Click-Chemistry (CuAAC) Trimerization of an αvβ6 Integrin Targeting Ga-68-Peptide: Enhanced Contrast for in-Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts

α_vβ₆ Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with α_vβ₆ integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the α_vβ₆-specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH₂) to enhance α_vβ₆ integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)₃ showed a 28-fold higher α_vβ₆ affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC₅₀ of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC₅₀-based selectivity over the related integrin α_vβ₈ (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)₃ holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.     

Interplay of the phase and the chemical composition of the powder feedstock on the properties of porous 8YSZ thermal barrier coatings

Some chemical impurities enhance sintering kinetics of ceramic Thermal Barrier Coatings (TBCs) which can cause their premature failure during operation in gas turbine engine by causing reduction in coating’s strain compliance as well as faster bond-coat oxidation due to increased thermal conductivity. Certain chemical impurities are also believed to suppress resistance to tetragonal to monoclinic phase transformation in 8YSZ, which can also be an important factor regarding TBC’s performance. Most of the impurities and some of the monoclinic phase present in the powder feedstocks can survive into the as-sprayed coating. Therefore, there is a general trend towards OEMs requiring the lowest amounts of chemical impurities and the lowest amounts of monoclinic phase in the powder feedstocks. This paper presents a comprehensive investigation aimed at understanding the role and the relative importance of the chemical and phase purities of the powder feedstock for the properties and performance of thick 8YSZ TBCs.     

Substrate Flexibility of the Flavin-Dependent Dihydropyrrole Oxidases PigB and HapB Involved in Antibiotic Prodigiosin Biosynthesis

In the biosynthesis of the tripyrrolic pigment prodigiosin, PigB is a predicted flavin-dependent oxidase responsible for the formation of 2-methyl-3-amylpyrrole (MAP) from a dihydropyrrole. To prove which dihydropyrrole is the true intermediate, both possibilities, 5-methyl-4-pentyl-3,4-dihydro-2H-pyrrole ( 5 a , resulting from transamination of the aldehyde of 3-acetyloctanal) and 2-methyl-3-pentyl-3,4-dihydro-2H-pyrrole ( 6 , resulting from transamination of the ketone), were synthesised. Only 5 a restored pigment production in a strain of Serratia sp. ATCC 39006 blocked earlier in MAP biosynthesis. PigB is membrane-associated and inactive when its transmembrane domain was deleted, but HapB, its homologue in Hahella chejuensis, lacks the transmembrane domain and is active in solution. Two colourimetric assays for PigB and HapB were developed, and the HapB-catalysed reaction was kinetically characterised. Ten analogues of 5 a were synthesised, varying in the C2 and C3 side chains, and tested as substrates of HapB in vitro and for restoration of pigment production in Serratia ΔpigD in vivo. All lengths of side chain tested at C3 were accepted, but only short side chains at C2 were accepted. The knowledge that 5 a is an intermediate in prodigiosin biosynthesis and the ease of synthesis of analogues of 5 a makes a range of prodigiosin analogues readily available by mutasynthesis.     

Influence of Pluronic coating formulation on iron oxide nanoparticle transport in natural and oil-impacted sandy aquifer media

Targeted delivery of nanoparticles has the potential to enhance remediation and characterization of sites contaminated with non-aqueous phase liquids (NAPLs) by ensuring delivery of treatment or contrast agents to the NAPL/water interface. For a targeted delivery technique to be successful, nanoparticles must be capable of transporting through porous media and binding to NAPLs under relevant geological conditions. In this study, successful targeted delivery of nanoparticles to sandy aquifer material mixed with crude oil was achieved using an active targeting technique based on an amphiphilic polymer coating. It was determined that the molecular structure and concentration of the nanoparticle coating greatly influenced the recovery of nanoparticles injected into saturated columns. Coatings with longer polymer molecules and lower polymer concentrations reduced recovery, and the nanoparticle coating formulation could be adjusted to improve transport while maintaining targeted binding behaviour. This study demonstrated that nanoparticle retention in oil-impacted sand exceeded that of clean sand in flow through experiments, indicating that a nanoparticle targeted delivery strategy for soil contaminated with LNAPLs such as crude oil is possible under the experimental conditions explored.     

Flow and spawning habitat relationships for Dolly Varden: Understanding habitat–population dynamics in the Canadian Western Arctic

Northern form Dolly Varden (Salvelinus malma malma) have been designated as a species of Special Concern in Canada due to declines in population abundance and potential threats. Concern over detrimental effects of low flows on population abundance prompted research on how variability in discharge regimes influence habitat availability. Habitat suitability indices for prespawning and spawning adult anadromous Dolly Varden from two streams were integrated into a two‐dimensional hydrodynamic habitat model to assess the effect of flow variability on usable habitat. Regional hydrographs were used to identify an ecologically relevant range of flows that provided optimal spawning habitat for these populations and examine the relationship between abundance and discharge. Adults spawned in the tail end of pools at moderate water depths and water velocities, and used pebble‐ to cobble‐sized substrate for building redds; whereas, prespawning adults occupied deeper pools with moderate velocities and used cobble for cover. Model outputs showed that spawning habitat availability was optimized at flow rates between 1.6 and 3.0 m³/s and between 1.0 and 6.0 m³/s in Fish Hole Creek (FHC) and Little Fish Creek, respectively. A positive relationship between flows during the fall spawning period and abundance of the FHC population suggests that higher flows coinciding with optimal habitat availability may have contributed to positive recruitment. To strengthen and refine this habitat–population relationship for Dolly Varden in this area requires investigation of a broader suite of variables associated with environmental regimes and physical habitat in reaches used for spawning.     

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.     

Social integration and shared living space: Psychiatric impairment among single men

This study examines the relationship between psychiatric impairment of single men in the new resource towns of north‐western Australia, and the type of dwelling occupied by these men. The data fail to provide any evidence that dwelling type directly or indirectly influences psychiatric impairment in this context. The analysis suggests that impairment may be positively influenced by stresses generated by sharing dwelling space. However, it also suggests that the sharing of internal dwelling space is a more important influence on such stress than the extent of social interaction that different dwelling types impose as a result of shared external dwelling space. A statistically significant relationship did emerge between perceived adequacy of social integration and stresses generated by sharing dwelling space. This suggests that the philosophy of providing accommodation for singles that facilitates contact with others, needs to be carefully considered in certain contexts. Where there are a variety of alternative forms of social contact, it may be that those who have most difficulty establishing an adequate social network will also have most difficulty with coping with sharing dwelling space.