Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development

Separation of specific single-enantiomer single-wall carbon nanotubes in the large-diameter regime

The enantiomer-level isolation of single-walled carbon nanotubes (SWCNTs) in high concentration and with high purity for nanotubes greater than 1.1 nm in diameter is demonstrated using a two-stage aqueous two-phase extraction (ATPE) technique. In total, five different nanotube species of ∼1.41 nm diameter are isolated, including both metallics and semiconductors. We characterize these populations by absorbance spectroscopy, circular dichroism spectroscopy, resonance Raman spectroscopy, and photoluminescence mapping, revealing and substantiating mod-dependent optical dependencies. Using knowledge of the competitive adsorption of surfactants to the SWCNTs that controls partitioning within the ATPE separation, we describe an advanced acid addition methodology that enables the fine control of the separation of these select nanotubes. Furthermore, we show that endohedral filling is a previously unrecognized but important factor to ensure a homogeneous starting material and further enhance the separation yield, with the best results for alkane-filled SWCNTs, followed by empty SWCNTs, with the intrinsic inhomogeneity of water-filled SWCNTs causing them to be worse for separations. Lastly, we demonstrate the potential use of these nanotubes in field-effect transistors

Validation of the A Posteriori Error Estimator Based on Polynomial Preserving Recovery for Linear Elements

In this paper the quality of the error estimator based on the Polynomial Preserving Recovery (PPR) is investigated using the computer-based approach proposed by Babiiska et al. A comparison is made between the error estimator based on the PPR and the one based on the Superconvergence Patch Recovery (SPR). It was found that the PPR is at least as good as the SPR

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. The immune system in patients with AH is hyperactive and yet dysfunctional. Here, we investigated whether this immune‐dysregulated state is related to the alcoholic impact on immune checkpoints (ICPs). We used multiplex immunoassays and enzyme‐linked immunosorbent assay to quantify plasma levels of 18 soluble ICPs (sICPs) from 81 patients with AH, 65 heavy drinkers without liver diseases (HDCs), and 39 healthy controls (HCs) at baseline, 33 patients with AH and 32 HDCs at 6‐month follow‐up, and 18 patients with AH and 29 HDCs at 12‐month follow‐up. We demonstrated that baseline levels of 6 sICPs (soluble T‐cell immunoglobulin and mucin domain 3 [sTIM‐3], soluble cluster of differentiation [sCD]27, sCD40, soluble Toll‐like receptor‐2 [sTLR‐2], soluble herpesvirus entry mediator [sHVEM], and soluble lymphotoxin‐like inducible protein that competes with glycoprotein D for herpes virus entry on T cells [sLIGHT]) were up‐regulated, while 11 sICPs (soluble B‐ and T‐lymphocyte attenuator [sBTLA], sCD160, soluble cytotoxic T‐lymphocyte‐associated protein 4 [sCTLA‐4], soluble lymphocyte‐activation gene 3 [sLAG‐3], soluble programmed death 1 [sPD‐1], sPD ligand 1 [sPD‐L1], sCD28, soluble glucocorticoid‐induced tumor necrosis factor receptor‐related protein [sGITR], sGITR ligand [sGITRL], sCD80, and inducible T‐cell costimulator [sICOS]) were down‐regulated in patients with AH compared to HDCs. The up‐regulated sICPs except sLIGHT and down‐regulated sCD80, sCD160, sCTLA‐4, and sLAG‐3 correlated positively or negatively with AH disease severity, bacterial translocation, and inflammatory factors. At follow‐up, abstinent patients with AH still had higher levels of several sICPs compared to HDCs. We also compared expression of 10 membrane‐bound ICPs (mICPs) on peripheral blood mononuclear cells (PBMCs) from patients with AH and HCs by flow cytometry and found that several mICPs were dysregulated on blood cells from patients with AH. The function and regulation of sICPs and mICPs were studied using PBMCs from patients with AH and HCs. Recombinant sHVEM affected tumor necrosis factor (TNF)‐α and interferon‐γ production by T cells from patients with AH and HCs. Conclusion: Both sICPs and mICPs were dysregulated in patients with AH, and alcohol abstinence did not fully reverse these abnormalities. The HVEM axis plays a role in regulating T‐cell function in patients with AH

Low-temperature electroluminescence excitation mapping of excitons and trions in short channel monochiral carbon nanotube device

Single walled carbon nanotubes as emerging quantum-light sources may fill a technological gap in silicon photonics due to their potential use as near infrared, electrically driven, classical or non-classical emitters. Unlike in photoluminescence, where nanotubes are excited with light, electrical excitation of single tubes is challenging and heavily influenced by device fabrication, architecture and biasing conditions. Here we present electroluminescence spectroscopy data of ultra short channel devices made from (9,8) carbon nanotubes emitting in the telecom band. Emissions are stable under current biasing and no quenching is observed down to 10 nm gap size. Low-temperature electroluminescence spectroscopy data also reported exhibits cold emission and linewidths down to 2 meV at 4 K. Electroluminescence excitation maps give evidence that carrier recombination is the mechanism for light generation in short channels. Excitonic and trionic emissions can be switched on and off by gate voltage and corresponding emission efficiency maps were compiled. Insights are gained into the influence of acoustic phonons on the linewidth, absence of intensity saturation and exciton exciton annihilation, environmental effects like dielectric screening and strain on the emission wavelength, and conditions to suppress hysteresis and establish optimum operation conditions

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma–induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. Conclusion: AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities

Persistent Hyperactivation of Endothelial Cells in Patients with Alcoholic Hepatitis

Background: Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up-regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM-1, VCAM-1, and VEGF-A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH. Methods: ELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6-month follow-up, and 18 AH patients and 25 HDC at 12-month follow-up. Results: At baseline, the 4 soluble markers were significantly up-regulated in AH patients compared with HDC and HC, whereas only sVCAM-1 was elevated in HDC relative to HC. At follow-ups, plasma levels of CD146, VCAM-1, and VEGF-A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors. Conclusions: The levels of soluble CD146, ICAM-1, VCAM-1, and VEGF-A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities

A Poincare-Covariant Parton Cascade Model for Ultrarelativistic Heavy-Ion Reactions

We present a new cascade-type microscopic simulation of nucleus-nucleus collisions at RHIC energies. The basic elements are partons (quarks and gluons) moving in 8N-dimensional phase space according to Poincare-covariant dynamics. The parton-parton scattering cross sections used in the model are computed within perturbative QCD in the tree-level approximation. The Q^2 dependence of the structure functions is included by an implementation of the DGLAP mechanism suitable for a cascade, so that the number of partons is not static, but varies in space and time as the collision of two nuclei evolves. The resulting parton distributions are presented, and meaningful comparisons with experimental data are discussed.Comment: 30 pages. 11 figures. Submitted to Phys.Rev.

Extraction and Characterization of Microplastics from Organic Solid Matrices and their Remediation

Plastics have become an essential commodity due to their superior engineering properties, durability and low cost to be used by a wide range of commercial products. However, the degradation of plastics due to mechanical, chemical, biological, and photolytic stresses has led to the formation of microplastics (MPs). MPs have risen to the top of environmental concerns due to their affinity to pollute the environment, and to pass to the food chain, threatening human health. In this context, attempts have been made to extract and characterize MPs from aqueous and solid matrices. A problem that not only hampers research but also regulatory decisions is the variety of methods used for the extraction and characterization of MPs, especially in organic solid matrices (OSMs) with organic (OM) \u3e 5%, making the comparison of results difficult. This paper aims to address this need, by critically assessing the methodologies and protocols used for extraction of MPs from OSMs, which includes sample collection, dispersion, OM removal, and separation, as well as the qualitative and quantitative characterization of MPs. Further, current impediments in the accurate characterization of MPs are identified along with recommendations for future developments. Finally, recent efforts by various countries to legislate against certain sources of MPs, as well as issues and novel techniques to remediate MPs from the soil, and wastewater have been highlighted