44 research outputs found
Transient vortex dynamics and evolution of Bose metal from a 2D superconductor on MoS
The true character of physical phenomena is thought to be reinforced as the
system becomes disorder-free. In contrast, the two-dimensional (2D)
superconductor is predicted to turn fragile and resistive away from the limit I
-> 0, B -> 0, in the pinning-free regime. It is intriguing to note that the
very vortices responsible for achieving superconductivity by pairing,
condensation, and, thereby reducing the classical dissipation, render the state
resistive driven by quantum fluctuations in the T -> 0. While cleaner systems
are being explored for technological improvements, the 2D superconductor
turning resistive when influenced by weak electric and magnetic fields has
profound consequences for quantum technologies. A metallic ground state in 2D
is beyond the consensus of both Bosonic and Fermionic systems, and its origin
and nature warrant a comprehensive theoretical understanding supplemented by
in-depth experiments. A real-time observation of the influence of vortex
dynamics on transport properties so far has been elusive. We explore the nature
and fate of a low-viscous, clean, 2D superconducting state formed on an
ionic-liquid gated few-layered MoS sample. The vortex-core being
dissipative, the elastic depinning, intervortex interaction, and the subsequent
dynamics of the vortex-lattice cause the system to behave like an overdamped
harmonic oscillator, leaving transient signatures in the transport
characteristics. The temperature and magnetic field dependence of the transient
nature and the noise characteristics of the magnetoresistance confirm that
quantum fluctuations are solely responsible for the Bose metal state and the
fragility of the superconducting state
Optogenetic regulation of site-specific subtelomeric DNA methylation
Telomere length homeostasis, critical for chromosomal integrity and genome stability, is controlled by intricate molecular regulatory machinery that includes epigenetic modifications. Here, we examine site-specific and spatiotemporal alteration of the subtelomeric methylation of CpG islands using optogenetic tools to understand the epigenetic regulatory mechanisms of telomere length maintenance. Human DNA methyltransferase3A (DNMT3A) were assembled selectively at chromosome ends by fusion to cryptochrome 2 protein (CRY2) and its interacting complement, the basic helix loop helix protein-1 (CIB1). CIB1 was fused to the telomere-associated protein telomere repeat binding factor-1 (TRF1), which localized the protein complex DNMT3A-CRY2 at telomeric regions upon excitation by blue-light monitored by single-molecule fluorescence analyses. Increased methylation was achieved selectively at subtelomeric CpG sites on the six examined chromosome ends specifically after blue-light activation, which resulted in progressive increase in telomere length over three generations of HeLa cell replications. The modular design of the fusion constructs presented here allows for the selective substitution of other chromatin modifying enzymes and for loci-specific targeting to regulate the epigenetic pathways at telomeres and other selected genomic regions of interest
Cerebral Venous Thrombosis and Acute Pulmonary Embolism following Varicella Infection
Varicella infection is caused by varicella-zoster virus (VZV) and commonly presents as a self-limiting skin manifestation in children. VZV also causes cerebral arterial vasculopathy and antibody-mediated hypercoagulable states leading to thrombotic complications in children, although there are very few such reports in adults. Postulated causal factors include vasculitis, direct endothelial damage, or acquired protein S deficiency secondary to molecular mimicry. These induced autoantibodies to protein S could lead to acquired protein S deficiency and produce a hypercoagulable state causing venous sinus thrombosis. Here we report the case of a 26-year-old man who presented with cortical venous sinus thrombosis and acute pulmonary embolism following varicella infection. Both conditions responded to anticoagulation treatment
Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay
SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant
A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide
The naturally occurring nucleotide 3′-deoxy-3′,4′-didehydro-cytidine-5′-triphosphate (ddhCTP) was recently found to exert potent and broad-spectrum antiviral activity. However, nucleoside 5′-triphosphates in general are not cell-permeable, which precludes the direct use of ddhCTP as a therapeutic. To harness the therapeutic potential of this endogenous antiviral nucleotide, we synthesized phosphoramidate prodrug HLB-0532247 (1) and found it to result in dramatically elevated levels of ddhCTP in cells. We compared 1 and 3′-deoxy-3′,4′-didehydro-cytidine (ddhC) and found that 1 more effectively reduces titers of Zika and West Nile viruses in cell culture with minimal nonspecific toxicity to host cells. We conclude that 1 is a promising antiviral agent based on a novel strategy of facilitating elevated levels of the endogenous ddhCTP antiviral nucleotide
Structure-Function Studies of DNA Binding Domain of Response Regulator KdpE Reveals Equal Affinity Interactions at DNA Half-Sites
Expression of KdpFABC, a K+ pump that restores osmotic balance, is controlled by binding of the response regulator KdpE to a specific DNA sequence (kdpFABCBS) via the winged helix-turn-helix type DNA binding domain (KdpEDBD). Exploration of E. coli KdpEDBD and kdpFABCBS interaction resulted in the identification of two conserved, AT-rich 6 bp direct repeats that form half-sites. Despite binding to these half-sites, KdpEDBD was incapable of promoting gene expression in vivo. Structure-function studies guided by our 2.5 Å X-ray structure of KdpEDBD revealed the importance of residues R193 and R200 in the α-8 DNA recognition helix and T215 in the wing region for DNA binding. Mutation of these residues renders KdpE incapable of inducing expression of the kdpFABC operon. Detailed biophysical analysis of interactions using analytical ultracentrifugation revealed a 2∶1 stoichiometry of protein to DNA with dissociation constants of 200±100 and 350±100 nM at half-sites. Inactivation of one half-site does not influence binding at the other, indicating that KdpEDBD binds independently to the half-sites with approximately equal affinity and no discernable cooperativity. To our knowledge, these data are the first to describe in quantitative terms the binding at half-sites under equilibrium conditions for a member of the ubiquitous OmpR/PhoB family of proteins
Warranty Cost Analysis And Optimization To Finalize Asuitable Warranty Period For An Organization
Since the beginning of industrialization, reliability and warranty concerns have taken top priority. It's mostly because the warranty failures costs a lot of money for the manufacturer (Glickman and Berger 1976). The turnover and profitability of the business are significantly impacted by the warranty cost. The goal of manufacturers is to extend the product warranty period not only to improve customer perception and satisfaction, but also to improve product development and production methods to reduce the warranty cost.The advancement in technology over the last decade has been tremendous. This rise in the use of digital technology has not only led to making the competition fierce among the industrial companies but also increase customer expectations towards products and services. Among the different choices, there has been an immense increase in the demand for product warranty and services related to warranty. The warranty period is one of the crucial elements in the decision-making process for consumers. Customers typically choose the product with the best warranty when choosing between numerous options with comparable features and specifications. All these factors have led to a stronger belief among the manufacturers to have a good warranty period and services related to warranty. In order to remain competitive in the market there is a need for the manufacturers to arrive at the best warranty policy in this competitive worldThis thesis study concerns using an existing failure data set from a manufacturing company based out of Sweden to • Develop an optimization model that would help the organization choose the optimal warranty period / policy based on current warranty costs and based on competitors’ warranty period or time frame.The above analysis would thus, help to answer the following research questionHow can the organization arrive at the optimal warranty period (i.e., free replacement warranty and pro rata warranty) and based on its current warranty failure rate and warranty cost