Extended interactions with prothrombinase enforce affinity and specificity for its macromolecular substrate.

The specific action of serine proteinases on protein substrates is a hallmark of blood coagulation and numerous other physiological processes. Enzymic recognition of substrate sequences preceding the scissile bond is considered to contribute dominantly to specificity and function. We have investigated the contribution of active site docking by unique substrate residues preceding the scissile bond to the function of prothrombinase. Mutagenesis of the authentic P(1)-P(3) sequence in prethrombin 2/fragment 1.2 yielded substrate variants that could be converted to thrombin by prothrombinase. Proteolytic activation was also observed with a substrate variant containing the P(1)-P(3) sequence found in a coagulation zymogen not known to be activated by prothrombinase. Lower rates of activation of the variants derived from a decrease in maximum catalytic rate but not in substrate affinity. Replacement of the P(1) residue with Gln yielded an uncleavable derivative that retained the affinity of the wild type substrate for prothrombinase but did not engage the active site of the enzyme. Thus, active site docking of the substrate contributes to catalytic efficiency, but it is does not determine substrate affinity nor does it fully explain the specificity of prothrombinase. Therefore, extended interactions between prothrombinase and substrate regions removed from the cleavage site drive substrate affinity and enforce the substrate specificity of this enzyme complex

Geomagnetic field variations at low and high latitude during the January 10-11, 1997 magnetic cloud

On Jan. 10-11, 1997 a wide magnetic cloud reached the Earth triggering intense geomagnetic activity. Observations performed at low and very high latitude show that the same features appear simultaneously in correspondence to different changes in the solar wind conditions. In particular, highly polarized modes are simultaneously observed at the same discrete frequencies after the passage of the high density solar wind region following the cloud. SI's and ULF waves polarization are also examined in a wide latitudinal and longitudinal extent

JAK inhibition differentially affects NK cell and ILC1 homeostasis

Janus kinase (JAK) inhibitors are widely used in the treatment of multiple autoimmune and inflammatory diseases. Immunologic and transcriptomic profiling have revealed major alterations on natural killer (NK) cell homeostasis associated with JAK inhibitions, while information on other innate lymphoid cells (ILCs) is still lacking. Herein, we observed that, in mice, the homeostatic pool of liver ILC1 was less affected by JAK inhibitors compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance

Impact of Ureteral Stent Material on Stent-related Symptoms: A Systematic Review of the Literature

CONTEXT Ureteral stents are essential implants that are used on a daily basis. Since their invention, advances in stent design have been directed towards alleviating stent-related symptoms. It remains unclear how the material composition of the stent affects stent-related symptoms. OBJECTIVE To review the literature and define the clinical impact of ureteral stent material on stent-related symptoms. EVIDENCE ACQUISITION A literature search of the Embase, MEDLINE (PubMed), and Web of Science databases was conducted on December 17, 2021 to collect articles comparing stent composition materials regarding stent-related symptoms. Thirteen publications met the inclusion criteria, of which only one met the high-quality requirements of the Cochrane Collaboration tool for assessing the risk of bias in randomized trials. EVIDENCE SYNTHESIS Most trials, including the highest quality trial, seem to support that silicone double-J (DJ) stents reduce stent-related symptoms compared to nonsilicone DJ stents. Regarding physical properties, it seems that "soft" or "flexible" DJ stents reduce stent-related symptoms. However, since there was only one high-quality study with a low risk of bias, it is impossible to draw a definitive conclusion owing to the lack of quality data. CONCLUSIONS Silicone DJ stents, and by extension "soft" DJ stents, appear to reduce stent-related symptoms compared to nonsilicone polymers and "hard" DJ stents. No definitive conclusion can be drawn owing to a lack of quality evidence. Creating a standard for measuring and reporting physical stent properties should be the first step for further research. PATIENT SUMMARY A ureteral stent is a small hollow tube placed inside the ureter to help urine drain from the kidney. We reviewed the literature on the impact of stent material on stent-related symptoms. We found that silicone may reduce stent-related symptoms, but no definitive conclusion can be drawn and further studies are needed

A WIMP detector with two-phase xenon

Abstract We describe an important new technique to search for WIMPs. This technique employs a method of background discrimination using double phase xenon as detector target. We describe the construction of a two-phase, 1-kg xenon detector. The detector will be installed at the underground laboratory in the Mt. Blanc tunnel, which provides a low background rate. A comparison between the sensitivity curve of our detector and the theoretical events limit from SUSY calculations is presented

Precise 3D track reconstruction algorithm for the ICARUS T600 liquid argon time projection chamber detector

Liquid Argon Time Projection Chamber (LAr TPC) detectors offer charged particle imaging capability with remarkable spatial resolution. Precise event reconstruction procedures are critical in order to fully exploit the potential of this technology. In this paper we present a new, general approach of three-dimensional reconstruction for the LAr TPC with a practical application to track reconstruction. The efficiency of the method is evaluated on a sample of simulated tracks. We present also the application of the method to the analysis of real data tracks collected during the ICARUS T600 detector operation with the CNGS neutrino beam.Comment: Submitted to Advances in High Energy Physic

Neutrino oscillation physics at an upgraded CNGS with large next generation liquid Argon TPC detectors

The determination of the missing $U_{e3}$ element (magnitude and phase) of the PMNS neutrino mixing matrix is possible via the detection of \numu\to\nue oscillations at a baseline $L$ and energy $E$ given by the atmospheric observations, corresponding to a mass squared difference $E/L \sim \Delta m^2\simeq 2.5\times 10^{-3} eV^2$. While the current optimization of the CNGS beam provides limited sensitivity to this reaction, we discuss in this document the physics potential of an intensity upgraded and energy re-optimized CNGS neutrino beam coupled to an off-axis detector. We show that improvements in sensitivity to $\theta_{13}$ compared to that of T2K and NoVA are possible with a next generation large liquid Argon TPC detector located at an off-axis position (position rather distant from LNGS, possibly at shallow depth). We also address the possibility to discover CP-violation and disentangle the mass hierarchy via matter effects. The considered intensity enhancement of the CERN SPS has strong synergies with the upgrade/replacement of the elements of its injector chain (Linac, PSB, PS) and the refurbishing of its own elements, envisioned for an optimal and/or upgraded LHC luminosity programme.Comment: 37 pages, 20 figure

Search for anomalies in the {\nu}e appearance from a {\nu}{\mu} beam

We report an updated result from the ICARUS experiment on the search for {\nu}{\mu} ->{\nu}e anomalies with the CNGS beam, produced at CERN with an average energy of 20 GeV and travelling 730 km to the Gran Sasso Laboratory. The present analysis is based on a total sample of 1995 events of CNGS neutrino interactions, which corresponds to an almost doubled sample with respect to the previously published result. Four clear {\nu}e events have been visually identified over the full sample, compared with an expectation of 6.4 +- 0.9 events from conventional sources. The result is compatible with the absence of additional anomalous contributions. At 90% and 99% confidence levels the limits to possible oscillated events are 3.7 and 8.3 respectively. The corresponding limit to oscillation probability becomes consequently 3.4 x 10-3 and 7.6 x 10-3 respectively. The present result confirms, with an improved sensitivity, the early result already published by the ICARUS collaboration

Status of ZEPLIN II and ZEPLIN IV study

Abstract We discribe the construction status of ZEPLIN II detector, a 30-kg two-phase discriminating xenon detector to be installed in Boulby Mine, UK, for the direct detection of WIMP dark matter. Both scintillation and ionization will be measure in order to discriminate the radioactive background. ZEPLIN-II will have very high radioactive-background rejection efficiency. We will also discuss the study of ton scale ZEPLIN IV. The ZEPLIN program is a collaborative work of UCLA, TAMU, UKMDMC, and CNR Torino, Italy