone nor co-expression with PS1dE9 caused mice to develop Alzheimer-type amyloid pathology by 24 months of age. We further tested whether mouse Abeta could accelerate the deposition of human Abeta by crossing the moAPP transgenic mice to a bigenic line expressing human APPswe with PS1dE9. The triple transgenic animals (moAPP x APPswe/PS1dE9) produced 20% more Abeta but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings. Instead, the additional mouse Abeta increased the detergent solubility of accumulated amyloid and exacerbated amyloid deposition in the vasculature. These findings suggest that, although mouse Abeta does not influence the rate of amyloid formation, the incorporation of Abeta peptides with differing sequences alters the solubility and localization of the resulting aggregates

GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.

Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness

CLEAR II: Evidence for Early Formation of the Most Compact Quiescent Galaxies at High Redshift

The origin of the correlations between mass, morphology, quenched fraction, and formation history in galaxies is difficult to define, primarily due to the uncertainties in galaxy star-formation histories. Star-formation histories are better constrained for higher redshift galaxies, observed closer to their formation and quenching epochs. Here we use "non-parametric" star-formation histories and a nested sampling method to derive constraints on the formation and quenching timescales of quiescent galaxies at $0.7<z<2.5$. We model deep HST grism spectroscopy and photometry from the CLEAR (CANDELS Lyman$-\alpha$ Emission at Reionization) survey. The galaxy formation redshifts, $z_{50}$ (defined as the point where they had formed 50\% of their stellar mass) range from $z_{50}\sim 2$ (shortly prior to the observed epoch) up to $z_{50} \simeq 5-8$. \editone{We find that early formation redshifts are correlated with high stellar-mass surface densities, $\log \Sigma_1 / (M_\odot\ \mathrm{kpc}^{-2}) >$10.25, where $\Sigma_1$ is the stellar mass within 1~pkpc (proper kpc). Quiescent galaxies with the highest stellar-mass surface density, $\log\Sigma_1 / (M_\odot\ \mathrm{kpc}^{-2}) > 10.25$, } show a \textit{minimum} formation redshift: all such objects in our sample have $z_{50} > 2.9$. Quiescent galaxies with lower surface density, $\log \Sigma_1 / (M_\odot\ \mathrm{kpc}^{-2}) = 9.5 - 10.25$, show a range of formation epochs ($z_{50} \simeq 1.5 - 8$), implying these galaxies experienced a range of formation and assembly histories. We argue that the surface density threshold$\log\Sigma_1/(M_\odot\ \mathrm{kpc}^{-2})>10.25$ uniquely identifies galaxies that formed in the first few Gyr after the Big Bang, and we discuss the implications this has for galaxy formation models.Comment: 13 pages, 7 figures, accepted for publication in ApJ. Includes an interactive online appendix (https://vince-ec.github.io/appendix/appendix

CLEAR I: Ages and Metallicities of Quiescent Galaxies at 1.0<z<1.8\mathbf{1.0 < z < 1.8} Derived from Deep Hubble Space Telescope Grism Data

We use deep \textit{Hubble Space Telescope} spectroscopy to constrain the metallicities and (\editone{light-weighted}) ages of massive ($\log M_\ast/M_\odot\gtrsim10$) galaxies selected to have quiescent stellar populations at $1.0<z<1.8$. The data include 12--orbit depth coverage with the WFC3/G102 grism covering $\sim$ $8,000<\lambda<11,500$~\AA\, at a spectral resolution of $R\sim 210$ taken as part of the CANDELS Lyman-$\alpha$ Emission at Reionization (CLEAR) survey. At $1.0<z<1.8$, the spectra cover important stellar population features in the rest-frame optical. We simulate a suite of stellar population models at the grism resolution, fit these to the data for each galaxy, and derive posterior likelihood distributions for metallicity and age. We stack the posteriors for subgroups of galaxies in different redshift ranges that include different combinations of stellar absorption features. Our results give \editone{light-weighted ages of $t_{z \sim 1.1}= 3.2\pm 0.7$~Gyr, $t_{z \sim 1.2}= 2.2\pm 0.6$~Gyr, $t_{z\sim1.3}= 3.1\pm 0.6$~Gyr, and $t_{z\sim1.6}= 2.0 \pm 0.6$~Gyr, \editone{for galaxies at $z\sim 1.1$, 1.2, 1.3, and 1.6. This} implies that most of the massive quiescent galaxies at $168$\% of their stellar mass by a redshift of $z>2$}. The posteriors give metallicities of \editone{$Z_{z\sim1.1}=1.16 \pm 0.29$~$Z_\odot$, $Z_{z\sim1.2}=1.05 \pm 0.34$~$Z_\odot$, $Z_{z\sim1.3}=1.00 \pm 0.31$~$Z_\odot$, and $Z_{z\sim1.6}=0.95 \pm 0.39$~$Z_\odot$}. This is evidence that massive galaxies had enriched rapidly to approximately Solar metallicities as early as $z\sim3$.Comment: 32 pages, 23 figures, Resubmited to ApJ after revisions in response to referee repor

The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries

BACKGROUND: Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations. OBJECTIVE: To characterize the diversity of cutaneous manifestations of COVID-19, and facilitate understanding of underlying pathophysiology. METHODS: Case series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies. RESULTS: The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, while retiform purpura presented exclusively in ill, hospitalized patients. LIMITATIONS: We cannot estimate incidence or prevalence. Confirmation bias is possible. CONCLUSION: This study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were non-specific, while others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology