Ubisol-Q10 Prevents Glutamate-Induced Cell Death by Blocking Mitochondrial Fragmentation and Permeability Transition Pore Opening

Mitochondrial dysfunction and oxidative stress are the major events that lead to the formation of mitochondrial permeability transition pore (mPTP) during glutamate-induced cytotoxicity and cell death. Coenzyme Q10 (CoQ10) has widely been used for the treatment of mitochondrial disorders and neurodegenerative diseases. Comparing to traditional lipid-soluble CoQ10, water soluble CoQ10 (Ubisol-Q10) has high intracellular and intra-mitochondrial distribution. The aims of the present study are to determine the neuroprotective effects of Ubisol-Q10 on glutamate-induced cell death and to explore its functional mechanisms. HT22 neuronal cells were exposed to glutamate. Cell viability was measured and mitochondrial fragmentation was assessed by mitochondrial imaging. The mPTP opening was determined by mitochondrial membrane potential and calcium retention capacity. The results revealed that the anti-glutamate toxicity effects of Ubisol-Q10 was associated with its ability to block mitochondrial fragmentation, to maintain calcium retention capacity and mitochondrial membrane potential, and to prevent mPTP formation, AIF release, and DNA fragmentation. We concluded that Ubisol-Q10 protects cells from glutamate toxicity by preserving the integrity of mitochondrial structure and function. Therefore, adequate CoQ10 supplementation may be beneficial in preventing cerebral stroke and other disorders that involve mitochondrial dysfunction

From MinX to MinC: Semantics-Driven Decompilation of Recursive Datatypes

Reconstructing the meaning of a program from its binary executable is known as reverse engineering; it has a wide range of applications in software security, exposing piracy, legacy systems, etc. Since reversing is ultimately a search for meaning, there is much interest in inferring a type (a meaning) for the elements of a binary in a consistent way. Unfortunately existing approaches do not guarantee any semantic relevance for their reconstructed types. This paper presents a new and semantically-founded approach that provides strong guarantees for the reconstructed types. Key to our approach is the derivation of a witness program in a high-level language alongside the reconstructed types. This witness has the same semantics as the binary, is type correct by construction, and it induces a (justifiable) type assignment on the binary. Moreover, the approach effectively yields a type-directed decompiler. We formalise and implement the approach for reversing Minx, an abstraction of x86, to MinC, a type-safe dialect of C with recursive datatypes. Our evaluation compiles a range of textbook C algorithms to MinX and then recovers the original structures

CD8 T-cell responses against the immunodominant Theileria parvapeptide Tp249-59 are composed of two distinct populations specific for overlapping 11-mer and 10-mer epitopes

Immunity against Theileria parva is associated with CD8 T-cell responses that exhibit immunodominance, focusing the response against limited numbers of epitopes. As candidates for inclusion in vaccines, characterization of responses against immunodominant epitopes is a key component in novel vaccine development. We have previously demonstrated that the Tp249–59 and Tp1214–224 epitopes dominate CD8 T-cell responses in BoLA-A10 and BoLA-18 MHC I homozygous animals, respectively. In this study, peptide–MHC I tetramers for these epitopes, and a subdominant BoLA-A10-restricted epitope (Tp298–106), were generated to facilitate accurate and rapid enumeration of epitope-specific CD8 T cells. During validation of these tetramers a substantial proportion of Tp249–59-reactive T cells failed to bind the tetramer, suggesting that this population was heterogeneous with respect to the recognized epitope. We demonstrate that Tp250–59 represents a distinct epitope and that tetramers produced with Tp50–59 and Tp49–59 show no cross-reactivity. The Tp249–59 and Tp250–59 epitopes use different serine residues as the N-terminal anchor for binding to the presenting MHC I molecule. Molecular dynamic modelling predicts that the two peptide–MHC I complexes adopt structurally different conformations and Tcell receptor β sequence analysis showed that Tp249–59 and Tp250–59 are recognized by non-overlapping T-cell receptor repertoires. Together these data demonstrate that although differing by only a single residue, Tp249–59 and Tp250–59 epitopes form distinct ligands for T-cell receptor recognition. Tetramer analysis of T. parva-specific CD8 T-cell lines confirmed the immunodominance of Tp1214–224 in BoLA-A18 animals and showed in BoLA-A10 animals that the Tp249–59 epitope response was generally more dominant than the Tp250–59 response and confirmed that the Tp298–106 response was subdominant

Preparing quantum many-body scar states on quantum computers

Quantum many-body scar states are highly excited eigenstates of many-body systems that exhibit atypical entanglement and correlation properties relative to typical eigenstates at the same energy density. Scar states also give rise to infinitely long-lived coherent dynamics when the system is prepared in a special initial state having finite overlap with them. Many models with exact scar states have been constructed, but the fate of scarred eigenstates and dynamics when these models are perturbed is difficult to study with classical computational techniques. In this work, we propose state preparation protocols that enable the use of quantum computers to study this question. We present protocols both for individual scar states in a particular model, as well as superpositions of them that give rise to coherent dynamics. For superpositions of scar states, we present both a system-size-linear depth unitary and a finite-depth nonunitary state preparation protocol, the latter of which uses measurement and postselection to reduce the circuit depth. For individual scarred eigenstates, we formulate an exact state preparation approach based on matrix product states that yields quasipolynomial-depth circuits, as well as a variational approach with a polynomial-depth ansatz circuit. We also provide proof of principle state-preparation demonstrations on superconducting quantum hardware.Comment: 20 Pages, 15 Figures, 2 Tables. V2: corrected typo

Coenzyme Q10 Ameliorates Ultraviolet B Irradiation Induced Cell Death Through Inhibition of Mitochondrial Intrinsic Cell Death Pathway

Ultraviolet B (UVB) induces cell death by increasing free radical production, activating apoptotic cell death pathways and depolarizing mitochondrial membrane potential. Coenzyme Q10 (CoQ10), an essential cofactor in the mitochondrial electron transport chain, serves as a potent antioxidant in the mitochondria. The aim of the present study is to establish whether CoQ10 is capable of protecting neuronal cells against UVB-induced damage. Murine hippocampal HT22 cells were treated with 0.01, 0.1 or 1 μM of CoQ10 3 or 24 h prior to the cells being exposed to UVB irradiation. The CoQ10 concentrations were maintained during irradiation and 24 h post-UVB. Cell viability was assessed by counting viable cells and MTT conversion assay. Superoxide production and mitochondrial membrane potential were measured using fluorescent probes. Levels of cleaved caspase-9, caspase-3, and apoptosis-inducing factor (AIF) were detected using immunocytochemistry and Western blotting. The results showed that UVB irradiation decreased cell viability and such damaging effect was associated with increased superoxide production, mitochondrial depolarization, and activation of caspase-9 and caspase-3. Treatment with CoQ10 at three different concentrations started 24 h before UVB exposure significantly increased the cell viability. The protective effect of CoQ10 was associated with reduction in superoxide production, normalization of mitochondrial membrane potential and inhibition of caspase-9 and caspase-3 activation. It is concluded that the neuroprotective effect of CoQ10 results from inhibiting oxidative stress and blocking caspase-3 dependent cell death pathway

Supernova Cosmology and the ESSENCE project

The proper usage of Type Ia supernovae (SNe Ia) as distance indicators has revolutionized cosmology, and added a new dominant component to the energy density of the Universe, dark energy. Following the discovery and confirmation era, the currently ongoing SNe Ia surveys aim to determine the properties of the dark energy. ESSENCE is a five year ground-based supernova survey aimed at finding and characterizing 200 SNe Ia in the redshift domain z=[0.2-0.8]. The goal of the project is to put constraints on the equation of state parameter, w, of the dark energy with an accuracy of <10%. This paper presents these ongoing efforts in the context of the current developments in observational cosmology.Comment: Submitted to EPS1

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms ( SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds ( a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines - in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases

TPU v4: An Optically Reconfigurable Supercomputer for Machine Learning with Hardware Support for Embeddings

In response to innovations in machine learning (ML) models, production workloads changed radically and rapidly. TPU v4 is the fifth Google domain specific architecture (DSA) and its third supercomputer for such ML models. Optical circuit switches (OCSes) dynamically reconfigure its interconnect topology to improve scale, availability, utilization, modularity, deployment, security, power, and performance; users can pick a twisted 3D torus topology if desired. Much cheaper, lower power, and faster than Infiniband, OCSes and underlying optical components are <5% of system cost and <3% of system power. Each TPU v4 includes SparseCores, dataflow processors that accelerate models that rely on embeddings by 5x-7x yet use only 5% of die area and power. Deployed since 2020, TPU v4 outperforms TPU v3 by 2.1x and improves performance/Watt by 2.7x. The TPU v4 supercomputer is 4x larger at 4096 chips and thus ~10x faster overall, which along with OCS flexibility helps large language models. For similar sized systems, it is ~4.3x-4.5x faster than the Graphcore IPU Bow and is 1.2x-1.7x faster and uses 1.3x-1.9x less power than the Nvidia A100. TPU v4s inside the energy-optimized warehouse scale computers of Google Cloud use ~3x less energy and produce ~20x less CO2e than contemporary DSAs in a typical on-premise data center.Comment: 15 pages; 16 figures; to be published at ISCA 2023 (the International Symposium on Computer Architecture

Beyond Ultra-Diffuse Galaxies I: Mass-Size Outliers Among the Satellites of Milky Way Analogs

Large diffuse galaxies are hard to find, but understanding the environments where they live, their numbers, and ultimately their origins, is of intense interest and importance for galaxy formation and evolution. Using Subaru's Hyper Suprime-Cam Strategic Survey Program, we perform a systematic search for low surface brightness galaxies and present novel and effective methods for detecting and modeling them. As a case study, we surveyed 922 Milky Way analogs in the nearby Universe ($0.01 < z < 0.04$) and build a large sample of satellite galaxies that are outliers in the mass-size relation. These ``ultra-puffy'' galaxies (UPGs), defined to be $1.5\sigma$ above the average mass-size relation, represent the tail of the satellite size distribution. We find that each MW analog hosts $N_{\rm UPG} = 0.31\pm 0.05$ ultra-puffy galaxies on average, which is consistent with but slightly lower than the observed abundance at this halo mass in the Local Volume. We also construct a sample of ultra-diffuse galaxies (UDGs) in MW analogs and find an abundance of $N_{\rm UDG} = 0.44\pm0.05$ per host. With literature results, we confirm that the UDG abundance scales with the host halo mass following a sublinear power law. We argue that our definition for ultra-puffy galaxies, which is based on the mass-size relation, is more physically-motivated than the common definition of ultra-diffuse galaxies, which depends on surface brightness and size cuts and thus yields different surface mass density cuts for quenched and star-forming galaxies.Comment: 19 pages, 7 figures, submitted to Ap

Rate Control of Atrial Arrhythmias Can Be Achieved by Selective Cardiac Neurostimulation

Introduction: Atrial arrhythmias (AA) occur in up to 40% of patients recovering from open-heart surgery (OHS). Pharmacologic treatment has been the main strategy used for the control of post-operative AA, but is associated with hypotension, pro-arrhythmia and myocardial dysfunction. There is a need for a reversible, modulated solution to rate control. We demonstrated the efficacy of vagal stimulation at inferior right fat pad (FP) to slow the ventricular response (VR) of atrial fibrillation (AF) and junctional ectopic tachycardia (JET). We hypothesized that the VR response to AA could be improved by alterations in 1) the site of stimulation (anterior right FP vs. inferior right FP), 2) site within the two FP regions tested, and 3) whether there was a relationship between stimulation voltage (V) and electrophysiologic effect. Methods: Eight mongrel dogs, age 8.7 ± 3.9 months and weighing 21.5 ± 2.5 kg, underwent open heart surgery replicating Tetralogy of Fallot repair. Stimulation of the anterior right (AR) and inferior right (IR) fat pad was used to control the VR of AF and JET. A 7-pole electrode was sutured to the AR and IR FP and used to deliver stimulation therapy. Tested parameters included: 1) FP site, 2) stimulation pole configuration, and 3) stimulation (1-25) V on the VR to AF and JET. Stimulation frequency was 30 Hz, and pulse width was 0.15 msec. Results: 1). The inferior right FP was more effective in slowing the VR response to AF (-0.43 ± 0.18 vs. -0.18 ± 0.11 %, p =0.03) and JET (-0.16 ± 0.06 vs. 0.0 ±0.0, p =0.06.) 2). Selective site stimulation within a FP region could augment the effect of stimulation during AF (-0.48 ± 0.21 (maximum effect) vs. 0.0 ± 0.0 % (least effect), p=0.01). Stimulation of electrodes 2+3 produced the greatest reduction in HR with a maximum percent VR reduction of 34.8% 3). FP stimulation at increasing V demonstrated a voltage-dependent effect (-0.12 ± 0.19 (low V) vs. -0.63 ± 0.21 (high V) %, p=0.01)