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Topology optimization for engineering problems often requires multiphysics (dual objective functions) and multi-timescale considerations to be coupled with manufacturing constraints across a range of target values. We present a dual neural network approach to topology optimization to optimize a 3-dimensional thermal-electromagnetic device (optical shutter) for maximum temperature rise across a range of extinction ratios while also considering manufacturing tolerances. One neural network performs the topology optimization, allocating material to each sub-pixel within a repeating unit cell. The size of each sub-pixel is selected with manufacturing considerations in mind. The other neural network is trained to predict performance of the device using extinction ratio and temperature rise over a given time period. Training data is generated using a finite element model for both the electromagnetic wave frequency domain and thermal time domain problems. Optimized designs across a range of targets are shown. [Display omitted] • A dual neural network is utilized to perform topology optimization of a thermal-electromagnetic device (optical shutter). • Vanadium dioxide is used as the shutter material, due to its ability to rapidly change phase from semi-transparent to reflective. • Solving the inverse design problem with a dual neural network approach allows for rapid updates to target values or loss function. [ABSTRACT FROM AUTHOR]

Single-step, contactless femtosecond laser micromachining of substrates to impart specific surface morphologies has been the focus of considerable recent work. This work has primarily focused on experimentation with metallic substrates, with fs-laser micromachining of polymeric materials being in its infancy. In the present work, we report on the fs-laser micromachining of urethane based, amorphous, non-block co-polymeric networks, where previously published literature has, to-date, solely discussed micromachining of homopolymeric substrates. The results of this work show that there exists regimes of micromachining where the imparted microstructure resembles those of selected irradiated homopolymers. Further inspection reveals the role of co-monomer added in determining the imparted microstructure through measurement of the material ionization threshold fluence, and incubation coefficient. Chemical and optical effects of co-monomer addition are also considered through XPS and UV–Vis spectroscopic analyses, respectively. Unlabelled Image • Porous microstructures are manifested on fs-laser irradiated copolymeric substrates. • The porous microstructures resemble those reported for irradiated homopolymers. • The regime for pore formation is governed by the material threshold fluence. • The addition of a comonomer depresses the material threshold fluence. • No correlation is seen between comonomer added and micromachining parameters. [ABSTRACT FROM AUTHOR]

Understanding how to influence ice adhesion to structures and prevent icing catastrophes is a paramount research question. Conventional industrial anti-icing methods are active, requiring an energy source. However, active strategies are energy intensive. Passive anti-icing surfaces have thus become an area of engineering interest. Such strategies, like low surface energy chemical coatings, produce highly anti-icing surfaces on a lab-scale but they have not succeeded in industrial applications. They lack efficacy over repeated icing/de-icing cycles and their materials are unsuited for harsh environments. The body feather of the sub-Antarctic Gento penguin Pygoscelis papua , which ornithologists note is perpetually free of ice despite its freezing environment, serves as a compelling source of passive anti-icing biomimetic inspiration which may overcome these aforementioned deficiencies. Through studying these feathers, it has become clear that two aspects of anti-icing (water-shedding and ice-shedding) are addressed in distinct ways by the Gentoo penguin. The water-shedding functionality of the feathers is derived from an air cushion created by the wire-like microstructure of the feather and is augmented by nano-scale grooves in the feather coated in preen oil. The preen oil is necessary to maintain water-shedding functionality, however once removed the ice-shedding functionality of the feathers is maintained. The ice-shedding functionality appears to be derived from wire-like morphology of the penguin body feather barbs and barbules which induce cracks that are easily opened at the ice-feather interface. Such a design strategy shows promise in addressing the common failings of passive systems. These anti-icing strategies were then tested on metallic biomimetic substrates. The barb structure of the penguin body feather was mimicked using ultra-fine woven stainless-steel wire cloth. Some stainless-steel wire cloths were laser machined to mimic the texturing and surface chemistry of the feathers. These cloths were indeed hydrophobic like the feathers. Both stainless-steel wire cloths had significantly reduced ice adhesion strengths compared to those of the flat monolithic stainless-steel sample. The laser-machined wire cloth had an ice adhesion strength of 63 ± 10 kPa compared to 603 ± 236 kPa for the flat sample. This both indicates that the ice-shedding capabilities of the sample are imparted by the structure and further strengthens the argument that water-shedding and ice-shedding are distinct phenomena that need to be addressed with two separate design strategies. • The sub-Antarctic penguin body feather exhibits ice-shedding and water-shedding functionality. • Ice-shedding functionality is derived from the wire-like morphology of the body feather. • Water-shedding functionality is derived from superimposed nano-ripples and preening oil. • Biomimicry using a woven cloth allows us to create a passive ice-shedding surface out of bare metal. • Laser-induced nano-ripples superimposed on the wire cloth mimics water-shedding functionality. [ABSTRACT FROM AUTHOR]

Herein we describe the continued optimization of M 4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3- c ]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology. [ABSTRACT FROM AUTHOR]

This letter details the continued chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3- c ]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M 4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. [ABSTRACT FROM AUTHOR]

Abstract ASTM F3043 twist-off type tension control bolt assemblies have a nominal strength of 200 ksi, representing a 33% increase in strength over ASTM F3125 Grade A490 bolts. Grade 2 of the ASTM F3043 bolt, manufactured in Japan, has been used in Japan since its first commercial application in 2001. The installation procedures for twist-off type tension control bolts used in the U.S. are based on the Research Council for Structural Connections (RCSC) Specification, which differs from those procedures used in Japan. Testing of 210 pretensioned assemblies was performed to verify that the RCSC procedures produce the specified minimum pretensions in F3043 Grade 2 bolt assemblies, under a variety of conditions: varying size and length, exposure to wetting, corrosion, relubrication, high and low temperatures, different hole sizes, and sloped surfaces. Tension tests were also conducted to compare the tension behavior of ASTM F3043 Grade 2 bolts to A325 and A490 bolts. Pretension tests were conducted using four unique bolt lengths for each of the available bolt diameters: 1 in., 1–1/8 in., and 1–1/4 in. Cumulative probability density functions were created for each group of pretension force results and normal distributions were fit to the data. For the 42 specimens tested at 70 °F with standard size holes and as-received lubrication, all bolt assemblies achieved a pretension force greater than the minimum specified with an average pretension 13% greater than the minimum required. Highlights • ASTM F3043 bolt assemblies have 33% larger strength than A490 bolts. • An experimental program was conducted to validate pretension methods. • Results show that RCSC procedures for pretensioning are applicable for these bolts. • Effect of variations in conditions on resulting bolt pretension were investigated. [ABSTRACT FROM AUTHOR]

Abstract Right-wing authoritarianism (RWA) has shown inconsistent results as a predictor of beliefs in conspiracy theories (CTs). The present investigation attempted to clarify these results by separating anti-establishment CTs, which challenge the existing social order, from pro-establishment CTs, which seek to justify and reinforce it against external threats. In two MTurk samples (N = 294, 200), RWA correlated strongly with pro-establishment CTs but weakly with anti-establishment CTs. Regression analyses suggest that after controlling for exposure to the CTs, this gap in the predictive power of RWA can be explained by differences in attitudes toward their alleged perpetrators, highlighting the importance of intergroup attitudes as an important driver of CT endorsement. [ABSTRACT FROM AUTHOR]

This letter describes the further chemical optimization of the 5-amino-thieno[2,3- c ]pyridazine series (VU0467154/VU0467485) of M 4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 ( 8p ). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson’s disease model has been reported with 8p , this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties. [ABSTRACT FROM AUTHOR]

This letter describes the chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3- c ]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 ( 5 ). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration). [ABSTRACT FROM AUTHOR]

This Letter describes the chemical optimization of a novel series of M 4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M 4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M 4 PAM activity. [ABSTRACT FROM AUTHOR]

Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a novel pharmacologic mechanism, it is prudent to ensure that no new off-target activities have arisen, particularly within the context of in vivo experiments. Reported here, is the in vitro and in vivo characterization of a novel M1 agonist tool compound, PPBI, and demonstrations that the primary biological effects of PPBI are mediated through M1. PPBI reverses d -amphetamine locomotor activity, but fails to do so in transgenic mice that do not express M1. PPBI also reverses a natural deficit in a rat cognition model at a level of exposure which also activates cortical circuitry. Most notably, PPBI is analgesic in a variety of rat and mouse models and the analgesic effect of PPBI is reversed by an M1-preferring antagonist and an M1-selective toxin. Finally, the pharmacokinetic/pharmacodynamic measures of PPBI are compared across multiple endpoints which highlights that activity in models of psychosis and pain require higher exposures than that required in the cognition model. [ABSTRACT FROM AUTHOR]

This Letter describes the chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3- d ]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma K p = 0.74), within the original core after several rounds of optimization; however, the thieno[2,3- d ]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M 4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K p > 10). Moreover, this campaign provided fundamentally distinct M 4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target. [ABSTRACT FROM AUTHOR]

Initially associated with cancer diagnosis and therapy, the sigma 2 receptor (σ 2 R) has recently been implicated in several disorders of the central nervous system (CNS). It remained a poorly characterized target until we identified it as the transmembrane protein 97 (TMEM97). As part of a program to identify novel compounds that bind with high affinity and selectivity to σ 2 R/TMEM97 relative to the sigma 1 receptor (σ 1 R) and other CNS proteins, we employed a scaffold simplification strategy to design novel sets of piperazine–substituted aminotetralins based on analogous norbenzomorphans that we previously developed. JVW-1601 was identified as a reference aminotetralin analog that had high affinity (K i = 5.5 nM) and selectivity (36-fold) for σ 2 R/TMEM97 versus σ 1 R. An expanded investigation of structure-activity relationships (SAR) in several structural regions of this compound was conducted, and among the ligands thus prepared, many had K i values < 20 nM for σ 2 R/TMEM97 and selectivities of >20-fold versus σ 1 R. Structural features that enhance σ 2 R/TMEM97 affinity and selectivity were identified, leading to an optimized compound having a high σ 2 R/TMEM97 affinity (K i of 4.5 nM) and 366-fold selectivity relative to σ 1 R. Significantly, during the course of this work we discovered JVW-1625 , which enabled the isolation and identification of σ 2 R as TMEM97 and resolved a question that had eluded researchers for decades. Computational docking studies for selected aminotetralins suggest they adopt similar poses upon binding to σ 2 R/TMEM97, engaging in highly conserved salt bridges with Asp29 and cation-π interactions with Tyr150. Collectively, these studies show that aminotetralins are useful tool compounds for studying the mechanism and function of σ 2 R/TMEM97. [Display omitted] • Simplified analogs of σ 2 R/TMEM97-selective B-norbenzomorphan designed and synthesized. • Binding studies show new ligands generally have high σ 2 R/TMEM97 affinity and selectivity. • Computational docking studies show all ligands bind similarly to σ 2 R/TMEM97. • Studies support design rationale of aminotetralins as simplified σ 2 R/TMEM97 ligands. [ABSTRACT FROM AUTHOR]

We will never have data to populate all of the potential radioecological modelling parameters required for wildlife assessments. Therefore, we need robust extrapolation approaches which allow us to make best use of our available knowledge. This paper reviews and, in some cases, develops, tests and validates some of the suggested extrapolation approaches. The concentration ratio (CR product-diet or CR wo-diet ) is shown to be a generic (trans-species) parameter which should enable the more abundant data for farm animals to be applied to wild species. An allometric model for predicting the biological half-life of radionuclides in vertebrates is further tested and generally shown to perform acceptably. However, to fully exploit allometry we need to understand why some elements do not scale to expected values. For aquatic ecosystems, the relationship between log 10 ( a ) (a parameter from the allometric relationship for the organism-water concentration ratio) and log( K d ) presents a potential opportunity to estimate concentration ratios using K d values. An alternative approach to the CR wo-media model proposed for estimating the transfer of radionuclides to freshwater fish is used to satisfactorily predict activity concentrations in fish of different species from three lakes. We recommend that this approach (REML modelling) be further investigated and developed for other radionuclides and across a wider range of organisms and ecosystems. Ecological stoichiometry shows potential as an extrapolation method in radioecology, either from one element to another or from one species to another. Although some of the approaches considered require further development and testing, we demonstrate the potential to significantly improve predictions of radionuclide transfer to wildlife by making better use of available data. [ABSTRACT FROM AUTHOR]

Abstract: Many neuropsychiatric drugs interact with more than one molecular target, and therapeutic indices might be improved by prospectively designing compounds with profiles optimized against a combination of targets. The dibenzo-epine scaffold is considered a privileged structure, and this scaffold has been explored rigorously in the search for potential novel neuropharmacologic treatments. Members of this chemical class are known to interact with many receptors and transporters, particularly those of the biogenic amine class. In this study, four points of diversity within a dibenzo-epine scaffold were varied systematically and the pharmacologic profiles of the compounds were assessed across 14 receptors and transporters thought to be important to clinical profiles of efficacy and safety. The resulting data were analyzed using a modified forward selection linear regression procedure, thus revealing potential pharmacophoric relationships of the assessed targets within this chemical class. The results highlight a strong covariance across numerous targets. Moreover, the outcome quantifies the innately problematic issue of prospectively designing compounds with defined affinities across multiple targets. Finally, an exploration of the correspondence of binding affinities to in vitro functional activity reveals an additional layer of complexity central to prospectively designing compounds to engage multiple targets. The apparent relatedness of the 5-HT2a and D2 activities suggests that the structural pharmacophores of these receptors overlap more closely with each other than with members of their respective families. [Copyright &y& Elsevier]

Abstract: A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux. [Copyright &y& Elsevier]

Abstract: With high population densities concentrated in predominately coastal zones, the South Pacific will, in this century, be heavily impacted by global temperature and sea level rises. Small island developing states do have a number of unique problems, namely, small scale economic development together with environmental sustainability. This paper presents the lessons learnt from the implementation of the first cleaner production and design initiative project conducted in a Pacific small island developing state(s) (SIDS) using the design for sustainability (D4S) methodology. The final product was analysed using the life cycle assessment (LCA) method. Implemented within a medium-sized enterprise operating in Fiji, the Cook Islands, and Samoa, the project focused on improving an existing product and its associated life cycle to make it more environmentally friendly to manufacture, retail, and dispose of. The project outcomes revealed that D4S provides a suitable tool for a country like Fiji to pursue more intensively an eco-friendly manufacturing agenda. However, when combined with LCA, the qualitative nature of D4S shows that not all solutions produce the best overall result. Specifically, the “improved” design, whilst being less impactful on Fiji in terms of disposal, has a higher impact globally due to the production and manufacture of the new materials used. For this reason designers need to address the impact criteria and decide whether a domestic or international agenda is of greater concern within the SIDS context. [ABSTRACT FROM AUTHOR]

Abstract: A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037–0.15nM range. [ABSTRACT FROM AUTHOR]

Abstract: The influence of the multiplication order of the constituent basis matrices on the Mueller matrix decomposition-derived polarization parameters in complex tissue-like turbid media exhibiting simultaneous scattering and polarization effects are investigated. A polarization sensitive Monte Carlo (MC) simulation model was used to generate Mueller matrices from turbid media exhibiting simultaneous linear birefringence, optical activity and multiple scattering effects. Mueller matrix decomposition was performed with different selected multiplication orders of the constituent basis matrices, which were further analyzed to derive quantitative individual polarization medium properties. The results show that for turbid medium having weak diattenuation (differential attenuation of two orthogonal polarization states), the decomposition-derived polarization parameters are independent of the multiplication order. Importantly, the values for the extracted polarization parameters were found to be in excellent agreement with the controlled inputs, showing self-consistency in inverse decomposition analysis and successful decoupling of the individual polarization effects. These results were corroborated further by selected experimental results from phantoms having optical (scattering and polarization) properties similar to those used in the MC model. Results from tissue polarimetry confirm that the magnitude of diattenuation is generally lower compared to other polarization effects, so that the demonstrated self-consistency of the decomposition formalism with respect to the potential ambiguity of ordering of the constituent matrices should hold in biological applications. [Copyright &y& Elsevier]

Abstract: This paper presents the application of three publicly available biota dose assessment models (the ERICA Tool, R&D128/SP1a and RESRAD-BIOTA) to an assessment of the Drigg coastal sand dunes. Using measured 90Sr, 99Tc, 137Cs, 238Pu, 239+240Pu and 241Am activity concentrations in sand dune soil, activity concentration and dose rate predictions are made for a range of organisms including amphibians, birds, invertebrates, mammals, reptiles, plants and fungi. Predicted biota activity concentrations are compared to measured data where available. The main source of variability in the model predictions is the transfer parameters used and it is concluded that developing the available transfer databases should be a focus of future research effort. The value of taking an informed user approach to investigate the way in which models may be expected to be applied in practice is highlighted and a strategy for the future development of intercomparison exercises is presented. [Copyright &y& Elsevier]

Abstract: A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP K i =0.035nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved. [Copyright &y& Elsevier]

Abstract: This report describes the clinical presentation, isolation and treatment of two dogs naturally infected with Bartonella henselae and Bartonella vinsonii subsp. berkhoffii. Chronic and progressive polyarthritis was the primary complaint for dog #1, from which B. henselae and B. vinsonii subsp. berkhoffii were cultured on three independent occasions from blood and joint fluid samples, despite administration of nearly 4 months of non-consecutive antibiotic therapy. A clinically atypical and progressively severe trauma-associated seroma was the primary complaint for dog #2, from which B. henselae and B. vinsonii subsp. berkhoffii were isolated from serum, blood and seroma fluid. Dogs can be co-infected with two Bartonella spp. and infection with these organisms should not be ruled out if specific antibodies are not detected. Specialized culture techniques should be used for isolation and to assess antibiotic efficacy. [Copyright &y& Elsevier]

Abstract: A series of experiments studied the effects of the κ-opioid receptor agonist U50,488H on consummatory successive negative contrast (cSNC) in rats. In cSNC, previous experience with a 32% sucrose solution leads to greater rejection of 4% sucrose than exclusive experience with 4% sucrose. Experiments 1 and 2 revealed that U50,488H failed to influence cSNC when administered before the first downshifted trial, but either attenuated (1mg/kg) or enhanced (3 and 10mg/kg) cSNC when administered before the second downshift trial. Experiment 3 showed that U50,488H administered immediately after the first downshift trial had no effect on cSNC at the 1mg/kg dose, but tended to increase cSNC at the 3mg/kg dose. However, Experiment 4 suggested that the apparent enhancement of cSNC after 3mg/kg U50 administered posttrial 11 may have reflected the development of a conditioned taste aversion. The trial-selective attenuating effect of the low dose may reflect an anxiolytic-like property of U50,488H. [Copyright &y& Elsevier]

Abstract: Detection depth and sampling volume of polarized light in highly turbid, cylindrically-shaped samples are estimated using pathlength distributions calculated from a polarization-sensitive Monte Carlo model. Due to defined ranges of the polarized light pathlength distribution, the estimated penetration depth and the interrogated volume of the polarization-maintaining photon subpopulation are smaller than those of the whole collected photon population, the latter exhibiting a wider pathlength distribution resulting from multiple scattering. It is also demonstrated that the spatial interrogation extent of polarized light in turbid media is greatly affected by the experimental detection geometry. [Copyright &y& Elsevier]

Abstract: Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating α-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure. [Copyright &y& Elsevier]

Abstract: In this paper, a tabbed double cantilevered beam test is performed on Vectran® stitched laminated composites with varying stitch distributions. The woven carbon fibre plies were laid-up in a symmetrical manner [0,±45,90]2, then stitched in dry preform state followed by a resin film infusion stage. To prevent the stitched specimens from failing in flexure, thick aluminium reinforcing tabs were adhesively bonded to either side of the composite specimen, along with loading blocks. An INSTRON 5567 testing machine was used to test the specimens at a crosshead speed of 0.5mm/min with crack lengths, crack opening displacements and peak load data being recorded after the crack front had propagated several millimetres. A variation of the compliance method was used to post process the test data. It is revealed that for stitched specimens with identical stitch densities but different stitch distributions, there exists significant variations in critical strain energy release rates, G Ic. A 2-node beam and 4-node plate finite element analysis was conducted to model the TDCB experiment with a special 2-node axial, tension only, rod element used to discretely simulate the stitches. The FEA results support the experimental findings identifying stitch distribution as a key parameter in determining the improvement that stitching provides in bridging Mode I delaminations. [Copyright &y& Elsevier]

Abstract: Through-the-thickness stitching has been shown to have the capacity of improving the poor interlaminar toughness of laminated composites for many years. Double cantilever beam (DCB) testing has been used to assess the enhanced delamination toughness of stitched laminates. To avoid the premature flexure failure of delaminated substrate beams, thick tabs are bonded to either side of the standard DCB specimens. Consequently, higher opening load can be applied to the stitched tabbed DCB (TDCB) specimens to propagate the delamination crack due to the enlarged bending stiffness and strength. This creates a significant bending of the loading pin, which needs to be accounted for in the numerical analysis. In this paper, a parametric analysis was conducted to investigate the effect of reinforcing tab thickness on the measured and predicted delamination toughness. [Copyright &y& Elsevier]

Abstract: Three experiments explored the role of the opioid system in consummatory successive negative contrast. In Experiment 1, rats treated with the nonspecific opioid-receptor antagonist naloxone (2mg/kg) exhibited increased suppression after a shift from 32% to 6% sucrose solution (32→6), relative to 6→6 unshifted controls. A similar but shorter effect was observed with the delta-opioid receptor antagonist naltrindole (1mg/kg). In Experiment 2, naloxone increased suppression after a more conventional 32→4 sucrose shift. In Experiment 3, rats classified as expressing slow recovery from contrast (after a 32→4 sucrose downshift) were more sensitive to naloxone in an activity test than fast-recovery rats. Whereas it was previously known that contrast was reduced by the extrinsic administration of opioid agonists, the effects reported here with antagonists provide the first evidence that the opioid system is intrinsically engaged by situations involving surprising reward loss. [Copyright &y& Elsevier]

More stringent environmental legislation and new or updated water management strategies have been adopted at both federal and local levels to address the growing problem of increasing demand on limited fresh water resources. Competition for access to available fresh water resources is increasing the pressure for sustainable water management practices that emphasize water reuse and recycle, with reduced fresh water withdrawals. In some jurisdictions targets for fresh water withdrawals have been set to zero, demanding innovative new technologies and applications of existing technologies to supplement natural fresh water sources. The serious need for new sources of potable water for human consumption has been widely recognized for some time, leading to a rapidly growing use of reverse osmosis (RO) for seawater desalination as well as significant advances in membrane technology itself. However, it is only in recent years that the implications of limited fresh water availability have begun to be seriously examined in other sectors. The usage of fresh water in the industrial sector has been immense, often leading to large volumes of contaminated waste water to be disposed of. In many instances the predominant contaminant is salt. Past practices in many industries have also left large volumes of salt contaminated surface and sub-surface soils at existing and/or abandoned industrial sites. Rain water or natural ground water flowing through these soils leaches out the salt, threatening fresh water resources. The growing recognition of the potential toxicity of the soil at these sites has led to increased requirements for environmental remediation prior to removing land from industrial usage. This, in turn, has led to increased volumes of salt contaminated waste water that must be disposed of, with a corresponding increase in the difficulty and cost of disposal. More economical, environmentally sound alternatives to current disposal methods must be found. Preliminary design calculations have been performed to establish a suitable configuration for a reverse osmosis environmental remediation system that can address this situation. The key design objectives for the system were to significantly reduce the volume of salt-contaminated leachate from environmental remediation operations that must be disposed of as contaminated waste water, to produce relatively large volumes of clean water at an environmentally acceptable level to allow its reuse or safe return to the environment, and to significantly reduce or eliminate the threat to adjacent fresh water sources. The preliminary analyses carried out to date indicate that these objectives are achievable and that an RO environmental remediation system can provide an economical solution to this problem. RO system design and operation is site specific, depending among other things on feedwater conditions such as salinity, total dissolved solids (TDS), feedwater temperature, silt density index (SDI), etc. In order to progress from theoretical studies to implementation, a pilot project aimed at identifying and establishing system design specifications and requirements at a specific site was undertaken. An existing seawater desalination demonstration rig was modified to operate in a mode suitable for pilot scale developmental testing in an environmental remediation application. The mobile pilot test unit was taken to a remote industrial site currently undergoing environmental remediation. On-site testing was aimed at developing an understanding of the specific limitations and constraints of RO systems operating in such an environment and investigating how those might be most effectively overcome. The pilot plant testing allowed experimental investigation of potential operating modes and system design and operating parameters in order to obtain the necessary data for an informed evaluation of performance vs. cost in setting system design characteristics. The results of the testing are being used to guide the design of an operational system that can be used successfully over the next several years of site remediation. [Copyright &y& Elsevier]

Salmonella outer protein D (SopD) is a type III secreted virulence effector protein from Salmonella enterica. Full-length SopD and SopD lacking 16 amino acids at the N-terminus (SopDΔN) have been expressed as fusions with GST in Escherichia coli, purified with a typical yield of 20–30 mg per litre of cell culture and crystallized. Biophysical characterization has been carried out mainly on SopDΔN. Analytical size exclusion chromatography shows that SopDΔN is monomeric and probably globular in aqueous solution. The secondary structure composition, calculated from the CD spectrum, is mixed (38% α-helix and 26% β-strand). Sequence analysis indicates that SopD contains a coiled coil motif, as found in numerous other type III secretion system-associated proteins. This suggests that SopD has the potential for one or more heterotypic protein–protein interactions. Limited trypsin digestion of SopDΔN, monitored by both one-dimensional proton NMR spectroscopy and SDS-PAGE, shows that the protein has a large, protease-resistant core domain of 286 amino acid residues. This single-domain architecture suggests that SopD lacks a cognate chaperone. In crystallization trials, SopDΔN produced better crystals than either full-length SopD or trypsin-digested SopDΔN. Diffraction to 3.0 Å resolution has so far been obtained from crystals of SopDΔN. [Copyright &y& Elsevier]

Homocysteine, an atherogenic amino acid, promotes iron-dependent oxidation of low-density lipoprotein (LDL). We investigated whether vitamin C, a physiological antioxidant, could protect LDL from homocysteine-mediated oxidation. LDL (0.2 mg of protein/ml) was incubated at 37°C with homocysteine (1000 μM) and ferric iron (10–100 μM) in either the absence (control) or presence of vitamin C (5–250 μM). Under these conditions, vitamin C protected LDL from oxidation as evidenced by an increased lag time preceding lipid diene formation (≥ 5 vs. 2.5 h for control), decreased thiobarbituric acid-reactive substances accumulation (≤ 19 ± 1 nmol/mg when vitamin C ≥ 10 μM vs. 32 ± 3 nmol/mg for control, p < .01), and decreased lipoprotein anodic electrophoretic mobility. Near-maximal protection was observed at vitamin C concentrations similar to those in human blood (50–100 μM); also, some protection was observed even at low concentrations (5–10 μM). This effect resulted neither from altered iron redox chemistry nor enhanced recycling of vitamin E in LDL. Instead, similar to previous reports for copper-dependent LDL oxidation, we found that vitamin C protected LDL from homocysteine-mediated oxidation through covalent lipoprotein modification involving dehydroascorbic acid. Protection of LDL from homocysteine-mediated oxidation by vitamin C may have implications for the prevention of cardiovascular disease. [Copyright &y& Elsevier]

A novel process for the one-step conversion of primary alcohols into carbamate-protected amines has been developed using a modified Burgess reagent. Although this letter mainly focuses on the conversion of alcohols into the corresponding Cbz-protected amines, the potential for extending this process to a wide range of carbamates has also been demonstrated. A detailed catalytic cycle has been proposed. While exploring the scope of this new reagent, an N-aryl piperidine to an N-aryl pyrrolidine rearrangement has been observed and rationalized. [Copyright &y& Elsevier]

The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in 15.2% overall yield requiring only seven linear steps from commercially available reagents. The approach features a tandem vinylogous Mannich reaction and an intramolecular hetero Diels-Alder reaction to access the cis -oxahydroisoquinolone core. Following the coupling of this cis- oxahydroisoquinolone subunit with a 3-methylindole derivative via a Suzuki reaction, a novel tactic to induce the challenging diastereoselective reduction of the cyclic vinyl ether moiety was discovered. Completion of the synthesis was achieved using a new procedure we developed for iridium-catalyzed, reductive formation of aminals from tertiary lactams, thereby expanding the utility of tertiary amides and lactams as surrogates for iminium ions. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: In recent years, Clostridium difficile-associated infection has emerged as an increasingly problematic entity. More virulent strains have been isolated and new manifestations of the infection have been described.Purpose: The primary aim of this manuscript is to describe what we believe to be the first reported case of devastating C. difficile enteritis in a patient with an ileal reservoir.Conclusion: A high index of suspicion is required in the appropriate clinical setting in light of the apparently changing spectrum of C. difficile disease. [ABSTRACT FROM AUTHOR]

The growth in online retail purchases has increased significantly, especially through the COVID-19 pandemic, yet causes more packaging waste than brick-and-mortar retail. Free and easy returns further exacerbate the problem. Current research addressing post-consumer packaging waste has focused on packaging design and material choices. Yet, effective guidelines, policies, strategies, and practices for e-commerce packaging waste management must be determined (Escursell et al., 2021). Therefore, this research identifies global best practices to address transport packaging waste in e-commerce, focusing on Canada. A systematic review of the extant literature (2011–2020) revealed five key objectives of packaging sustainability guidelines: Optimizing Resources, Responsible Sourcing, Resource Recovery, Material Health, and Consumer Engagement. The analysis showed that Responsible Sourcing and Resources Recovery were highlighted in 41% of publications, Optimizing Resources in 31%, and Consumer Engagement in 23% of the studies. The most popular waste reduction strategy was Design for Environment under the Optimizing Resources guideline. This work is the first to identify and articulate clear guidelines, policies, and practices to support industry and policy decision-makers in addressing the transport packaging waste problem in e-commerce. [ABSTRACT FROM AUTHOR]

• First disclosure of VU6005806/AZN-00016130, an M 4 PAM profiled as a putative candidate. • Novel SAR findings based on novel variations to the C3 position on the pyridazine core. • Minimum effective dose of 0.56 mg/kg po in rat AHL. This letter describes progress towards an M 4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3- c ]pyridazine core has been a consistent feature of key M 4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • First description of the role of the β-aminocarboxamide moiety within M 4 PAM scaffolds. • Novel des -amino and tricyclic variant M 4 PAMs. • The role of the IMHB motif was established, and could be re-enforced by tricycles. Abstract This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M 4 PAMs and question if the NH 2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the β-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH 2 , generating des -amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M 4 PAMs with poor DMPK properties. Cyclization of the β-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M 4 PAMs, many as potent as the classical bicyclic β-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the β-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M 4 PAM activity within classical bicyclic M 4 PAM scaffolds. [ABSTRACT FROM AUTHOR]

Dosimeters attached to wild animals can be used to validate regulatory assessment approaches and models for estimating radiation exposure of wild animals. Such measurements are also necessary to ensure that robust dose-effect relationships can be developed from the results of field research programmes. This paper presents the first comprehensive evaluation of the different dosimetry technologies available for specifically measuring the external exposure of wildlife. Guidance is provided on the selection of appropriate passive dosimetry approaches for directly measuring external exposure of terrestrial wildlife under field conditions. The characteristics and performance of four available dosimetry technologies (thermoluminescent dosimeter (TLD), optically stimulated luminescent dosimeter (OSLD), radiophotoluminescent dosimeter (RPLD) and direct ion storage, (DIS)) are reviewed. Dosimeter properties, detection limit and dose range, study organisms and the intended application are variables that need to be considered when selecting a suitable dosimetry technology. Evaluated against these criteria, it is suggested that LiF based and Al 2 O 3 :C TLDs, OSLD and RPLD could all be used to estimate doses to wildlife. However, only LiF based TLDs have been used to directly measure wildlife doses in field studies to date. DIS is only suitable for comparatively large species (e.g. medium to large mammals), but has the advantage that temporal variation in dose can be recorded. In all cases, dosimeter calibration is required to ensure that the dose measurements reported can be interpreted appropriately for the organisms of interest. [ABSTRACT FROM AUTHOR]

The contact angle (CA) of a drop is a common quantitative measurement that describes a surface's wettability. However, manual selection of the drop's solid–liquid–vapor contact points (CPs) by the user introduces substantial human error to the final measured CA. Hence, in this article we introduce a novel method for CA measurement that uses a smoothing spline function to simultaneously cancel probable image noise, find the solid–liquid contact point, and calculate the CA at the contact point. The accuracy of this technique is tested through measurement of a series of synthetic drop images with known CAs ranging from 5°to 175°, which are generated using a new mathematical approach and include a reflection area to accurately model real experiments. In these tests, the smoothing splines approach is shown to be extremely accurate in measuring both the CP position and the CA, with negligible error ( R 2 = 0. 9999). Then, for added validation, the smoothing splines approach is tested on four real surfaces of different wettability: glass, single crystal silicon, polished polytetrafluoroethylene, and patterned superhydrophobic polytetrafluoroethylene. When tested on real surfaces, the smoothing splines measurement approach provides reliable contact angle data for all four different surfaces tested, while also reducing human error. Overall, our proposed measurement approach for the CA is shown to be more accurate than traditional measurement approaches such as the commonly used polynomial fitting approach, and the more recently introduced mask approach, which also includes automatic CP detection. [Display omitted] • Automated contact point detection. • Smooth spline method is implemented to find the contact point and measure the contact angle. • Canceling probable noises. • Creating synthetic drop to evaluate the method accuracy. • Testing method with real surfaces of different wettability. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M 4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M 1 /M 4 -preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N -methyl- d -aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M 4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile. [ABSTRACT FROM AUTHOR]

Premature clopidogrel discontinuation is an important cause of stent thrombosis, myocardial infarction, and death after drug-eluting stent (DES) placement. Previous studies of clopidogrel nonadherence after DES placement have had short follow-up and have relied on self-reported adherence. All patients who underwent DES placement from January 2008 to December 2011 at a single safety-net hospital and received medications through the county-subsidized health plan were considered for inclusion; those with <1-year follow-up were excluded. We retrospectively collected 1-year refill data from a large, closed pharmacy system. Our primary outcome was time to failure to obtain a clopidogrel refill, allowing a 5-day grace period. Our study cohort (n = 369) was 34% female, 39% Hispanic, 26% white, and 26% African-American; 26% identified Spanish as their primary language. The time to failure to obtain a clopidogrel refill was 153 days. Cumulative failure to obtain at least 1 refill was 23% for the first refill, increasing to 52% at 6 months and 68% at 1 year. Examining the proportion of days covered (PDC), 21% of patients had 100% coverage, whereas 34% had PDC <80%. There were no independent predictors of nonadherence (PDC <80%). In conclusion, we identified a high rate of clopidogrel nonadherence in a multiethnic urban poor patient population where clopidogrel was provided at discharge and at nominal cost thereafter. In this cohort, prediction models of nonadherence performed poorly. Novel strategies are needed to address this important problem. [ABSTRACT FROM AUTHOR]

A new nonlinear finite stitch element is proposed for parametric analysis on the effect of distribution of through-thickness stitching reinforcement on improving the delamination crack growth resistance in double cantilever beam (DCB) specimens. Both the classical and Timoshenko beam theories are used to analyze the DCB specimens. A novel two-node rod element is developed to model the stitches along the crack plane and the micromechanical stitching models available in the literature are adopted to simulate the mechanical behavior of the stitches. The bridging traction of each discrete stitch is simulated as a nonlinear spring. The numerical examples show that stitch distribution can significantly affects the improvement on delamination crack growth resistance in DCB specimens. When keeping the stitch density or stitch volume fraction as a constant, the stress intensity factor at the delamination crack tip can be significantly affected by altering the stitch distribution along the crack plane. [Copyright &y& Elsevier]

Implantable continuous biosensors would improve disease management but long term function of such devices have been limited by a hypovascular foreign body capsule that inhibits influx of analytes. To assess whether capsule vascularity could be increased, we studied the histologic effects of a 28-day continuous infusion of vascular endothelial growth factor (VEGF) (0.45 μg/day) vs. saline from the surface of a model disk biosensor that was implanted subcutaneously in rats. At day 40, tissue was obtained at varying distances from the infusion port and capsular microvessels were counted using two histologic techniques. VEGF treatment led to a marked increase in capillary density. In tissue located 1 mm away from the infusion site, capillary density in VEGF-treated animals was 200–300% higher than in saline controls. Tissue located 13 mm away, but not 25 mm away, also demonstrated neovascularization. Serum obtained from a distant vein during the infusion did not show an elevated concentration of VEGF. These data demonstrate that a subcutaneous infusion of VEGF creates localized neovascularization of the foreign body capsule and suggest that systemic effects of VEGF are avoidable. Vascularization of a foreign body capsule surrounding a subcutaneous biosensor might well extend its useful life. [Copyright &y& Elsevier]

Introduction: Invasive monitoring of cerebral autoregulation using the pressure reactivity index (PRx) allows for the determination of optimal mean arterial pressure (MAPOPT) in hypoxic ischemic brain injury (HIBI) patients following cardiac arrest. However, the utility of non-invasive surrogates to determine MAPOPT has not been addressed. We aimed to determine the agreement between PRx-derived MAPOPT versus MAPOPT determined by the near-infrared spectroscopy (NIRS) based cerebral oximetry index (COx).Methods: Ten HIBI patients were enrolled. PRx-derived MAPOPT, lower (LLA) and upper limits of autoregulation (ULA) were compared against COx-derived MAPOPT, LLA and ULA. Multimodal neuromonitoring included mean arterial pressure, intracranial pressure, brain tissue oxygenation, jugular venous oxygen saturation, and NIRS-derived regional cerebral oxygen saturation.Results: Repeated measures Bland-Altman plots demonstrated limited agreement between MAPOPT derived from COx and PRx (mean bias: 1.4 mmHg; upper limit of agreement: 25.9 mmHg; lower limit of agreement: -23.0 mmHg). Similarly, there was limited agreement between the absolute values of PRx and COx. Mean bias was 0.26 and the upper and lower limits of agreement were 1.05 and -0.53, respectively. Systematic bias was apparent, whereby at low PRx values COx overestimated PRx and at high PRx values, COx underestimated PRx. COx was limited in its ability to determine impaired autoregulation defined by PRx (receiver operator characteristic area under the curve was 0.488).Conclusion: Collectively, we demonstrate that COx-based determination of MAPOPT lacks agreement with MAPOPT derived from PRx. Further research must be done to evaluate the physiologic and clinical efficacy of PRx derived MAPOPT in HIBI. [ABSTRACT FROM AUTHOR]

Models and approaches have been developed to predict radiation exposure of wildlife under field conditions. However, there have been few attempts to directly measure radiation exposure of wildlife in the field and confirm the doses predicted by models. This is a potential issue for stakeholder acceptance of modelling-based assessments. Here is presented a comprehensive study comparing the results of different dosimeters fitted to free-ranging reindeer inhabiting an area that received comparatively high radiocaesium deposition from the 1986 Chernobyl accident. The external dose of reindeer was measured using the four dosimeter types in aluminium box mounted on the GPS collar. The measurements were compared with two model predictions: (i) external dose to reindeer across the entire range area of the herd; and (ii) external doses of individual reindeer predicted using GPS tracking data to determine locations. It was found that although significant differences between the estimates of the various dosimeters were found these were small with no practical implication. Also, the mean predicted external doses using the GPS tracking data were not significantly different to estimates from two of the four passive dosimeter results. The average external dose predicted across the herd area was significantly lower than doses recorded by the dosimeters and also estimates using GPS data to determine reindeer location (and hence exposure). For 137Cs the average external dose from the GPS tracking data was about twice that predicted across the herd area, because collared animals favoured the more contaminated area of the study site. This suggests that in some circumstances the assumption of averaging contamination over an assumed home range within assessments may be inadequate though this would need to be balanced against other uncertainties. Natural radiation was the greatest contribution to reindeer exposure and a function of the high altitude. Unlabelled Image • Common radiological environmental assessment models have not been fully validated. • Dosimeters and GPS units were attached to reindeer at a site contaminated by 137Cs. • Direct dosimetry measurements were compared to different model predictions. • Exposure from natural radionuclides and cosmic radiation demonstrated. • Commonly used assumptions may underestimate the exposure of animals to radiation. [ABSTRACT FROM AUTHOR]

This letter describes progress towards an M 4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3- c ]pyridine core to an equipotent, non-CNS penetrant thieno[2,3- c ]pyrdin-7(6 H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M 4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats. [ABSTRACT FROM AUTHOR]

A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CL int were achieved through changes in ring size and the N -alkyl group of the isoquinuclidine itself, with des-alkyl derivatives ( 40 – 41 , 44 ) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 μmol/kg compared to control. [ABSTRACT FROM AUTHOR]