Cytotoxic Rhodium(III) and Iridium(III) Polypyridyl Complexes: Structure–Activity Relationships,Antileukemic Activity,and Apoptosis Induction

Whereas the cytostatic agents mer‐[RhX₃(DMSO)(pp)] (X=Cl, Br; pp=phen, dpq) are considerably more potent than their facial isomers, this order is reversed for the analogous kinetically more inert Ir^III polypyridyl complexes. The complexes induce specific apoptotic cell death in leukemia and lymphoma cells via the intrinsic mitochondrial pathway and cause negligible necrotic damage.

     

Improved Adhesion, Growth and Maturation of Vascular Smooth Muscle Cells on Polyethylene Grafted with Bioactive Molecules and Carbon Particles

High-density polyethylene (PE) foils were modified by an Ar⁺ plasma discharge and subsequent grafting with biomolecules, namely glycine (Gly), polyethylene glycol (PEG), bovine serum albumin (BSA), colloidal carbon particles (C) or BSA and C (BSA + C). As revealed by atomic force microscopy (AFM), goniometry and Rutherford Backscattering Spectroscopy (RBS), the surface chemical structure and surface morphology of PE changed dramatically after plasma treatment. The contact angle decreased for the samples treated by plasma, mainly in relation to the formation of oxygen structures during plasma irradiation. A further decrease in the contact angle was obvious after glycine and PEG grafting. The increase in oxygen concentration after glycine and PEG grafting proved that the two molecules were chemically linked to the plasma-activated surface. Plasma treatment led to ablation of the PE surface layer, thus the surface morphology was changed and the surface roughness was increased. The materials were then seeded with vascular smooth muscle cells (VSMC) derived from rat aorta and incubated in a DMEM medium with fetal bovine serum. Generally, the cells adhered and grew better on modified rather than on unmodified PE samples. Immunofluorescence showed that focal adhesion plaques containing talin, vinculin and paxillin were most apparent in cells on PE grafted with PEG or BSA + C, and the fibres containing α-actin, β-actin or SM1 and SM2 myosins were thicker, more numerous and more brightly stained in the cells on all modified PE samples than on pristine PE. An enzyme-linked immunosorbent assay (ELISA) revealed increased concentrations of focal adhesion proteins talin and vinculin and also a cytoskeletal protein β-actin in cells on PE modified with BSA + C. A contractile protein α-actin was increased in cells on PE grafted with PEG or Gly. These results showed that PE activated with plasma and subsequently grafted with bioactive molecules and colloidal C particles, especially with PEG and BSA + C, promotes the adhesion, proliferation and phenotypic maturation of VSMC.     

Biochemical Functions of Geophagy in Parrots: Detoxification of Dietary Toxins and Cytoprotective Effects

This study tests hypotheses on the biochemical functions of geophagy in parrots: mechanical enhancement of digestion, acid buffering capacity, mineral supplementation, adsorption of dietary toxins, and gastrointestinal cytoprotection. Parrots showed clear preferences for specific soil horizons. Comparisons of preferred and nonpreferred soils from several sites suggest that soils have little ability to enhance grinding and no measurable ability to buffer gastric pH. Soils offered insignificant mineral supplementation since most minerals occurred at similar levels in samples regardless of preference, and the minerals were generally more plentiful in the birds' diets. Sodium was available in moderate levels at some sites (>1000 ppm), but was well below sodium detection thresholds of parrots. X-ray diffraction, cation exchange capacity, and in vitro adsorptive trials showed that the preferred soils are capable of exchanging substantial quantities of cations and are capable of adsorbing low-molecular-weight secondary compounds. In captive Amazona parrots, orally administered clay reduced the bioavailability of the alkaloid quinidine by roughly 60%, demonstrating that in vivo adsorption of potentially toxic compounds may be a biologically important function of geophagy. Labeled clay remained in the lower gastrointestinal tract of captive parrots for >12 hr, which along with high adsorptive capacities, further suggests a potential role in protecting the gastrointestinal lining from various biological and chemical insults. Detoxification and cytoprotection are the most likely functions of geophagy for parrots and herbivores with similar ecologies. Given the variety of chemically defended seeds consumed by these herbivores, geophagy likely protects consumers from dietary toxins, allowing increased diet breadth and/or enhancing digestibility.     

Coke yield and heat transfer in reaction of liquid–solid agglomerates of Athabasca vacuum residue

The ultimate coke yield was determined for agglomerates of Athabasca vacuum residue and coke particles by heating on Curie‐point alloy strips in an induction furnace at 503 and 530°C until all toluene‐soluble material was converted. Coke yield results from agglomerates were compared to the coke yield results from reacting thin films of vacuum residue. The average coke yield from the agglomerates was 23%, while the coke yield from thin films of 20 µm thickness was 11%, which supports the role of mass transfer in coke formation reactions. The ultimate coke yield was insensitive to vacuum residue concentration, agglomerate size, and reaction temperature. The temperature profile within agglomerates was measured by implanting a thermocouple, and a simple heat transfer model was used to describe the temperature variation with time. The effective thermal diffusivity of the agglomerates was 0.20 × 10^?6 m²/s. Control experiments on reaction in thin liquid films confirmed that heating rates in the range of 14.8–148 K/s had no effect on the ultimate yield of coke yield.     

Multi-Omics Revealed Molecular Mechanisms Underlying Guard Cell Systemic Acquired Resistance

Systemic Acquired Resistance (SAR) improves immunity of plant systemic tissue after local exposure to a pathogen. Guard cells that form stomatal pores on leaf surfaces recognize bacterial pathogens via pattern recognition receptors, such as Flagellin Sensitive 2 (FLS2). However, how SAR affects stomatal immunity is not known. In this study, we aim to reveal molecular mechanisms underlying the guard cell response to SAR using multi-omics of proteins, metabolites and lipids. Arabidopsis plants previously exposed to pathogenic bacteria Pseudomonas syringae pv. tomato DC3000 (Pst) exhibit an altered stomatal response compared to control plants when they are later exposed to the bacteria. Reduced stomatal apertures of SAR primed plants lead to decreased number of bacteria in leaves. Multi-omics has revealed molecular components of SAR response specific to guard cells functions, including potential roles of reactive oxygen species (ROS) and fatty acid signaling. Our results show an increase in palmitic acid and its derivative in the primed guard cells. Palmitic acid may play a role as an activator of FLS2, which initiates stomatal immune response. Improved understanding of how SAR signals affect stomatal immunity can aid biotechnology and marker-based breeding of crops for enhanced disease resistance.     

Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.     

Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase**

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.     

Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons

Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca²⁺ content and lower frequency of spontaneous Ca²⁺ signals in SGCE MSNs. Blocking of voltage-gated Ca²⁺ channels by verapamil was less efficient in suppressing KCl-induced Ca²⁺ peaks of SGCE MSNs. Ca²⁺ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca²⁺ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.     

Development of a Phytochemical-Based Lure for the Dried Bean Beetle Acanthoscelides obtectus Say (Coleoptera: Chrysomelidae)

The dried bean beetle, Acanthoscelides obtectus, is an economically important, worldwide pest of legume crops including dry beans, Phaseolus vulgaris. Assessment of A. obtectus infestation levels in pre-harvest field crops and post-harvest granaries is difficult to achieve because there is no effective monitoring tool for early detection so that interventions can be deployed as needed. Because A. obtectus is a generic pollen and nectar feeder, we adopted an electrophysiological (EAG) screening approach, using the antennae of female A. obtectus to identify physiologically active, volatile phytochemicals, which could then be investigated for their attractiveness to A. obtectus in laboratory behavioral assays and preliminary field tests. Of the 27 compounds tested in EAG screening, 5 compounds, i.e., methyl anthranilate, methyl eugenol, benzyl alcohol, (RS)-lavandulol, and 2-phenylethanol, elicited stronger EAG responses than the standard (1-phenylethanol). In 4-arm olfactometer bioassays, female A. obtectus preferred the olfactometer arm containing the odor of either methyl anthranilate or benzyl alcohol compared to the solvent control. In preliminary field tests using these 2 compounds as a binary mixture, at least 5 times as many beetles were caught on baited traps compared to non-baited traps. The field data also suggested that benzyl alcohol was primarily responsible for the field activity of the blend. We hypothesize that the attraction of A. obtectus to the combined benzyl alcohol/methyl anthranilate and the single benzyl alcohol baits is connected to the species` nectar- and pollen-feeding behaviour and not to its intraspecific communication. To our knowledge, this is the first evidence that A. obtectus behavior in the field can be modified by the deployment of plant-derived semiochemicals.