Critical role of NKT cells in posttransplant alloantibody production

We previously reported that posttransplant alloantibody production in CD8-deficient hosts is IL-4+ CD4+ T cell-dependent and IgG1 isotype-dominant. The current studies investigated the hypothesis that IL-4-producing natural killer T cells (NKT cells) contribute to maximal alloantibody production. To investigate this, alloantibody levels were examined in CD8-deficient WT, CD1d KO and Jα18 KO transplant recipients. We found that the magnitude of IgG1 alloantibody production was critically dependent on the presence of type I NKT cells, which are activated by day 1 posttransplant. Unexpectedly, type I NKT cell contribution to enhanced IgG1 alloantibody levels was interferon-γ-dependent and IL-4-independent. Cognate interactions between type I NKT and B cells alone do not stimulate alloantibody production. Instead, NKT cells appear to enhance maturation of IL-4+ CD4+ T cells. To our knowledge, this is the first report to substantiate a critical role for type I NKT cells in enhancing in vivo antibody production in response to endogenous antigenic stimuli

Gel meloksikama za topičku primjenu: In vitro i in vivo vrednovanje

Skin delivery of NSAIDs offers several advantages over the oral route associated with potential side effects. In the present investigation, topical gel of meloxicam (MLX) was formulated using N-methyl pyrrolidone (NMP) as a solubilizer and Carbopol Ultrez 10® as a gelling polymer. MLX gel was evaluated with respect to different physicochemical parameters such as pH, viscosity and spreadability. Irritation potential of MLX gel was studied on rabbits. Permeation of MLX gel was studied using freshly excised rat skin as a membrane. Anti-inflammatory activity of MLX gel was studied in rats and compared with the commercial formulation of piroxicam (Pirox® gel, 0.5 %, m/m). Accelerated stability studies were carried out for MLX gel for 6 months according to ICH guidelines. MLX gel was devoid of any skin irritation in rabbits. After 12 h, cumulative permeation of MLX through excised rat skin was 3.0 ± 1.2 mg cm2 with the corresponding flux value of 0.24 ± 0.09 mg cm2 h1. MLX gel exhibited significantly higher anti-inflammatory activity in rats compared to Pirox® gel. Physicochemically stable and non-irritant MLX gel was formulated which could deliver significant amounts of active substance across the skin in vitro and in vivo to elicit the anti-inflammatory activity.Primjena nesteroidnih protuupalnih lijekova na kožu ima nekoliko prednosti nad peroralnim načinom primjene uz koju se vežu određene nuspojave. U radu je opisana priprava gela meloksikama (MLX) za topičku primjenu. U pripravi gela korišten je N-metil pirolidon (NMP) kao otapalo i Carbopol ultrez 10® kao polimer za geliranje. Određivani su različiti fizikokemijski parametri kao što su pH, viskoznost i razmazljivost. Potencijalna iritacija MLX gela testirana je na kunićima, a svojstvo permeacije na svježim izrescima kože štakora. Protuupalno djelovanje praćeno je na štakorima i uspoređeno s registriranim pripravkom piroksikama (Pirox® gel, 0,5 % m/m). Testovi ubrzanog starenja MLX gela rađeni su tijekom 6 mjeseci prema ICH protokolu. Dobiveni rezultati ukazuju da MLX gel nimalo ne iritira kožu kunića. Kumulativna permeacija nakon 12 h bila je 3,0 ± 1,2 mg cm2, s odgovarajućem vrijednošću fluksa 0,24 ± 0,09 mg cm2 h1. MLX gel pokazao je značajno jače protuupalno djelovanje u odnosu na Pirox® gel. Pripravljeni gel je stabilan, ne iritira kožu, te in vitro i in vivo doprema kroz kožu ljekovitu tvar u dovoljnoj količini da ispolji protuupalno djelovanje

On the exactness of the cavity method for Weighted b-Matchings on Arbitrary Graphs and its Relation to Linear Programs

We consider the general problem of finding the minimum weight b-matching on arbitrary graphs. We prove that, whenever the linear programming relaxation of the problem has no fractional solutions, then the cavity or belief propagation equations converge to the correct solution both for synchronous and asynchronous updating

Detection of Repeating FRB 180916.J0158+65 Down to Frequencies of 300 MHz

We report on the detection of seven bursts from the periodically active, repeating fast radio burst (FRB) source FRB 180916.J0158+65 in the 300-400-MHz frequency range with the Green Bank Telescope (GBT). Emission in multiple bursts is visible down to the bottom of the GBT band, suggesting that the cutoff frequency (if it exists) for FRB emission is lower than 300 MHz. Observations were conducted during predicted periods of activity of the source, and had simultaneous coverage with the Low Frequency Array (LOFAR) and the FRB backend on the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope. We find that one of the GBT-detected bursts has potentially associated emission in the CHIME band (400-800 MHz) but we detect no bursts in the LOFAR band (110-190 MHz), placing a limit of $\alpha > -1.0$ on the spectral index of broadband emission from the source. We also find that emission from the source is severely band-limited with burst bandwidths as low as $\sim$40 MHz. In addition, we place the strictest constraint on observable scattering of the source, $<$ 1.7 ms, at 350 MHz, suggesting that the circumburst environment does not have strong scattering properties. Additionally, knowing that the circumburst environment is optically thin to free-free absorption at 300 MHz, we find evidence against the association of a hyper-compact HII region or a young supernova remnant (age $<$ 50 yr) with the source.Comment: Accepted for publication in ApJ

On the Complexity of Scheduling in Wireless Networks

We consider the problem of throughput-optimal scheduling in wireless networks subject to interference constraints. We model the interference using a family of K-hop interference models, under which no two links within a K-hop distance can successfully transmit at the same time. For a given K, we can obtain a throughput-optimal scheduling policy by solving the well-known maximum weighted matching problem. We show that for K > 1, the resulting problems are NP-Hard that cannot be approximated within a factor that grows polynomially with the number of nodes. Interestingly, for geometric unit-disk graphs that can be used to describe a wide range of wireless networks, the problems admit polynomial time approximation schemes within a factor arbitrarily close to 1. In these network settings, we also show that a simple greedy algorithm can provide a 49-approximation, and the maximal matching scheduling policy, which can be easily implemented in a distributed fashion, achieves a guaranteed fraction of the capacity region for "all K." The geometric constraints are crucial to obtain these throughput guarantees. These results are encouraging as they suggest that one can develop low-complexity distributed algorithms to achieve near-optimal throughput for a wide range of wireless networksopen1

A fast radio burst localized at detection to a galactic disk using very long baseline interferometry

Fast radio bursts (FRBs) are millisecond-duration, luminous radio transients of extragalactic origin. These events have been used to trace the baryonic structure of the Universe using their dispersion measure (DM) assuming that the contribution from host galaxies can be reliably estimated. However, contributions from the immediate environment of an FRB may dominate the observed DM, thus making redshift estimates challenging without a robust host galaxy association. Furthermore, while at least one Galactic burst has been associated with a magnetar, other localized FRBs argue against magnetars as the sole progenitor model. Precise localization within the host galaxy can discriminate between progenitor models, a major goal of the field. Until now, localizations on this spatial scale have only been carried out in follow-up observations of repeating sources. Here we demonstrate the localization of FRB 20210603A with very long baseline interferometry (VLBI) on two baselines, using data collected only at the time of detection. We localize the burst to SDSS J004105.82+211331.9, an edge-on galaxy at $z\approx 0.177$, and detect recent star formation in the kiloparsec-scale vicinity of the burst. The edge-on inclination of the host galaxy allows for a unique comparison between the line of sight towards the FRB and lines of sight towards known Galactic pulsars. The DM, Faraday rotation measure (RM), and scattering suggest a progenitor coincident with the host galactic plane, strengthening the link between the environment of FRB 20210603A and the disk of its host galaxy. Single-pulse VLBI localizations of FRBs to within their host galaxies, following the one presented here, will further constrain the origins and host environments of one-off FRBs.Comment: 40 pages, 13 figures, submitted. Fixed typo in abstrac

Localizing FRBs through VLBI with the Algonquin Radio Observatory 10 m Telescope

The Canadian Hydrogen Intensity Mapping Experiment (CHIME)/FRB experiment has detected thousands of fast radio bursts (FRBs) due to its sensitivity and wide field of view; however, its low angular resolution prevents it from localizing events to their host galaxies. Very long baseline interferometry (VLBI), triggered by FRB detections from CHIME/FRB will solve the challenge of localization for non-repeating events. Using a refurbished 10 m radio dish at the Algonquin Radio Observatory located in Ontario Canada, we developed a testbed for a VLBI experiment with a theoretical λ/D ≲ 30 mas. We provide an overview of the 10 m system and describe its refurbishment, the data acquisition, and a procedure for fringe fitting that simultaneously estimates the geometric delay used for localization and the dispersive delay from the ionosphere. Using single pulses from the Crab pulsar, we validate the system and localization procedure, and analyze the clock stability between sites, which is critical for coherently delay referencing an FRB event. We find a localization of ∼200 mas is possible with the performance of the current system (single-baseline). Furthermore, for sources with insufficient signal or restricted wideband to simultaneously measure both geometric and ionospheric delays, we show that the differential ionospheric contribution between the two sites must be measured to a precision of 1 × 10-8 pc cm-3 to provide a reasonable localization from a detection in the 400-800 MHz band. Finally we show detection of an FRB observed simultaneously in the CHIME and the Algonquin 10 m telescope, the first non-repeating FRB in this long baseline. This project serves as a testbed for the forthcoming CHIME/FRB Outriggers project

Periodic activity from a fast radio burst source

Fast radio bursts (FRBs) are bright, millisecond-duration radio transients originating from extragalactic distances. Their origin is unknown. Some FRB sources emit repeat bursts, ruling out cataclysmic origins for those events. Despite searches for periodicity in repeat burst arrival times on time scales from milliseconds to many days, these bursts have hitherto been observed to appear sporadically, and though clustered, without a regular pattern. Here we report the detection of a $16.35\pm0.15$ day periodicity (or possibly a higher-frequency alias of that periodicity) from a repeating FRB 180916.J0158+65 detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project (CHIME/FRB). In 38 bursts recorded from September 16th, 2018 through February 4th, 2020, we find that all bursts arrive in a 5-day phase window, and 50% of the bursts arrive in a 0.6-day phase window. Our results suggest a mechanism for periodic modulation either of the burst emission itself, or through external amplification or absorption, and disfavour models invoking purely sporadic processes

Molecular evolution of the vertebrate TLR1 gene family - a complex history of gene duplication, gene conversion, positive selection and co-evolution

<p>Abstract</p> <p>Background</p> <p>The Toll-like receptors represent a large superfamily of type I transmembrane glycoproteins, some common to a wide range of species and others are more restricted in their distribution. Most members of the Toll-like receptor superfamily have few paralogues; the exception is the TLR1 gene family with four closely related genes in mammals TLR1, TLR2, TLR6 and TLR10, and four in birds TLR1A, TLR1B, TLR2A and TLR2B. These genes were previously thought to have arisen by a series of independent gene duplications. To understand the evolutionary pattern of the TLR1 gene family in vertebrates further, we cloned the sequences of TLR1A, TLR1B, TLR2A and TLR2B in duck and turkey, constructed phylogenetic trees, predicted codons under positive selection and identified co-evolutionary amino acid pairs within the TLR1 gene family using sequences from 4 birds, 28 mammals, an amphibian and a fish.</p> <p>Results</p> <p>This detailed phylogenetic analysis not only clarifies the gene gains and losses within the TLR1 gene family of birds and mammals, but also defines orthologues between these vertebrates. In mammals, we predict amino acid sites under positive selection in TLR1, TLR2 and TLR6 but not TLR10. We detect co-evolution between amino acid residues in TLR2 and the other members of this gene family predicted to maintain their ability to form functional heterodimers. In birds, we predict positive selection in the TLR2A and TLR2B genes at functionally significant amino acid residues. We demonstrate that the TLR1 gene family has mostly been subject to purifying selection but has also responded to directional selection at a few sites, possibly in response to pathogen challenge.</p> <p>Conclusions</p> <p>Our phylogenetic and structural analyses of the vertebrate TLR1 family have clarified their evolutionary origins and predict amino acid residues likely to be important in the host's defense against invading pathogens.</p