Visible-Light Switching of Metallosupramolecular Assemblies**

A photoswitchable ligand and palladium(II) ions form a dynamic mixture of self-assembled metallosupramolecular structures. The photoswitching ligand is an ortho-fluoroazobenzene with appended pyridyl groups. Combining the E-isomer with palladium(II) salts affords a double-walled triangle with composition [Pd3L6]6+ and a distorted tetrahedron [Pd4L8]8+ (1 : 2 ratio at 298 K). Irradiation with 410 nm light generates a photostationary state with approximately 80 % of the E-isomer of the ligand and results in the selective disassembly of the tetrahedron, the more thermodynamically stable structure, and the formation of the triangle, the more kinetically inert product. The triangle is then slowly transformed back into the tetrahedron over 2 days at 333 K. The Z-isomer of the ligand does not form any well-defined structures and has a thermal half-life of 25 days at 298 K. This approach shows how a thermodynamically preferred self-assembled structure can be reversibly pumped to a kinetic trap by small perturbations of the isomer distribution using non-destructive visible light

Spectral Decomposition of Broad-Line AGNs and Host Galaxies

Using an eigenspectrum decomposition technique, we separate the host galaxy from the broad line active galactic nucleus (AGN) in a set of 4666 spectra from the Sloan Digital Sky Survey (SDSS), from redshifts near zero up to about 0.75. The decomposition technique uses separate sets of galaxy and quasar eigenspectra to efficiently and reliably separate the AGN and host spectroscopic components. The technique accurately reproduces the host galaxy spectrum, its contributing fraction, and its classification. We show how the accuracy of the decomposition depends upon S/N, host galaxy fraction, and the galaxy class. Based on the eigencoefficients, the sample of SDSS broad-line AGN host galaxies spans a wide range of spectral types, but the distribution differs significantly from inactive galaxies. In particular, post-starburst activity appears to be much more common among AGN host galaxies. The luminosities of the hosts are much higher than expected for normal early-type galaxies, and their colors become increasingly bluer than early-type galaxies with increasing host luminosity. Most of the AGNs with detected hosts are emitting at between 1% and 10% of their estimated Eddington luminosities, but the sensitivity of the technique usually does not extend to the Eddington limit. There are mild correlations among the AGN and host galaxy eigencoefficients, possibly indicating a link between recent star formation and the onset of AGN activity. The catalog of spectral reconstruction parameters is available as an electronic table.Comment: 18 pages; accepted for publication in A

Development and characterisation of a novel three-dimensional inter-kingdom wound biofilm model

Chronic diabetic foot ulcers are frequently colonised and infected by polymicrobial biofilms that ultimately prevent healing. This study aimed to create a novel in vitro inter-kingdom wound biofilm model on complex hydrogel-based cellulose substrata to test commonly used topical wound treatments. Inter-kingdom triadic biofilms composed of Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus were shown to be quantitatively greater in this model compared to a simple substratum when assessed by conventional culture, metabolic dye and live dead qPCR. These biofilms were both structurally complex and compositionally dynamic in response to topical therapy, so when treated with either chlorhexidine or povidone iodine, principal component analysis revealed that the 3-D cellulose model was minimally impacted compared to the simple substratum model. This study highlights the importance of biofilm substratum and inclusion of relevant polymicrobial and inter-kingdom components, as these impact penetration and efficacy of topical antiseptics

Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25–75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300–5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72–0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71–0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60–0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD

Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25–75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300–5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72–0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71–0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60–0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD

Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25–75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300–5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72–0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71–0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60–0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD

Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25–75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300–5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72–0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71–0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60–0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD

Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility

Mineral chemistry of igneous melanite garnets from analcite-bearing volcanic rocks, Alberta, Canada

The mineral chemistry of melanite garnets from the Crowsnest volcanic rocks of SW Alberta, Canada, has been investigated by using electron microprobe scans, quantitative analyses and multivariate statistical analysis. The garnets occur with aegirine-augite, sanidine, analcite and rare plagioclase as phenocrysts in trachyte and phonolite flows, agglomerates and tuffs. Wavelength dispersive microprobe scans reveal complex zonation patterns, both normal and oscillatory. The results of fifty quantitative analyses were subjected to R-mode factor analysis to delineate the chemical exchanges producing the zonation. The chemical zonation of the garnets may be attributed to four independent binary exchanges; Al-Fe3+, Si-Ti, Ca-Mn and Mg-Fe2+. The stoichiometry of these garnets, based on microprobe and wet chemical Fe analyses, combined with the strongly antithetic behavior of Si and Ti lead us to infer that the Ti in these garnets is dominantly tetravalent. It is clear from this study that quantitative modelling of the processes of crystal growth and zonation of melanite garnets in alkaline, undersaturated igneous rocks should be aimed at simulating the four chemical exchanges listed above

Ordinal-Level Phylogenomics of the Arthropod Class Diplopoda (Millipedes) Based on an Analysis of 221 Nuclear Protein-Coding Loci Generated Using Next-Generation Sequence Analyses

Background The ancient and diverse, yet understudied arthropod class Diplopoda, the millipedes, has a muddled taxonomic history. Despite having a cosmopolitan distribution and a number of unique and interesting characteristics, the group has received relatively little attention; interest in millipede systematics is low compared to taxa of comparable diversity. The existing classification of the group comprises 16 orders. Past attempts to reconstruct millipede phylogenies have suffered from a paucity of characters and included too few taxa to confidently resolve relationships and make formal nomenclatural changes. Herein, we reconstruct an ordinal-level phylogeny for the class Diplopoda using the largest character set ever assembled for the group. Methods Transcriptomic sequences were obtained from exemplar taxa representing much of the diversity of millipede orders using second-generation (i.e., next-generation or high-throughput) sequencing. These data were subject to rigorous orthology selection and phylogenetic dataset optimization and then used to reconstruct phylogenies employing Bayesian inference and maximum likelihood optimality criteria. Ancestral reconstructions of sperm transfer appendage development (gonopods), presence of lateral defense secretion pores (ozopores), and presence of spinnerets were considered. The timings of major millipede lineage divergence points were estimated. Results The resulting phylogeny differed from the existing classifications in a number of fundamental ways. Our phylogeny includes a grouping that has never been described (Juliformia+Merocheta+Stemmiulida), and the ancestral reconstructions suggest caution with respect to using spinnerets as a unifying characteristic for the Nematophora. Our results are shown to have significantly stronger support than previous hypotheses given our data. Our efforts represent the first step toward obtaining a well-supported and robust phylogeny of the Diplopoda that can be used to answer many questions concerning the evolution of this ancient and diverse animal group