The Hyaluronan Receptor for Endocytosis Mediates Hyaluronan-Dependent Signal Transduction via Extracellular Signal-Regulated Kinases

The hyaluronan (HA) receptor for endocytosis (HARE) mediates the endocytotic clearance of HA and other glycosaminoglycans from lymph and blood. Two isoforms of human HARE, 315- and 190-kDa, are highly expressed in sinusoidal endothelial cells of liver, lymph node, and spleen; HARE is also in specialized cells in the eye, heart, brain, and kidney. Here we determined whether HA binding to HARE initiates intracellular signaling in Flp-In 293 cells stably expressing either the 315- and 190-kDa HARE or the 190-kDa HARE alone. HARE was co-immunoprecipitated with extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 members of the mitogen-activated protein kinase signaling cascade. ERK phosphorylation increased in a dose- and time-dependent manner when HA was added to cells expressing full-length or 190-kDa HARE, but not cells with vector-only or a HARE(ΔLink) construct with greatly decreased (~90%) HA uptake. HA did not induce phosphorylation of JNK or p38. A maximum increase in phospho-ERK1/2 occurred within 30 min at 5 μg/ml HA, and the response was dampened at \u3e20 μg/ml HA. HA binding did not increase the level of HARE-ERK complexes, but did increase HARE phosphorylation. These findings demonstrate a novel functional response, when HARE binds HA, that leads to activation of ERK1/2, important mediators of intracellular signal transduction

Diffusion limit for single-server retrial queues with renewal input and outgoing calls

This paper studies a single-server retrial queue with two types of calls (incoming and outgoing calls). Incoming calls arrive at the server according to a renewal process, and outgoing calls of N − 1 (N ≥ 2) categories occur according to N − 1 independent Poisson processes. Upon arrival, if the server is occupied, an incoming call joins a virtual infinite queue called the orbit, and after an exponentially distributed time in orbit enters the server again, while outgoing calls are lost if the server is busy at the time of their arrivals. Although M/G/1 retrial queues and their variants are extensively studied in the literature, the GI/M/1 retrial queues are less studied due to their complexity. This paper aims to obtain a diffusion limit for the number of calls in orbit when the retrial rate is extremely low. Based on the diffusion limit, we built an approximation to the distribution of the number of calls in orbit

Semi-Markov resource flow as a bit-level model of traffic

In this paper, we consider semi-Markov flow as a bit-level model of traffic. Each request of the flow brings some arbitrary distributed amount of information to the system. The current paper aims to investigate the amount of information received in semi-Markov flow during time unit. We use the asymptotic analysis method under the limit condition of growing time of observation to derive the limiting probability distribution of the amount of information received in the flow and build the approximation of its prelimit distribution function

Mathematical model of Scheduler with Semi-Markov input and bandwidth sharing discipline

In this paper, we consider single server queueing system with multiple semi-Markov inputs and buffers. Each request of the flows brings to the system some random amount of information. According to the bandwidth sharing discipline, each buffer has its own part of the throughput and the server transmits the information from buffers simultaneously. The aim of the current research is to derive the probability distribution of the amount of information in single buffer

Control and regulation of S‐Adenosylmethionine biosynthesis by the regulatory β subunit and quinolone‐based compounds

Methylation is an underpinning process of life and provides control for biological processes such as DNA synthesis, cell growth, and apoptosis. Methionine adenosyltransferases (MAT) produce the cellular methyl donor, S‐Adenosylmethionine (SAMe). Dysregulation of SAMe level is a relevant event in many diseases, including cancers such as hepatocellular carcinoma and colon cancer. In addition, mutation of Arg264 in MATα1 causes isolated persistent hypermethioninemia, which is characterized by low activity of the enzyme in liver and high level of plasma methionine. In mammals, MATα1/α2 and MATβV1/V2 are the catalytic and the major form of regulatory subunits, respectively. A gating loop comprising residues 113–131 is located beside the active site of catalytic subunits (MATα1/α2) and provides controlled access to the active site. Here, we provide evidence of how the gating loop facilitates the catalysis and define some of the key elements that control the catalytic efficiency. Mutation of several residues of MATα2 including Gln113, Ser114, and Arg264 lead to partial or total loss of enzymatic activity, demonstrating their critical role in catalysis. The enzymatic activity of the mutated enzymes is restored to varying degrees upon complex formation with MATβV1 or MATβV2, endorsing its role as an allosteric regulator of MATα2 in response to the levels of methionine or SAMe. Finally, the protein–protein interacting surface formed in MATα2:MATβ complexes is explored to demonstrate that several quinolone‐based compounds modulate the activity of MATα2 and its mutants, providing a rational for chemical design/intervention responsive to the level of SAMe in the cellular environment

A multi-wavelength polarimetric study of the blazar CTA 102 during a Gamma-ray flare in 2012

We perform a multi-wavelength polarimetric study of the quasar CTA 102 during an extraordinarily bright $\gamma$-ray outburst detected by the {\it Fermi} Large Area Telescope in September-October 2012 when the source reached a flux of F$_{>100~\mathrm{MeV}} =5.2\pm0.4\times10^{-6}$ photons cm$^{-2}$ s$^{-1}$. At the same time the source displayed an unprecedented optical and NIR outburst. We study the evolution of the parsec scale jet with ultra-high angular resolution through a sequence of 80 total and polarized intensity Very Long Baseline Array images at 43 GHz, covering the observing period from June 2007 to June 2014. We find that the $\gamma$-ray outburst is coincident with flares at all the other frequencies and is related to the passage of a new superluminal knot through the radio core. The powerful $\gamma$-ray emission is associated with a change in direction of the jet, which became oriented more closely to our line of sight ($\theta\sim$1.2$^{\circ}$) during the ejection of the knot and the $\gamma$-ray outburst. During the flare, the optical polarized emission displays intra-day variability and a clear clockwise rotation of EVPAs, which we associate with the path followed by the knot as it moves along helical magnetic field lines, although a random walk of the EVPA caused by a turbulent magnetic field cannot be ruled out. We locate the $\gamma$-ray outburst a short distance downstream of the radio core, parsecs from the black hole. This suggests that synchrotron self-Compton scattering of near-infrared to ultraviolet photons is the probable mechanism for the $\gamma$-ray production.Comment: Accepted for publication in The Astrophysical Journa

Probing the Inner Jet of the Quasar PKS 1510-089 with Multi-waveband Monitoring during Strong Gamma-ray Activity

We present results from monitoring the multi-waveband flux, linear polarization, and parsec-scale structure of the quasar PKS 1510-089, concentrating on eight major gamma-ray flares that occurred during the interval 2009.0-2009.5. The gamma-ray peaks were essentially simultaneous with maxima at optical wavelengths, although the flux ratio of the two wavebands varied by an order of magnitude. The optical polarization vector rotated by 720 degrees during a 5-day period encompassing six of these flares. This culminated in a very bright, roughly 1 day, optical and gamma-ray flare as a bright knot of emission passed through the highest-intensity, stationary feature (the "core") seen in 43 GHz Very Long Baseline Array images. The knot continued to propagate down the jet at an apparent speed of 22c and emit strongly at gamma-ray energies as a months-long X-ray/radio outburst intensified. We interpret these events as the result of the knot following a spiral path through a mainly toroidal magnetic field pattern in the acceleration and collimation zone of the jet, after which it passes through a standing shock in the 43 GHz core and then continues downstream. In this picture, the rapid gamma-ray flares result from scattering of infrared seed photons from a relatively slow sheath of the jet as well as from optical synchrotron radiation in the faster spine. The 2006-2009.7 radio and X-ray flux variations are correlated at very high significance; we conclude that the X-rays are mainly from inverse Compton scattering of infrared seed photons by 20-40 MeV electrons.Comment: 10 pages of text + 5 figures, to be published in Astrophysical Journal Letters in 201