Distributed Computing with Adaptive Heuristics

We use ideas from distributed computing to study dynamic environments in which computational nodes, or decision makers, follow adaptive heuristics (Hart 2005), i.e., simple and unsophisticated rules of behavior, e.g., repeatedly "best replying" to others' actions, and minimizing "regret", that have been extensively studied in game theory and economics. We explore when convergence of such simple dynamics to an equilibrium is guaranteed in asynchronous computational environments, where nodes can act at any time. Our research agenda, distributed computing with adaptive heuristics, lies on the borderline of computer science (including distributed computing and learning) and game theory (including game dynamics and adaptive heuristics). We exhibit a general non-termination result for a broad class of heuristics with bounded recall---that is, simple rules of behavior that depend only on recent history of interaction between nodes. We consider implications of our result across a wide variety of interesting and timely applications: game theory, circuit design, social networks, routing and congestion control. We also study the computational and communication complexity of asynchronous dynamics and present some basic observations regarding the effects of asynchrony on no-regret dynamics. We believe that our work opens a new avenue for research in both distributed computing and game theory.Comment: 36 pages, four figures. Expands both technical results and discussion of v1. Revised version will appear in the proceedings of Innovations in Computer Science 201

Glucocerebrosidase activity, cathepsin D and monomeric α-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.

The presence of GBA1 gene mutations increases risk for Parkinson's disease (PD), but the pathogenic mechanisms of GBA1 associated PD remain unknown. Given that impaired α-synuclein turnover is a hallmark of PD pathogenesis and cathepsin D is a key enzyme involved in α-synuclein degradation in neuronal cells, we have examined the relationship of glucocerebrosidase (GCase), cathepsin D and monomeric α-synuclein in human neural crest stem cell derived dopaminergic neurons. We found that normal activity of GCase is necessary for cathepsin D to perform its function of monomeric α-synuclein removal from neurons. GBA1 mutations lead to a lower level of cathepsin D protein and activity, and higher level of monomeric α-synuclein in neurons. When GBA1 mutant neurons were treated with GCase replacement or chaperone therapy; cathepsin D protein levels and activity were restored, and monomeric α-synuclein decreased. When cathepsin D was inhibited, GCase replacement failed to reduce monomeric α-synuclein levels in GBA1 mutant neurons. These data indicate that GBA1 gene mutations increase monomeric α-synuclein levels via an effect on lysosomal cathepsin D in neurons

Structural and Compositional Changes in Aging Bone: Osteopenia in Lumbar Vertebrae of Wistar Female Rats

Changes in vertebral bone mineral content and density during aging were quantified in female Wistar rats. This study represents a longitudinal follow up utilizing single photon absorptiometry for the measurement of bone mineral content (BMC), quantitative computed tomography (OCT) for the measurement of bone mineral density (BMD), and image analysis histomorphometry for the measurement of trabecular bone volume (TBV) and bone cortical area (BCA). The above measurements were accompanied by biochemical assays of calcium concentrations in the respective bones. All aging animals experienced significant decreases in BMC, BMD, TBV, BCA and in the calcium content of their bones. The above features have been further emphasized through the use of scanning electron micrographs showing the age-related structural changes in a three-dimentional fashion. New, advanced technologies will enable the quantitation of 3-dimensional images that are currently obtained from the scanning electron micrograph; thus will provide new consideration as related to trabecular bone compactness (density). Energy dispersive x-ray spectroscopy indicated that the nature of crystals in aging bones does not differ markedly from that encountered in young specimens. Data are also provided with regard to the health of the animals, and it became apparent that aging rats undergo changes in their kidneys yet do not show any significant change in renal functional parameters as measured in both the serum and the urine. Hence, new noninvasive methodologies are currently available for longitudinal studies related to the skeleton in laboratory animals enabling reliable monitoring of age-related and hormonally induced changes in bones (spine and hip) of well defined experimental models

Euler-Bessel and Euler-Fourier Transforms

We consider a topological integral transform of Bessel (concentric isospectral sets) type and Fourier (hyperplane isospectral sets) type, using the Euler characteristic as a measure. These transforms convert constructible \zed-valued functions to continuous $\real$-valued functions over a vector space. Core contributions include: the definition of the topological Bessel transform; a relationship in terms of the logarithmic blowup of the topological Fourier transform; and a novel Morse index formula for the transforms. We then apply the theory to problems of target reconstruction from enumerative sensor data, including localization and shape discrimination. This last application utilizes an extension of spatially variant apodization (SVA) to mitigate sidelobe phenomena

Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy

Impairment of the autophagy-lysosome pathway (ALP) is implicated with the changes in α-synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resultingin ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH-SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock down (KD) cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB KD.. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC-1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain ALP and mitochondrial biogenesis. Therefore strategies to increase TFEB may improve both the clearance of α-synuclein and mitochondrial dysfunction in PD. This article is protected by copyright. All rights reserved

A variant of the Mukai pairing via deformation quantization

We give a new method to prove a formula computing a variant of Caldararu's Mukai pairing \cite{Cal1}. Our method is based on some important results in the area of deformation quantization. In particular, part of the work of Kashiwara and Schapira in \cite{KS} as well as an algebraic index theorem of Bressler, Nest and Tsygan in \cite{BNT},\cite{BNT1} and \cite{BNT2} are used. It is hoped that our method is useful for generalization to settings involving certain singular varieties.Comment: 8 pages. Comments and suggestions welcom