Synthesis and Magnetic Properties of Antimony-Ligated Co(II) Complexes: Stibines versus Phosphines.

Herein, we test the hypothesis that neutral, heavy-atom stibine donors can increase the extent of spin-orbit coupling on light, 3d transition metal. To this end, we developed a novel synthetic route toward coordinating a paramagnetic 3d metal ion─cobalt(II)─with neutral stibine ligands. Such complexes have not been reported in the literature due to the weak σ donor strength of stibines and the hard-soft mismatch between a 3d metal and a 5p ligand─which herein has been overcome using alkylated Sb donors.

Low- and no-calorie sweetener intakes in the Brazilian population estimated using added sugar substitution modelling.

This research examined the intakes of six low- and no-calorie sweeteners (LNCS) (acesulfame-K, aspartame, cyclamate, saccharin, steviol glycosides, and sucralose) by the Brazilian population using an added sugar substitution approach. Detailed exposure modelling requires the use of proprietary concentration data, which can be difficult to obtain. Two exposure models were conducted using nationally representative food consumption data.

An updated estimate of benzoate intakes from non-alcoholic beverages in Canada and the United States.

In 2017, the results of a comprehensive assessment of intake for benzoic acid and its salts from non-alcoholic beverages were published for four regions (Brazil, Canada, Mexico, and the United States [U.S.]).

Selective inhibition of peripheral cathepsin S reverses tactile allodynia following peripheral nerve injury in mouse.

Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor.

Phosphoinositide 3-kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune-mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of δγ isoforms in immune signaling.

Prevalence of Low Back Pain, Pelvic Girdle Pain, and Combination Pain in a Pregnant Ontario Population.

Objective: The purpose of the current pilot study is to determine the point and period prevalence of site-specific back pain, low back pain (LBP), pelvic girdle pain (PGP), and combined pain (Combo Pain) in pregnant women at a large urban centre in Ontario.

Methods: Point and period prevalence for LBP, PGP, and Combo Pain were determined using a questionnaire and accompanying pain diagram. Women were included in the study if they were healthy, of child-bearing age (18-45 years), currently experiencing a singleton pregnancy (any trimester), and proficient in the English language.

RORγt and RORα signature genes in human Th17 cells.

RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells.

T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.

Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation.

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4(+) Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists.

Targeting the ion channel Kv1.3 with scorpion venom peptides engineered for potency, selectivity, and half-life.

Ion channels are an attractive class of drug targets, but progress in developing inhibitors for therapeutic use has been limited largely due to challenges in identifying subtype selective small molecules. Animal venoms provide an alternative source of ion channel modulators, and the venoms of several species, such as scorpions, spiders and snails, are known to be rich sources of ion channel modulating peptides. Importantly, these peptides often bind to hyper-variable extracellular loops, creating the potential for subtype selectivity rarely achieved with small molecules.

Cost-effectiveness analysis of vaccinating children in Malawi with RTS,S vaccines in comparison with long-lasting insecticide-treated nets.

Background: New RTS,S malaria vaccines may soon be licensed, yet its cost-effectiveness is unknown. Before the widespread introduction of RTS,S vaccines, cost-effectiveness studies are needed to help inform governments in resource-poor settings about how best to prioritize between the new vaccine and existing malaria interventions.

Methods: A Markov model simulated malaria progression in a hypothetical Malawian birth cohort.

Comparison of RNA-Seq and microarray in transcriptome profiling of activated T cells.

To demonstrate the benefits of RNA-Seq over microarray in transcriptome profiling, both RNA-Seq and microarray analyses were performed on RNA samples from a human T cell activation experiment. In contrast to other reports, our analyses focused on the difference, rather than similarity, between RNA-Seq and microarray technologies in transcriptome profiling. A comparison of data sets derived from RNA-Seq and Affymetrix platforms using the same set of samples showed a high correlation between gene expression profiles generated by the two platforms.

PI3Kγ kinase activity is required for optimal T-cell activation and differentiation.

Phosphatidylinositol-3-kinase gamma (PI3Kγ) is a leukocyte-specific lipid kinase with signaling function downstream of G protein-coupled receptors to regulate cell trafficking, but its role in T cells remains unclear. To investigate the requirement of PI3Kγ kinase activity in T-cell function, we studied T cells from PI3Kγ kinase-dead knock-in (PI3Kγ(KD/KD)) mice expressing the kinase-inactive PI3Kγ protein. We show that CD4(+) and CD8(+) T cells from PI3Kγ(KD/KD) mice exhibit impaired TCR/CD28-mediated activation that could not be rescued by exogenous IL-2.

Conscious monitoring and control (reinvestment) in surgical performance under pressure.

Background: Research on intraoperative stressors has focused on external factors without considering individual differences in the ability to cope with stress. One individual difference that is implicated in adverse effects of stress on performance is "reinvestment," the propensity for conscious monitoring and control of movements. The aim of this study was to examine the impact of reinvestment on laparoscopic performance under time pressure.

Development and validation of a surgical workload measure: the surgery task load index (SURG-TLX).

Background: The purpose of the present study was to develop and validate a multidimensional, surgery-specific workload measure (the SURG-TLX), and to determine its utility in providing diagnostic information about the impact of various sources of stress on the perceived demands of trained surgical operators. As a wide range of stressors have been identified for surgeons in the operating room, the current approach of considering stress as a unidimensional construct may not only limit the degree to which underlying mechanisms may be understood but also the degree to which training interventions may be successfully matched to particular sources of stress.

Methods: The dimensions of the SURG-TLX were based on two current multidimensional workload measures and developed via focus group discussion.

A comparison of evaluation, time pressure, and multitasking as stressors of psychomotor operative performance.

Background: There is gathering interest in determining the typical sources of stress for an operating surgeon and the effect that stressors might have on operative performance. Much of the research in this field, however, has failed to measure stress levels and performance concurrently or has not acknowledged the differential impact of potential stressors. Our aim was to examine empirically the influence of different sources of stress on trained laparoscopic performance.

A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling.

The interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) is a member of the IRAK kinase family that plays a pivotal role in the Toll/IL-1 receptor (TIR) family signaling cascade. We have identified a novel splice variant, IRAK1c, which lacks a region encoded by exon 11 of the IRAK1 gene. IRAK1c expression was confirmed by both RNA and protein detection.

Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation.

1. During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H(4) but not H(3) receptors.

IgE-dependent mast cell activation potentiates airway responses in murine asthma models.

We have studied murine models of asthma using FcepsilonRIalpha-chain-deficient (FcepsilonRIalpha(-/-)) mice to investigate the role of IgE-dependent mast cell activation in these models. When mice were either 1) immunized once with OVA in alum i.p.

Behavioral characterization of mice lacking histamine H(3) receptors.

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors.