Testing White Dwarf Crystallization Theory with Asteroseismology of the Massive Pulsating DA Star BPM 37093

It was predicted more than 40 years ago that the cores of the coolest white dwarf stars should eventually crystallize. This effect is one of the largest sources of uncertainty in white dwarf cooling models, which are now routinely used to estimate the ages of stellar populations in both the Galactic disk and the halo. We are attempting to minimize this source of uncertainty by calibrating the models, using observations of pulsating white dwarfs. In a typical mass white dwarf model, crystallization does not begin until the surface temperature reaches 6000-8000 K. In more massive white dwarf models the effect begins at higher surface temperatures, where pulsations are observed in the ZZ Ceti (DAV) stars. We use the observed pulsation periods of BPM 37093, the most massive DAV white dwarf presently known, to probe the interior and determine the size of the crystallized core empirically. Our initial exploration of the models strongly suggests the presence of a solid core containing about 90% of the stellar mass, which is consistent with our theoretical expectations.Comment: minor changes for length, accepted for ApJ Letter

Continuous macroscopic limit of a discrete stochastic model for interaction of living cells

In the development of multiscale biological models it is crucial to establish a connection between discrete microscopic or mesoscopic stochastic models and macroscopic continuous descriptions based on cellular density. In this paper a continuous limit of a two-dimensional Cellular Potts Model (CPM) with excluded volume is derived, describing cells moving in a medium and reacting to each other through both direct contact and long range chemotaxis. The continuous macroscopic model is obtained as a Fokker-Planck equation describing evolution of the cell probability density function. All coefficients of the general macroscopic model are derived from parameters of the CPM and a very good agreement is demonstrated between CPM Monte Carlo simulations and numerical solution of the macroscopic model. It is also shown that in the absence of contact cell-cell interactions, the obtained model reduces to the classical macroscopic Keller-Segel model. General multiscale approach is demonstrated by simulating spongy bone formation from loosely packed mesenchyme via the intramembranous route suggesting that self-organizing physical mechanisms can account for this developmental process.Comment: 4 pages, 3 figure

Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Neurobiology of Aging 47 (2016): 113–126, doi:10.1016/j.neurobiolaging.2016.07.015.Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.This work was supported by NIH grants R01 AG044372 (Nicholas M. Kanaan), R01 NS082730 (Nicholas M. Kanaan and Scott T. Brady), BrightFocus Foundation (A2013364S, Nicholas M. Kanaan), the Jean P. Schultz Biomedical Research Endowment (Nicholas M. Kanaan), the Secchia Family Foundation (Nicholas M. Kanaan) and NS066942A (Gerardo Morfini)

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport

AbstractIn Alzheimer's disease (AD), tau undergoes numerous modifications, including increased phosphorylation at serine-422 (pS422). In the human brain, pS422 tau protein is found in prodromal AD, correlates well with cognitive decline and neuropil thread pathology, and appears associated with increased oligomer formation and exposure of the N-terminal phosphatase-activating domain (PAD). However, whether S422 phosphorylation contributes to toxic mechanisms associated with disease-related forms of tau remains unknown. Here, we report that S422-pseudophosphorylated tau (S422E) lengthens the nucleation phase of aggregation without altering the extent of aggregation or the types of aggregates formed. When compared to unmodified tau aggregates, the S422E modification significantly increased the amount of SDS-stable tau dimers, despite similar levels of immunoreactivity with an oligomer-selective antibody (TOC1) and another antibody that reports PAD exposure (TNT1). Vesicle motility assays in isolated squid axoplasm further revealed that S422E tau monomers inhibited anterograde, kinesin-1 dependent fast axonal transport (FAT). Unexpectedly, and unlike unmodified tau aggregates, which selectively inhibit anterograde FAT, aggregates composed of S422E tau were found to inhibit both anterograde and retrograde FAT. Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT. Taken together, these findings identify a novel mechanistic basis by which pS422 confers upon tau a toxic effect that may directly contribute to axonal dysfunction in AD and other tauopathies

Tau: a signaling hub protein

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mueller, R. L., Combs, B., Alhadidy, M. M., Brady, S. T., Morfini, G. A., & Kanaan, N. M. Tau: a signaling hub protein. Frontiers in Molecular Neuroscience, 14, (2021): 647054, https://doi.org/10.3389/fnmol.2021.647054.Over four decades ago, in vitro experiments showed that tau protein interacts with and stabilizes microtubules in a phosphorylation-dependent manner. This observation fueled the widespread hypotheses that these properties extend to living neurons and that reduced stability of microtubules represents a major disease-driving event induced by pathological forms of tau in Alzheimer’s disease and other tauopathies. Accordingly, most research efforts to date have addressed this protein as a substrate, focusing on evaluating how specific mutations, phosphorylation, and other post-translational modifications impact its microtubule-binding and stabilizing properties. In contrast, fewer efforts were made to illuminate potential mechanisms linking physiological and disease-related forms of tau to the normal and pathological regulation of kinases and phosphatases. Here, we discuss published work indicating that, through interactions with various kinases and phosphatases, tau may normally act as a scaffolding protein to regulate phosphorylation-based signaling pathways. Expanding on this concept, we also review experimental evidence linking disease-related tau species to the misregulation of these pathways. Collectively, the available evidence supports the participation of tau in multiple cellular processes sustaining neuronal and glial function through various mechanisms involving the scaffolding and regulation of selected kinases and phosphatases at discrete subcellular compartments. The notion that the repertoire of tau functions includes a role as a signaling hub should widen our interpretation of experimental results and increase our understanding of tau biology in normal and disease conditions.This work was supported by NIH grants (R01AG067762 and R01AG044372 to NK, R01NS082730 to NK and SB, R01NS118177 and R21NS120126 to GM, R01NS023868 and R01NS041170 to SB), a gift from Neurodegenerative Research Inc. (GM), a Zenith Award from the Alzheimer’s Association (SB), a grant from the Secchia Family Foundation (NK), NIH/National Institute on Aging (NIA) funded Michigan Alzheimer’s Disease Research Center 5P30AG053760 (BC), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer-Reviewed Alzheimer’s Research Program (Award No. W81XWH-20-1-0174 to BC), and an Alzheimer’s Association Research Grant 20-682085 (BC)

Revisiting the anatomy of the cephalic vein, its origin, course and possible clinical correlations in relation to the anatomical snuffbox among Jordanian

Background: The cephalic vein is one of the most distinguished superficial veins of the upper limb. Its clinical value lies in venous access. There is little known about the variation of its formation in relation to the anatomical snuffbox. Hence, anatomical variants in the origin of the cephalic vein are important in clinical practice. Subsequently, this study was designed to examine the variation of the cephalic vein formation in relation to the anatomical snuffbox. Materials and methods: A cross-sectional study of 438 subjects (722 hands), was prepared to study the cephalic vein among Jordanian students and staff of one of the major governmental Medical College in Jordan, by using infrared illumination system. The obtained data was analysed according to; gender, sidedness, and handedness. Results: Four sites for the formation of the cephalic vein in relation to the anatomical snuffbox were found. There was a significant relation between gender and sidedness, and the sites of formation of the cephalic vein (p < 0.0001 and p = 0.048, respectively). Conclusions: For the first time this study identified different sites for the formation of the cephalic vein in relation to the anatomical snuffbox. However, regardless of its sites of formation, the cephalic vein was running in 98% of the examined hands in the anatomical snuffbox

Accelerated Diagnostic Protocols Using High-sensitivity Troponin Assays to “Rule In” or “Rule Out” Myocardial Infarction in the Emergency Department : A Systematic Review

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