Sleep disturbance mediates the link between both self-compassion and self-criticism and psychological distress during prolonged periods of stress.

Poor sleep and subsequent decline in mental health often occur during times of prolonged stress, such as a pandemic. Self-compassion is linked with improved sleep and better mental health, while self-criticism is linked with poorer sleep and psychological distress. Given there is little evidence of the interrelationships of these constructs, we examined whether higher self-compassion or lower levels of self-criticism can reduce psychological distress directly and indirectly via sleep during times of prolonged stress. Structural equation modelling was used to analyse two samples (N = 722, Study 1, and N = 622, Replication Study) of university students during different stages of the pandemic. An aggregate psychological distress construct was calculated using depression, anxiety and stress measures. We created models that showed insomnia symptoms mediated the relationship between self-compassion/self-criticism and psychological distress. Sleep partially mediated both relationships, and this was the strongest effect in both samples. This suggests that improving self-compassion and reducing self-criticism will improve sleep, leading to reduced psychological distress. As our findings are robust and held at two time points, future research should investigate broader demographics and differing stress responses.

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.

ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

A feasibility randomised controlled trial to evaluate the role of computed tomography in adults with atypical right iliac fossa pain.

BACKGROUND: In patients with right iliac fossa pain, the need for surgery is largely determined by the likelihood of appendicitis. Patients often undergo ultrasound scanning despite a low diagnostic accuracy for appendicitis. This study aimed to determine the feasibility of a larger trial of computed tomography in the evaluation of patients with atypical right iliac fossa pain. MATERIALS AND METHODS: A single-centre, unblinded, parallel randomised controlled trial of computed tomography in the assessment of patients with atypical right iliac fossa pain. After a retrospective evaluation, standard care was defined as serial examination with or without ultrasound. Atypical right iliac fossa pain was defined as no firm diagnosis after initial senior review. Simple descriptions of the risks and benefits of computed tomography were devised for patients to consider. Primary objectives were to assess feasibility and acceptability of the study procedures. RESULTS: A total of 71 patients were invited to participate and 68 were randomised. Final analysis included 31 participants in the standard care arm and 33 in the computed tomography arm, with comparable demographics. Computed tomography was associated with superior diagnostic accuracy, with 100% positive and negative predictive value. The proportion of scans that positively influenced management was 73% for computed tomography and 0% for ultrasound. In the computed tomography arm, there was a trend towards a shorter length of stay (2.3 vs 3.1 days) and a lower negative laparoscopy rate (2 of 11 vs 4 of 9). CONCLUSION: A large randomised trial to evaluate the use of unenhanced computed tomography in atypical right iliac fossa pain appears feasible and justified.

Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction.

The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

Pulsed laser deposition films from a Ba2FeMoO6 target onto SrTiO3[001]: Chemical and magnetic inhomogeneity.

Pulsed laser deposition films from Ba2FeMoO6 (BFMO) targets onto SrTiO3[001] (STO) substrates have been reported previously to have non-zero magnetism at 300 K, a majority of magnetic ordering at 240 K that is less than the 370 K ordering temperature of polycrystalline BFMO, and suppressed saturation magnetization compared to polycrystalline BFMO. To interrogate these previously reported observations of BFMO on STO, we have used a combination of x-ray diffraction, atomic force microscopy, x-ray and neutron reflectivity, and x-ray photoelectron spectroscopy that shows inhomogeneities. The present results show off-stoichiometry on the A-site by incorporation of Sr from the substrate and on the B-site to have %Fe/%Mo > 1 by evolution of BaMoO4. There is an enhanced ordering temperature and magnetic response nearer to the SrTiO3 interface compared to the air interface. Depth dependent strain and microstructure are needed to explain the magnetic response. Holistic considerations and implications are also discussed.

Computational imaging analysis of glycated fibrin gels reveals aggregated and anisotropic structures.

In this article, a computational imaging analysis method is presented for the evaluation of aggregation and anisotropy in both native (unglycated) and glycated fibrin matrix structures. The imaging analysis was used to test the hypothesis that glycated fibrin structures are more aggregated and anisotropic than unglycated (native) fibrin structures. Glycation of fibrinogen, and subsequently fibrin, occurs under normal physiological conditions; however, excess glycation due to disease states such as diabetes can disrupt the fibrin matrix and cause an abnormal structure and function. Studies that elucidate morphological changes in glucose incubated fibrin matrices are necessary to better understand thrombosis, which occurs due to hypercoagulable conditions. In this study, imaging algorithms were designed for the determination of aggregation of fibrin fibers within a matrix as well as preferential orientation (anisotropy) due to glycation. The results showed that glycated fibrin structures displayed an overall higher degree of aggregation and anisotropy as compared to unglycated fibrin structures. However, for glycated fibrin matrices that were polymerized utilizing extended incubation periods representative of physiological plasma glucose conditions, the results showed that fibrin aggregation and anisotropy decreased when compared to unglycated matrices. The algorithms showed that incorporation of the crosslinking agent FXIII into the fibrin matrix was shown to decrease both aggregation and anisotropy. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2191-2198, 2017.

Computational imaging analysis of fibrin matrices with the inclusion of erythrocytes from homozygous SS blood reveals agglomerated and amorphous structures.

Sickle cell disease is a single point mutation disease that is known to alter the coagulation system, leading to hypercoagulable plasma conditions. These hypercoagulable conditions can lead to complications in the vasculature, caused by fibrin clots that form undesirably. There is a need to understand the morphology and structure of fibrin clots from patients with sickle cell disease, as this could lead to further discovery of treatments and life-saving therapies. In this work, a computational imaging analysis method is presented to evaluate fibrin agglomeration in the presence of erythrocytes (RBCs) homozygous for the sickle cell mutation (SS). Numerical algorithms were used to determine agglomeration of fibrin fibers within a matrix with SS RBCs to test the hypothesis that fibrin matrices with the inclusion of SS RBCs possess a more agglomerated structure than native fibrin matrices with AA RBCs. The numerical results showed that fibrin structures with SS RBCs displayed an overall higher degree of agglomeration as compared to native fibrin structures. The computational algorithm was also used to evaluate fibrin fiber overlap (aggregation) and anisotropy (orientation) in normal fibrin matrices compared to fibrin matrices polymerized around SS RBCs; however, there was no statistical difference. Ultrasound measurements of stiffness revealed rigid RBCs in the case of samples derived from homozygous SS blood, and densely evolving matrices, when compared to normal fibrin with the inclusion of AA RBCs. An agglomeration model is suggested to quantify the fibrin aggregation/clustering near RBCs for both normal fibrin matrices and for the altered structures. The results of this work are important in the sense that the understanding of aggregation and morphology in fibrin clots with incorporation of RBCs from persons living with sickle cell anemia may elucidate the complexities of comorbidities and other disease complications.

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD).

This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.

The potential for biodiversity offsetting to fund effective invasive species control.

Compensating for biodiversity losses in 1 location by conserving or restoring biodiversity elsewhere (i.e., biodiversity offsetting) is being used increasingly to compensate for biodiversity losses resulting from development. We considered whether a form of biodiversity offsetting, enhancement offsetting (i.e., enhancing the quality of degraded natural habitats through intensive ecological management), can realistically secure additional funding to control biological invaders at a scale and duration that results in enhanced biodiversity outcomes. We suggest that biodiversity offsetting has the potential to enhance biodiversity values through funding of invasive species control, but it needs to meet 7 key conditions: be technically possible to reduce invasive species to levels that enhance native biodiversity; be affordable; be sufficiently large to compensate for the impact; be adaptable to accommodate new strategic and tactical developments while not compromising biodiversity outcomes; acknowledge uncertainties associated with managing pests; be based on an explicit risk assessment that identifies the cost of not achieving target outcomes; and include financial mechanisms to provide for in-perpetuity funding. The challenge then for conservation practitioners, advocates, and policy makers is to develop frameworks that allow for durable and effective partnerships with developers to realize the full potential of enhancement offsets, which will require a shift away from traditional preservation-focused approaches to biodiversity management.

Optimization of sphingosine-1-phosphate-1 receptor agonists: effects of acidic, basic, and zwitterionic chemotypes on pharmacokinetic and pharmacodynamic profiles.

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.

Measurement of band offsets in Y2O3/InGaZnO4 heterojunctions.

The valence band discontinuity (ΔE(v)) of Y2O3/InGaZnO4 (IGZO) heterojunctions was measured by a core-level photoemission method. The Y2O3 exhibited a band gap of -6.27 eV from absorption measurements. A value of ΔE(v) = 0.44 ± 0.21 eV was obtained by using the Ga 2p3/2, Zn 2p3/2 and in 3d5/2 energy levels as references. Given the experimental bandgap of 3.2 eV for the IGZO, this would indicate a conduction band offset ΔE(c) of - 2.63 eV in the Y2O3/IGZO heterostructures and a nested interface band alignment.

The flood pulse as the underlying driver of vegetation in the largest wetland and fishery of the Mekong Basin.

The Tonle Sap is the largest wetland in Southeast Asia and one of the world's most productive inland fisheries. The Mekong River inundates the Tonle Sap every year, shaping a mosaic of natural and agricultural habitats. Ongoing hydropower development, however, will dampen the flood pulse that maintains the Tonle Sap. This study established the current underlying relationship among hydrology, vegetation, and human use. We found that vegetation is strongly influenced by flood duration; however, this relationship was heavily distorted by fire, grazing, and rice cultivation. The expected flood pulse alteration will result in higher water levels during the dry season, permanently inundating existing forests. The reduction of the maximum flood extent will facilitate agricultural expansion into natural habitats. This study is the most comprehensive field survey of the Tonle Sap to date, and it provides fundamental knowledge needed to understand the underlying processes that maintain this important wetland.

A long-term experimental test of the dynamic equilibrium model of species diversity.

The dynamic equilibrium model of species diversity predicts that ecosystem productivity interacts with disturbance to determine how many species coexist. However, a robust test of this model requires manipulations of productivity and disturbance over a sufficient timescale to allow competitive exclusion, and such long-term experimental tests of this hypothesis are rare. Here we use long-term (27 years), large-scale (8 × 50-m plots), factorial manipulations of soil resource availability and sheep grazing intensity (disturbance) in grasslands to test the dynamic equilibrium model. As predicted by the model, increased productivity not only reduced plant species richness, but also moderated the effects of grazing intensity, shifting them from negative to neutral with increasing productivity. Reductions in species richness with productivity were associated with dominance by faster growing (i.e. high specific leaf area) and taller plants. Conversely, grazing favoured shorter plants and this effect became stronger with greater productivity, consistent with the view that grazing can lead to weaker asymmetric competition for light. Our study shows that the dynamic equilibrium model can help to explain changes in plant species richness following long-term increases in soil resource availability and grazing pressure, two fundamental drivers of change in grasslands worldwide.

Ultimate drivers of native biodiversity change in agricultural systems.

The ability to address land degradation and biodiversity loss while maintaining the production of plant and animal products is a key global challenge. Biodiversity decline as a result of vegetation clearance, cultivation, grazing, pesticide and herbicide application, and plantation establishment, amongst other factors, has been widely documented in agricultural ecosystems. In this paper we identify six ultimate drivers that underlie these proximate factors and hence determine what native biodiversity occurs in modern agricultural landscapes; (1) historical legacies; (2) environmental change; (3) economy; (4) social values and awareness; (5) technology and knowledge; and (6) policy and regulation. While historical legacies and environmental change affect native biodiversity directly, all six indirectly affect biodiversity by influencing the decisions that land managers make about the way they use their land and water resources. Understanding these drivers is essential in developing strategies for sustaining native biodiversity in agricultural landscapes into the future.

Identification of a series of 1,3,4-oxadiazol-2-amines as potent alpha-7 agonists with efficacy in the novel object recognition model of cognition.

A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.