Low coordinate Zn(II) organocations bearing extremely bulky NHC ligands: structural features, air-/water-tolerance and use in hydrosilylation and hydrogenation catalysis.

This work details the synthesis and characterization of low-coordinate Zn(II)-based organocations [(NHC)Zn(R)] incorporating extremely bulky NHCs [ITr] and [IAd] ([ITr] = ([ITr] = [(HCNCPh)C:]; [IAd] = [(HCNAd)C:], Ad = adamantyl)). Their structural features and particularities are thoroughly assessed as well as their air and water tolerance. Neutral ITr and IAd adducts [(ITr)Zn(R)] (1, R = Me; 2, R = Et) and [(IAd)Zn(R)] (3, R = Me; 4, R = Et) were synthesized by reaction of carbene [ITr] or [IAd] with a stoichiometric amount of [ZnR] and isolated in good yields.

Synthesis and Characterization of Transition Metal Complexes Supported by Phosphorus Ligands Obtained Using Hydrophosphination of Cyclic Internal Alkenes.

The design and study of rich, bulky phosphorus ligands is a key area of research for homogeneous catalysis. Here, we describe an original strategy using a hydrophosphination reaction to produce phosphines of interest for coordination chemistry and homogenous catalysis. In particular, the phosphine obtained by reacting diphenylphosphine with acenaphthylene (ligand ) gives a ligand that adopts an unusual spatial geometry.

Towards standardisation of surface electromyography measurements in the horse: Bipolar electrode location.

The use of surface electromyography in the field of animal locomotion has increased considerably over the past decade. However, no consensus exists on the methodology for data collection in horses. This study aimed to start the development of recommendations for bipolar electrode locations to collect surface electromyographic data from horses during dynamic tasks.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity.

Upadacitinib: Mechanism of action, clinical, and translational science.

Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other agencies around the world for the treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, and gastrointestinal diseases. Through inhibition of JAK, upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases. Upadacitinib more potently inhibits JAK1 than other JAK isoforms.

Targeting the Tyrosine Kinase 2 (TYK2) Pseudokinase Domain: Discovery of the Selective TYK2 Inhibitor ABBV-712.

Tyrosine kinase 2 (TYK2) is a nonreceptor tyrosine kinase that belongs to the JAK family also comprising JAK1, JAK2, and JAK3. TYK2 is an attractive target for various autoimmune diseases as it regulates signal transduction downstream of IL-23 and IL-12 receptors. Selective TYK2 inhibition offers a differentiated clinical profile compared to currently approved JAK inhibitors.

Differential properties of Janus kinase inhibitors in the treatment of immune-mediated inflammatory diseases.

Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory diseases, such as RA, psoriasis, atopic dermatitis and IBD. Several small-molecule JAK inhibitors (JAKis) are now approved for the treatment of various immune-mediated inflammatory diseases. There are, however, key differences between these agents that could potentially translate into unique clinical profiles.

Triphenylphosphonium-functionalized N-heterocyclic carbene platinum complexes [(NHC-TPP)Pt] induce cell death of human glioblastoma cancer stem cells.

A growing body of experimental and clinical evidence suggests that rare cell populations, known as cancer stem cells (CSCs), play an important role in the development and therapeutic resistance of several cancers, including glioblastoma. Elimination of these cells is therefore of paramount importance. Interestingly, recent results have shown that the use of drugs that specifically disrupt mitochondria or induce mitochondria-dependent apoptosis can efficiently kill cancer stem cells.

Detecting fatigue of sport horses with biomechanical gait features using inertial sensors.

Detection of fatigue helps prevent injuries and optimize the performance of horses. Previous studies tried to determine fatigue using physiological parameters. However, measuring the physiological parameters, e.

Genotype-by-environment and QTL-by-environment interactions in sweet cherry ( L.) for flowering date.

In sweet cherry ( L.), flowering date is strongly dependent on the environment conditions and, therefore, is a trait of major interest for adaptation to climate change. Such trait can be influenced by genotype-by-environment interaction (G×E), that refers to differences in the response of genotypes to different environments.

Prediction of continuous and discrete kinetic parameters in horses from inertial measurement units data using recurrent artificial neural networks.

Vertical ground reaction force (GRFz) measurements are the best tool for assessing horses' weight-bearing lameness. However, collection of these data is often impractical for clinical use. This study evaluates GRFz predicted using data from body-mounted IMUs and long short-term memory recurrent neural networks (LSTM-RNN).

New insights into flowering date in Prunus: fine mapping of a major QTL in sweet cherry.

Flowering date is an important trait in Prunus fruit species, especially for their adaptation in a global warming context. Numerous quantitative trait loci (QTLs) have been identified and a major one was previously located on LG4. The objectives of this study were to fine-map this QTL in sweet cherry, to identify robust candidate genes by using the new sweet cherry genome sequence of the cultivar 'Regina' and to define markers usable in marker-assisted selection (MAS).

Tuning the C/N Ratio of C-Rich Graphitic Carbon Nitride (g-C N ) Materials by the Melamine/Carboxylic Acid Adduct Route.

C-rich graphitic carbonitride materials (CN ) with a large range of compositions have been prepared thanks to the self-assembly, in different ratios, of melamine (M) and a panel of polycarboxylic acids (A) such as oxalic, tartaric and citric acid. The thermal conversion of the formed adducts (MA ), led to CN phases, with x ranging from 0.66 to 1.

Counter-gradient variation of reproductive effort in a widely distributed temperate oak ().

The genetic and phenotypic variability of life history traits determines the demographic attributes of tree populations and, thus, their responses to anthropogenic climate change. Growth- and survival-related traits have been widely studied in forest ecology, but little is known about the determinism of reproductive traits.Using an elevation gradient experiment in the Pyrenees we assessed the degree to which variations in reproductive effort along climatic gradients are environmentally or genetically driven, by comparing oak populations () growing under field and common garden conditions.

Molecular mechanisms of Guadecitabine induced FGFR4 down regulation in alveolar rhabdomyosarcomas.

Fibroblast growth factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA methyltransferase inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5 days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 or H3K27.

A drop does not fall in a straight line: a rationale for the width of stalagmites.

Drops loaded in calcium ions detach from stalactites and impact the underlying stalagmites, thereby allowing these latter to grow through calcite precipitation. Nevertheless, little is known about the influence of the drop free fall and splash dynamics on stalagmite shape and width. Through high-speed imaging of impacting drops on stalagmites from several caves, we observed that the impact point position of the drops is scattered, sometimes over several centimetres.

Description of Two Cases of Anaplastic Large Cell Lymphoma Associated with a Breast Implant.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized provisional entity in the 2017 revision of the World Health Organization classification of lymphoid neoplasms. Although the majority of the cases described in the literature demonstrate an effusion confined to the capsule of the breast implant, this rare pathology can also invade the capsule and adjacent tissues and/or involve lymph nodes. We hereby report two new cases of BIA-ALCL in a 58-year-old and a 47-year-old Caucasian female who received a silicone breast implant.

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494).

Background: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia.

One-Pot Soft-Template Synthesis of Nanostructured Copper-Supported Mesoporous Carbon FDU-15 Electrocatalysts for Efficient CO Reduction.

Copper-supported mesoporous carbon nanocatalysts (Cu/FDU-15) were synthesized using an easy and convenient one-pot soft-template method for low-overvoltage CO electroreduction. TEM imaging revealed the presence of large Cu nanoparticles (diameter 140 nm) with Cu O nanoparticles (16 nm) as an additional phase. From the electron tomography observations, we found that the copper particles were placed inside and on the exterior surface of the porous FDU-15 support, providing an accessible surface for electrocatalytic reactions.

Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity.

6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring.

Adipose tissue inflammation in breast cancer survivors: effects of a 16-week combined aerobic and resistance exercise training intervention.

Purpose: Obesity is a leading modifiable contributor to breast cancer mortality due to its association with increased recurrence and decreased overall survival rate. Obesity stimulates cancer progression through chronic, low-grade inflammation in white adipose tissue, leading to accumulation of adipose tissue macrophages (ATMs), in particular, the pro-inflammatory M1 phenotype macrophage. Exercise has been shown to reduce M1 ATMs and increase the more anti-inflammatory M2 ATMs in obese adults.

Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin.

Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME).

A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro.

L-Asparaginases (ASNases) have been used as first line drugs for paediatric Acute Lymphoblastic Leukaemia (ALL) treatment for more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently used in the clinics are characterized by high in vivo instability, short half-life and the requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they are sensitive to proteases (cathepsin B and asparagine endopeptidase) that are over-expressed by resistant leukaemia lymphoblasts, thereby impairing drug activity and pharmacokinetics.