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The Australian Curriculum requires teachers of all learning areas to include Aboriginal and Torres Strait Islander Peoples' Culture and History where there is opportunity to do so meaningfully. Despite this requirement, there are few studies considering culturally responsive pedagogy for those perspectives in the teaching of Physical Education (PE) in Australian schools. This study investigated a Year 7 PE teaching team in one school's implementation of a unit of work in the Games and Sport focus area directly incorporating the Cross-curriculum Priority: Aboriginal and Torres Strait Islander Histories and Cultures. Four teachers participated in end-of-unit interviews using an appreciative inquiry approach to gain their insights on the work. The results revealed teachers grew in appreciation and awareness of the Cross-curriculum Priority, but experienced cultural and competency barriers during implementation. However, the teachers felt empowered in shaping new ways of student learning. In this study, we demonstrate how rebuilding ways of thinking, knowing and doing provide opportunity for existing games teaching structures to be interrogated, and new ways of knowledge able then to find passage into teachers' assumptions of PE processes. [ABSTRACT FROM AUTHOR]

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key cellular enzyme, with major roles in both glycolysis, and 'moonlighting' activities in the nucleus (uracil DNA glycosylase activity, nuclear protein nitrosylation), as a regulator of mRNA stability, a transferrin receptor, and as an antimicrobial agent. These activities are dependent, at least in part, on the integrity of an active site Cys residue, and a second neighboring Cys. These residues are differentially sensitive to oxidation, and determine both its catalytic activity and the redox signaling capacity of the protein. Such Cys modification is critical to cellular adaptation to oxidative environments by re-routing metabolic pathways to favor NADPH generation and antioxidant defenses. Despite the susceptibility of GAPDH to oxidation, it remains a puzzle as to how this enzyme acts as a redox signaling hub for oxidants such as hydrogen peroxide (H 2 O 2) in the presence of high concentrations of specialized high-efficiency peroxide-removing enzymes. One possibility is that crowded environments, such as the cell cytosol, alter the oxidation pathways of GAPDH. In this study, we investigated the role of crowding (induced by dextran) on H 2 O 2 - and SIN-1-induced GAPDH oxidation, with data for crowded and dilute conditions compared. LC-MS/MS data revealed a lower extent of modification of the catalytic Cys under crowded conditions (i.e. less monomer units modified), but enhanced formation of the sulfonic acid resulting from hyper-oxidation. This effect was not observed with SIN-1. These data indicate that molecular crowding can modulate the oxidation pathways of GAPDH and its extent of oxidation and inactivation. [Display omitted] • Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an oxidant-sensitive cysteine (Cys) in its active site. • Effects of macromolecular crowding on GAPDH oxidation by H 2 O 2 and SIN-1 was investigated. • Dextran differentially affects H 2 O 2 - and SIN-1-mediated GAPDH cross-linking. • Higher yields of active site Cys-derived sulfonic acids were detected with crowding. [ABSTRACT FROM AUTHOR]

Background: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. Purpose: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of β-agonism on this novel process. Study Design: Controlled laboratory study. Methods: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a β-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with β-agonists and dimethyl sulfoxide. Results: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a β-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P <.0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. Conclusion: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with β-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. Clinical Relevance: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears. [ABSTRACT FROM AUTHOR]

Biological milieus are highly crowded and heterogeneous systems where organization of macromolecules within nanodomains (e.g. membraneless compartments) is vital to the regulation of metabolic processes. There is an increasing interest in understanding the effects that such packed environments have on different biochemical and biological processes. In this context, the redox biochemistry and redox signaling fields are moving towards investigating oxidative processes under conditions that exhibit these key features of biological systems in order to solve existing paradigms including those related to the generation and transmission of specific redox signals within and between cells in both normal physiology and under conditions of oxidative stress. This review outlines the effects that crowding, nanodomain formation and altered local viscosities can have on biochemical processes involving proteins, and then discusses some of the reactions and pathways involving proteins and oxidants that may, or are known to, be modulated by these factors. We postulate that knowledge of protein modification processes (e.g. kinetics, pathways and product formation) under conditions that mimic biological milieus, will provide a better understanding of the response of cells to endogenous and exogenous stressors, and their role in ageing, signaling, health and disease. [Display omitted] • Biological systems are heavily crowded and heterogeneous environments. • These factors may influence protein oxidation, glycation and redox signaling. • Crowding modulates reaction kinetics, and the extent and sites of modification. • Crowding enhances chain reactions, and alters product yields and cross-linking. • Nanodomains and membraneless organelles can facilitate redox signaling. [ABSTRACT FROM AUTHOR]

Amorphous ices govern a range of cosmological processes and are potentially key materials for explaining the anomalies of liquid water. A substantial density gap between low-density and high-density amorphous ice with liquid water in the middle is a cornerstone of our current understanding of water. However, we show that ball milling “ordinary” ice Ih at low temperature gives a structurally distinct medium-density amorphous ice (MDA) within this density gap. These results raise the possibility that MDA is the true glassy state of liquid water or alternatively a heavily sheared crystalline state. Notably, the compression of MDA at low temperature leads to a sharp increase of its recrystallization enthalpy, highlighting that H2O can be a high-energy geophysical material. [ABSTRACT FROM AUTHOR]

The subsequent years coincided with an explosion of interest in free radicals in biology generally, and Robin's contributions expanded rapidly to include major contributions to diverse areas of free radical chemistry and biology. The Newcastle group focused on reactions of radicals produced on radiolysis of aqueous solutions of nucleic acids, and Robin's first papers were in this area; he was awarded his PhD in 1966. It is with great sadness that we announce the passing of one of the "founding fathers" of the free radical and redox fields, Professor Robin Linhope Willson. In thinking about what highlights to include of the many discoveries associated with Robin Willson, and particularly those of the widest and most-enduring interest to the field of free radical chemistry and biology, the direct observation of the "repair" of radicals formed from the antioxidants, vitamin E and thiols, by ascorbate (vitamin C) immediately springs to mind [[1]]. [Extracted from the article]

The Recently proposed Vector Approximate Message Passing (VAMP) algorithm demonstrates a great reconstruction potential at solving compressed sensing related linear inverse problems. VAMP provides high per-iteration improvement, can utilize powerful denoisers like BM3D, has rigorously defined dynamics and is able to recover signals measured by highly undersampled and ill-conditioned linear operators. Yet, its applicability is limited to relatively small problem sizes due to the necessity to compute the expensive LMMSE estimator at each iteration. In this work we consider the problem of upscaling VAMP by utilizing Conjugate Gradient (CG) to approximate the intractable LMMSE estimator. We propose a rigorous method for correcting and tuning CG withing CG-VAMP to achieve a stable and efficient reconstruction. To further improve the performance of CG-VAMP, we design a warm-starting scheme for CG and develop theoretical models for the Onsager correction and the State Evolution of Warm-Started CG-VAMP (WS-CG-VAMP). Additionally, we develop robust and accurate methods for implementing the WS-CG-VAMP algorithm. The numerical experiments on large-scale image reconstruction problems demonstrate that WS-CG-VAMP requires much fewer CG iterations compared to CG-VAMP to achieve the same or superior level of reconstruction. [ABSTRACT FROM AUTHOR]

Background: Muscle atrophy, fibrosis, and fatty infiltration are common to a variety of sports-related and degenerative conditions and are thought to be irreversible. Fibroadipogenic progenitors (FAPs) are multipotent resident muscle stem cells with the capacity to differentiate into fibrogenic as well as white and beige adipose tissue (BAT). FAPs that have assumed a BAT differentiation state (FAP-BAT) have proven efficacious in treating muscle degeneration in numerous injury models. Purpose: To characterize the subpopulation of murine FAPs with FAP-BAT activity, determine whether their promyogenic effect is mediated via exosomes, and analyze human FAPs for an analogous promyogenic exosome-rich subpopulation. Study Design: Controlled laboratory study. Methods: FAPs from UCP1 reporter mice were isolated via fluorescence-activated cell sorting and sorted according to the differential intensity of the UCP1 signal observed: negative for UCP1 (UCP1–), intermediate intensity (UCP1+), and high intensity (UCP1++). Bulk RNA sequencing was performed on UCP1–, UCP1+, and UCP1++ FAPs to evaluate distinct characteristics of each population. Exosomes were harvested from UCP1++ FAP-BAT exosomes (Exo-FB) as well as UCP1– non–FAP-BAT exosomes (Exo-nFB) cells using cushioned-density gradient ultracentrifugation and used to treat C2C12 cells and mouse embryonic fibroblasts in vitro, and the myotube fusion index was assessed. Exo-FB and Exo-nFB were then used to treat wild type C57B/L6J mice that had undergone a massive rotator cuff tear. At 6 weeks mice were sacrificed, and supraspinatus muscles were harvested and analyzed for muscle atrophy, fibrosis, fatty infiltration, and UCP1 expression. Single-cell RNA sequencing was then performed on FAPs isolated from human muscle that were treated with the beta-agonist formoterol or standard media to assess for the presence of a parallel promyogenic subpopulation of FAP-BAT cells in humans. Results: Flow cytometry analysis of sorted UCP1 reporter mouse FAPs revealed a trimodal distribution of UCP1 signal intensity, which correlated with 3 distinct transcriptomic profiles characterized with bulk RNA sequencing. UCP1++ cells were marked by high mitochondrial gene expression, BAT markers, and exosome surface makers; UCP1– cells were marked by fibrogenic markers; and UCP1+ cells were characterized differential enrichment of white adipose tissue markers. Exo-FB treatment of C2C12 cells resulted in robust myotube fusion, while treatment of mouse embryonic fibroblasts resulted in differentiation into myotubes. Treatment of cells with Exo-nFB resulted in poor myotube formation. Mice that were treated with Exo-FB at the time of rotator cuff injury demonstrated markedly reduced muscle atrophy and fatty infiltration as compared with treatment with Exo-nFB or phosphate-buffered saline. Single-cell RNA sequencing of human FAPs from the rotator cuff revealed 6 distinct subpopulations of human FAPs, with one subpopulation demonstrating the presence of UCP1+ beige adipocytes with a distinct profile of BAT, mitochondrial, and extracellular vesicle–associated markers. Conclusion: FAP-BAT cells form a subpopulation of FAPs with upregulated beige gene expression and exosome production that mediate promyogenic effects in vitro and in vivo, and they are present as a transcriptomically similar subpopulation of FAPs in humans. Clinical Relevance: FAP-BAT cells and their exosomes represent a potential therapeutic avenue for treating rotator cuff muscle degeneration. [ABSTRACT FROM AUTHOR]

There has been unprecedented progress in the development of systemic therapies for patients with metastatic melanoma over the last decade. There is now tremendous potential and momentum to further and markedly reduce the impact of this disease. However, developing more effective treatments for metastases to the CNS remains a critical challenge for patients with melanoma. Melanoma patients with active CNS metastases have largely been excluded from both early‐phase and registration trials for all currently approved targeted and immune therapies for this disease. While this exclusion has generally been justified in clinical research due to concerns about poor prognosis, lack of CNS penetration of agents and/or risk of toxicities, recent post‐approval trials have shown the feasibility, safety and clinical benefit of clinical investigation in these patients. These trials have also identified key areas for which more effective strategies are needed. In parallel, recent translational and preclinical research has provided insights into novel immune, molecular and metabolic features of melanoma brain metastases that may mediate the aggressive biology and therapeutic resistance of these tumors. Together, these advances suggest the need for new paradigms for therapeutic development for melanoma patients with CNS metastasis. [ABSTRACT FROM AUTHOR]

Background: Fatty infiltration of rotator cuff muscle is a limiting factor in the success of repairs. Fibroadipogenic progenitors (FAPs) are a population of stem cells within the rotator cuff that can differentiate into white adipocytes, fibroblasts, and beige adipocytes. The effects of patient age and rotator cuff tendon tear size on the number, differentiation patterns, and gene expression profiles of FAPs have not yet been analyzed. Purpose: To determine if patient age and rotator cuff tear size independently regulate FAP number, differentiation patterns, and gene expression profiles. Study Design: Controlled laboratory study. Methods: Supraspinatus muscle samples were collected from 26 patients between the ages of 42 and 76 years with partial- or full-thickness rotator cuff tears. FAPs were quantified using fluorescence-activated cell sorting. Gene expression analysis was performed across a custom 96-gene panel using NanoString. In vitro differentiation assays of FAPs were conducted using adipogenic, fibrogenic, and beige-inducing (amibegron-treated) media, and quantitative polymerase chain reaction was used to assess gene expression differences between adipogenic and amibegron media conditions. Multivariable linear regressions were performed using Stata to independently analyze the effects of age and rotator cuff tear size on FAP number, differentiation, and gene expression. Results: Increasing age and tear size were independently correlated with increased FAP number (βage = 0.21, P =.03; βtear size = 3.86, P =.05). There was no clear association between age and gene expression of freshly sorted FAPs. Under adipogenic and fibrogenic media conditions, increasing age and tear size were independently associated with increased adipogenic and fibrogenic differentiation of FAPs. Under amibegron treatment conditions, age positively correlated with increased beige differentiation (β = 1.03; P <.0001), while increasing tear size showed a trend toward decreased beige differentiation (β = −4.87; P =.1). When gene expression patterns between adipogenic and amibegron media conditions were compared, larger tear size strongly inhibited beige gene expression, while advanced age did not. Conclusion: Patient age and rotator cuff tear size independently regulated FAP number, differentiation, and gene expression. Age and tear size were positively correlated with increased FAP number and fibrogenic/adipogenic differentiation. Advancing patient age did not limit FAP beige differentiation and gene expression, while increasing rotator cuff tear size strongly inhibited these processes. [ABSTRACT FROM AUTHOR]

It is in Bunyan's narrative fictions and allegories, especially I The Pilgrim's Progress i , that Parry identifies Bunyan's "imaginative persuasion" operating most effectively. Despite a title that might promise an account of language and style in seventeenth-century Puritan "conversion" narratives, David Parry's rich, scholarly, and impressively wide-ranging book considers instead "the rhetoric of conversion that seeks to bring about conversion in its readers" (2): the practical business of converting from the perspective of "the godly persuader" (24). The rhetoric of conversion in English Puritan writing from Perkins to Milton: by David Parry, London, Bloomsbury Academic, 2022, viii + 273 pp., £85.00 (hardback), ISBN 9781350165144. [Extracted from the article]

Biological maturation has been shown to affect male youths’ responses to plyometric training (PT). However, to date, no researcher has examined the effect of maturation on the effects of PT in female youth. We undertook the first controlled intervention study to examine this, focusing on adaptive responses to countermovement jump (CMJ), reactive strength index (RSI), and change of direction (COD) performance in groups of female youth divided by maturation status (years from peak height velocity [PHV]). The training program lasted 7 weeks with subjects undertaking 2 sessions of PT per week. In the mid-PHV group, there was a small increase (effect size; 90% confidence interval 50.40; -0.23 to 1.03) in CMJ performance. No changes were observed in the post-PHV group (0.02; -0.68 to 0.72). For RSI, there was a moderate increase in the mid-PHV group (0.94; 0.29–1.59) with only a trivial increase in the post-PHV group (0.06; -0.65 to 0.76). The intervention exerted no positive effect on COD performance in any group. Plyometric training seems to enhance CMJ and RSI in female youth, although the magnitude of adaptation could be affected by maturation status. A twice-per-week program of multidirectional jumping and hopping, with bilateral and unilateral components, can be used as a preparatory precursor to physical education classes or recreational sport. [ABSTRACT FROM AUTHOR]

The heme peroxidase family generates a battery of oxidants both for synthetic purposes, and in the innate immune defence against pathogens. Myeloperoxidase (MPO) is the most promiscuous family member, generating powerful oxidizing species including hypochlorous acid (HOCl). Whilst HOCl formation is important in pathogen removal, this species is also implicated in host tissue damage and multiple inflammatory diseases. Significant oxidant formation and damage occurs extracellularly as a result of MPO release via phagolysosomal leakage, cell lysis, extracellular trap formation, and inappropriate trafficking. MPO binds strongly to extracellular biomolecules including polyanionic glycosaminoglycans, proteoglycans, proteins, and DNA. This localizes MPO and subsequent damage, at least partly, to specific sites and species, including extracellular matrix (ECM) components and plasma proteins/lipoproteins. Biopolymer-bound MPO retains, or has enhanced, catalytic activity, though evidence is also available for non-catalytic effects. These interactions, particularly at cell surfaces and with the ECM/glycocalyx induce cellular dysfunction and altered gene expression. MPO binds with higher affinity to some damaged ECM components, rationalizing its accumulation at sites of inflammation. MPO-damaged biomolecules and fragments act as chemo-attractants and cell activators, and can modulate gene and protein expression in naïve cells, consistent with an increasing cycle of MPO adhesion, activity, damage, and altered cell function at sites of leukocyte infiltration and activation, with subsequent tissue damage and dysfunction. MPO levels are used clinically both diagnostically and prognostically, and there is increasing interest in strategies to prevent MPO-mediated damage; therapeutic aspects are not discussed as these have been reviewed elsewhere. [Display omitted] • Myeloperoxidase (MPO) is released extracellularly from leukocytes at sites of inflammation. • MPO generates multiple oxidants to kill pathogens, but also induces host tissue damage. • MPO binds to extracellular matrix proteins, glycosaminoglycans and plasma (lipo)proteins. • Binding via ionic interactions results in site-specific effects and localized modifications. • Biological effects are induced by both oxidant formation and ionic interactions. [ABSTRACT FROM AUTHOR]

Short term experimental studies by DiPerna and colleagues have demonstrated the efficacy of the Social Skills Improvement System (SSIS) to measure and improve the social skills and academic functioning of students from Preparatory year to Grade 3 and to decrease problem behaviours. This longitudinal school-led project applied the multi-tiered assessment and intervention components of the SSIS to achieve sustainable outcomes. In each of three project years up to 16 teachers completed the SSIS Performance Screening Guide for approximately 380 students, with nearly half having special needs. Students screened by their teachers as having low levels of prosocial behaviour were assessed using the comprehensive SSIS Rating Scale. The collective data informed the social skills goal priorities among 10 skills targeted and taught by classroom teachers using the SSIS Classwide Intervention Programme (CIP). Intervention effectiveness indicators included change in prosocial behaviour, academic achievement, problem behaviours, wellbeing, and attendance. Students showed marked improvement on all outcome indicators across the three project years, resulting in an improved school climate. Limitations to the evaluation are discussed, followed by recommendations for other schools to adopt similar interventions to achieve sustainable improvement in students' social skills and other outcomes, and school climate. [ABSTRACT FROM AUTHOR]

In sub-Saharan Africa, most transmission of mosquito-transmitted diseases, such as malaria or dengue, occurs within or around houses. Preventing mosquito house entry and reducing mosquito production around the home would help reduce the transmission of these diseases. Based on recent research, we make key recommendations for reducing the threat of mosquito-transmitted diseases through changes to the built environment. The mnemonic, DELIVER, recommends the following best practices: (i) Doors should be screened, self-closing and without surrounding gaps; (ii) Eaves, the space between the wall and roof, should be closed or screened; (iii) houses should be Lifted above the ground; (iv) Insecticide-treated nets should be used when sleeping in houses at night; (v) houses should be Ventilated, with at least two large-screened windows to facilitate airflow; (vi) Environmental management should be conducted regularly inside and around the home; and (vii) Roofs should be solid, rather than thatch. DELIVER is a package of interventions to be used in combination for maximum impact. Simple changes to the built environment will reduce exposure to mosquito-transmitted diseases and help keep regions free from these diseases after elimination. [ABSTRACT FROM AUTHOR]

Ovarian hyperstimulation syndrome is a well-known entity in assisted reproductive technology. However, it is unusual for this entity to occur without any medications that stimulate follicle stimulating hormone. Herein, we describe a case where a partial molar pregnancy with high human chorionic gonadotropin promiscuously activated follicle stimulating hormone receptors has resulted in spontaneous ovarian hyperstimulation syndrome. There are only eight other cases documented per our literature search of ovarian hyperstimulation syndrome in molar gestations, and this is the third report in partial molar gestation. In our case, it is an unique development of severe early onset pre-eclampsia in the second trimester. Our goal is to discuss the nuances in management of this entity as well as to add the available body of research on this subject. [ABSTRACT FROM AUTHOR]

During drug discovery and prior to the first human dose of a novel candidate drug, the pharmacokinetic (PK) behavior of the drug in humans is predicted from preclinical data. This helps to inform the likelihood of achieving therapeutic exposures in early clinical development. Once clinical data are available, the observed human PK are compared with predictions, providing an opportunity to assess and refine prediction methods. Application of best practice in experimental data generation and predictive methodologies, and a focus on robust mechanistic understanding of the candidate drug disposition properties before nomination to clinical development, have led to maximizing the probability of successful PK predictions so that 83% of AstraZeneca drug development projects progress in the clinic with no PK issues; and 71% of key PK parameter predictions [64% of area under the curve (AUC) predictions; 78% of maximum concentration (C max) predictions; and 70% of half-life predictions] are accurate to within twofold. Here, we discuss methods to predict human PK used by AstraZeneca, how these predictions are assessed and what can be learned from evaluating the predictions for 116 candidate drugs. It is now universally recognized that an acceptable human PK profile increases the probability of a candidate drug becoming a successful therapy. A variety of tools are available to predict human PK behavior in advance of clinical data, including scaling clearance from in vitro metabolic stability data, and physiologically based scaling of volume of distribution. To improve PK prediction methods, it is crucial to continually assess the performance of predictions with first-time-in-human PK data for new candidate drugs. To date, AstraZeneca have compared observed PK to predictions for 116 candidate drugs, and since the launch of our five-dimensional framework in 2011, we have driven sustained improvements in the quality of PK predictions. [ABSTRACT FROM AUTHOR]

Significance: The release of myeloperoxidase (MPO) by activated leukocytes is critical in innate immune responses. MPO produces hypochlorous acid (HOCl) and other strong oxidants, which kill bacteria and other invading pathogens. However, MPO also drives the development of numerous chronic inflammatory pathologies, including atherosclerosis, neurodegenerative disease, lung disease, arthritis, cancer, and kidney disease, which are globally responsible for significant patient mortality and morbidity. Recent Advances: The development of imaging approaches to precisely identify the localization of MPO and the molecular targets of HOCl in vivo is an important advance, as typically the involvement of MPO in inflammatory disease has been inferred by its presence, together with the detection of biomarkers of HOCl, in biological fluids or diseased tissues. This will provide valuable information in regard to the cell types responsible for releasing MPO in vivo, together with new insight into potential therapeutic opportunities. Critical Issues: Although there is little doubt as to the value of MPO inhibition as a protective strategy to mitigate tissue damage during chronic inflammation in experimental models, the impact of long-term inhibition of MPO as a therapeutic strategy for human disease remains uncertain, in light of the potential effects on innate immunity. Future Directions: The development of more targeted MPO inhibitors or a treatment regimen designed to reduce MPO-associated host tissue damage without compromising pathogen killing by the innate immune system is therefore an important future direction. Similarly, a partial MPO inhibition strategy may be sufficient to maintain adequate bacterial activity while decreasing the propagation of inflammatory pathologies. [ABSTRACT FROM AUTHOR]

Exposure of biological molecules to oxidants is inevitable and therefore commonplace. Oxidative stress in cells arises from both external agents and endogenous processes that generate reactive species, either purposely (e.g. during pathogen killing or enzymatic reactions) or accidentally (e.g. exposure to radiation, pollutants, drugs, or chemicals). As proteins are highly abundant and react rapidly with many oxidants, they are highly susceptible to, and major targets of, oxidative damage. This can result in changes to protein structure, function, and turnover and to loss or (occasional) gain of activity. Accumulation of oxidatively- modified proteins, due to either increased generation or decreased removal, has been associated with both aging and multiple diseases. Different oxidants generate a broad, and sometimes characteristic, spectrum of post-translational modifications. The kinetics (rates) of damage formation also vary dramatically. There is a pressing need for reliable and robust methods that can detect, identify, and quantify the products formed on amino acids, peptides, and proteins, especially in complex systems. This review summarizes several advances in our understanding of this complex chemistry and highlights methods that are available to detect oxidative modifications--at the amino acid, peptide, or protein level--and their nature, quantity, and position within a peptide sequence. Although considerable progress has been made in the development and application of new techniques, it is clear that further development is required to fully assess the relative importance of protein oxidation and to determine whether an oxidation is a cause, or merely a consequence, of injurious processes. [ABSTRACT FROM AUTHOR]

Flow sculpting is a powerful method for passive flow control that uses a sequence of bluff-body structures to engineer the structure of inertially flowing microfluidic streams. A variety of cross-sectional flow shapes can be created through this method, offering a new platform for flow manipulation or material fabrication useful in bioengineering, manufacturing, and chemistry applications. However, the inverse problem in flow sculpting – designing a device that produces a target fluid flow shape – remains challenging due to the complex, diverse, and enormous design space. Solutions to the inverse problem have been constrained to single-material fluid streams that are shaped into top–bottom symmetric shapes due to the bluff-body structures available in current libraries (pillars) that span the height of the channel. In this work, we introduce multi-material design and symmetry-breaking flow deformations enabled by half-height pillars, presented within an extremely fast simulation method for flow sculpting yielding a 34-fold reduction in runtime. The framework is deployed freely as a cross-platform application called "FlowSculpt". We detail its implementation and usage, and discuss the addition of enhanced search operations, which enable users to more easily design flow shapes that replicate their input drawings. With FlowSculpt, the microfluidics community can now quickly design flow shaping microfluidic devices on modest hardware, and easily integrate these complex physics into their research toolkit. [ABSTRACT FROM AUTHOR]

This paper provides a rationale for The Spectrum of Teaching Styles (The Spectrum) as a pedagogical model in teaching physical education (PE). Building on prior discussions/debates (SueSee et al., 2021), we will contest the view that the concept of teaching styles is different from that of a pedagogical model. In doing so, we highlight the most central aspects of The Spectrum and explain fundamental characteristics that warrant its representation with existing pedagogical models. The paper demonstrates for teachers how The Spectrum details the 'how', 'when' and 'why' of their pedagogical decisions, in understanding how they may meet educational outcomes for increased curriculum alignment, or successful enactment of models-based practices. The contention we present is The Spectrum is valuable to PE teachers in understanding the context-specific realities of teaching episodes and therefore improving teaching and learning practices in PE by helping teachers align their pedagogy with their desired learning outcomes. [ABSTRACT FROM AUTHOR]

It is well accepted that organoselenium compounds are powerful antioxidants that have potential therapeutic benefits. Unfortunately, the therapeutic value of many of these selenium-containing entities is often hampered by low solubility in aqueous solutions, which prevents them from reaching therapeutically relevant doses in plasma. We approached this problem by constructing selenosugars with infinite water solubilities. Work over many years led to the discovery of 1,4-anhydro-4-seleno-d-tallitol (SeTal), which has been shown to accelerate skin-tissue repair, heal wounds in (db/db and wt) rodent and porcine models, and prevent high-glucose-induced endothelial dysfunction in mouse aorta. This lead compound is currently being developed as a topical medicament for a variety of skin-repair scenarios. This article discusses the chemistry that led to the development of our selenium-containing carbohydrates, and showcases the remarkable therapeutic properties of SeTal. [ABSTRACT FROM AUTHOR]

The use of cannabis for medicinal/recreational purposes is widespread throughout the world. Smoke inhalation is known to cause airway irritation due to noxious substances (ie, benzene) within the mix. Thus, advanced vaporisation platforms (eg, Davinci IQ) have been developed to circumvent negative health implications. Here, we consider the impact that cannabis smoke and cannabis vapour have on simulated lung surfactant performance within a model pulmonary space (ie, 37°C, elevated humidity and related fluid hydrodynamics). In total, 50 mg of herbal material was ignited or placed within a Davinci IQ vaporiser with subsequent activation. The aliquots were collected and then analysed using gas chromatography‐mass spectroscopy for composition and cannabinoid (eg, Δ9‐tetrahydrocannabinol [Δ9‐THC]) concentration. The average content within cannabis smoke was 2.84% (0.07%, SD) Δ9‐THC, with the same for cannabis vapour being 0.88% (0.14%, SD). Aerosolised samples were transferred to the lung biosimulator. When compared with the pristine Curosurf system, challenge with cannabis smoke and cannabis vapour reduced the surface pressure term by 26% and 7% and increased film compressibility by 60% and 15% at 80% trough area, respectively. The net effect would be enhanced film elasticity and an increased work of breathing, being more pronounced on cannabis smoke inhalation. The trends noted were ascribed to two factors operating synergistically, namely the amount of Δ9‐THC (plus others) within the aerosolised samples and the associated toxicity profile. Further research is required to establish mass‐balance effects (ie, titrated outputs) along with detailed chemical profiling of material generated from the unrelated cannabis activation pathways. [ABSTRACT FROM AUTHOR]

Interfacial interactions of Nafion ionomer with superhydrophilic (Pt, Au), hydrophilic (SiO2), and hydrophobic (graphene, octyltrichlorosilane [OTS]‐modified SiO2) is investigated, using in situ thermal ellipsometry, by quantification of substrate‐ and thickness‐dependent thermal properties of the ultrathin Nafion films of nominal thickness ranging 25–135 nm. For sub‐50 nm thin Nafion films, the thermal expansion coefficient of films decreased in the order of most hydrophobic to most hydrophilic substrate: OTS > graphene > SiO2 > Au > Pt, implying weaker interpolymer and polymer–substrate interactions for films on hydrophobic substrates. Expansion coefficient of films on SiO2, graphene, and OTS‐modified SiO2 decreased with thickness whereas that of films on Au and Pt substrates increased with thickness. Above ~100 nm of thickness, films on all substrates converged toward a common value representative of bulk Nafion. Thermal transition temperature was found to be higher for films on hydrophilic SiO2 than that for films on hydrophobic graphene and OTS‐modified SiO2 but was not discernible for films on Au and Pt substrates. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019, 57, 343–352 Thin film studies have recently established that interfacial interactions of low‐crystallinity Nafion ionomers with different substrates influence the structure and properties. However, there are no simple methods or metrics to assess the favorability of these interactions. In this work, the authors demonstrate that Nafion thin film thermal expansion coefficients, determined using in situ thermal ellipsometry, show remarkable dependency on substrate hydrophilicity/hydrophobicity and may be useful for assessing the favorability of interfacial interactions. [ABSTRACT FROM AUTHOR]

Future increases in the intensity of heat waves (high heat and low water availability) are predicted to be one of the most significant impacts on organisms. Using six native grasses from Eastern Australia, we assessed their capacity to tolerate heat waves with low water availability. We were interested in understanding differential response between native grasses of differing photosynthetic pathways in terms of physiological and some molecular parameters to ecologically relevant summer heat waves that are associated with low rainfall. We used a simulation heatwave event in controlled temperature cabinets and investigated effects of the different treatments on four stress indicators: leaf senescence, leaf water content, photosynthetic efficiency and the relative expression of two heat shock proteins, Hsp70 and smHsp17.6. Leaf senescence was significantly greater under the combined stress treatment, while declines in leaf water content and photosynthetic efficiency were much larger for C3 than C4 plants, particularly under the combined stress treatment. Species showed an increase in expression of Hsp70 associated with heat treatment, rather than drought stress. In contrast Hsp17.6 was only detected in two species, responding to heat rather than drought, although species’ responses were variable. Overall, the C3 species were less tolerant than C4 species. Variation in individual plants within species was evident, especially under multiple stresses, and indicates that losses of individual plants may occur during a heat wave associated with this variability in tolerance. Heat waves will impose significant stress on plant communities that would not otherwise occur when heat and drought stress are experienced singly. Using ecologically relevant heat stress is likely to yield better predictability of how native plants will cope under a hotter, drier future. [ABSTRACT FROM AUTHOR]

Rotator cuff disease encompasses a broad spectrum of injury and pathology with an increasing incidence with age. Pain with overhead activity, localizing to the deltoid region, and loss of active range of motion of the shoulder are among the most common presenting symptoms. Treatment options are dependent on the extent of disease and patient symptoms, and may range from physical therapy to surgical repair using a variety of possible techniques. Tear thickness, size, and morphology frequently dictate the repair techniques that are used, such as margin convergence, anterior and posterior interval slides, and mobilization of the rotator interval and supraspinatus with a subscapularis repair. Establishing and maintaining a low-tension repair is important in optimizing tendon healing after surgery. Superior capsule reconstruction is an emerging treatment strategy for massive, otherwise irreparable cuff tears, though more long-term evidence is necessary to fully evaluate this option. [ABSTRACT FROM AUTHOR]

Software written in programming languages that permit manual memory management, such as C and C++, are often littered with exploitable memory errors. These memory bugs enable attackers to leak sensitive information, hijack program control flow, or otherwise compromise the system and are a critical concern for computer security. Many runtime monitoring and protection approaches have been proposed to detect memory errors in C and C++ applications, however, they require source code recompilation or binary instrumentation, creating compatibility challenges for applications using proprietary or closed source code, libraries, or plug-ins. This paper introduces a new approach for detecting heap memory errors that does not require applications to be recompiled or instrumented. We show how to leverage the calling convention of a processor to track all dynamic memory allocations made by an application during runtime. We also present a transparent tracking and caching architecture to efficiently verify program heap memory accesses. Performance simulations of our architecture using SPEC benchmarks and real-world application workloads show our architecture achieves hit rates over 95 percent for a 256-entry cache, resulting in only 2.9 percent runtime overhead. Security analysis using a software prototype shows our architecture detects 98 percent of heap memory errors from selected test cases in the Juliet Test Suite and real-world exploits. [ABSTRACT FROM AUTHOR]

[Display omitted] New compounds and pharmacological strategies offer alternatives for treating chronic skin diseases, such as atopic dermatitis (AD). Here, we investigated the incorporation of 1,4-anhydro-4-seleno- d -talitol (SeTal), a bioactive seleno-organic compound, in gelatin and alginate (Gel-Alg) polymeric films as a strategy for improving the treatment and attenuation of AD-like symptoms in a mice model. Hydrocortisone (HC) or vitamin C (VitC) were incorporated with SeTal in the Gel-Alg films, and their synergy was investigated. All the prepared film samples were able to retain and release SeTal in a controlled manner. In addition, appreciable film handling facilitates SeTal administration. A series of in-vivo / ex-vivo experiments were performed using mice sensitized with dinitrochlorobenzene (DNCB), which induces AD-like symptoms. Long-term topical application of the loaded Gel-Alg films attenuated disease symptoms and pruritus, with suppression of the levels of inflammatory markers, oxidative damage, and the skin lesions associated with AD. Moreover, the loaded films showed superior efficiency in attenuating the analyzed symptoms when compared to hydrocortisone (HC) cream, a traditional AD-treatment, and decreased the inherent drawbacks of this compound. In short, incorporating SeTal (by itself or with HC or VitC) in biopolymeric films provides a promising alternative for the long-term treatment of AD-type skin diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT: Rotator cuff (RC) tears are frequently complicated by muscle atrophy. Muscle stem cells (MuSCs) repair damaged myofibers following injury, but their role in the prevention or pathogenesis of atrophy following RC tears remains undefined. We hypothesized that the RC MuSC population would be affected by supraspinatus (SS) and infraspinatus (IS) tendon transection (TT) compared to uninjured muscle in a mouse model of RC tear. C57BL6/J mice underwent unilateral SS and IS TT and contralateral sham surgery. At 3, 8, or 14 weeks after injury, mice were euthanized, and SS and IS were harvested for FACS sorting of CD31‐/CD45‐/Sca1‐/ITGa7+/VCAM+ MuSCs or histological analysis. Ki‐67+ MuSCs from injured muscle increased 3.4‐fold at 3 weeks (p = 0.03) and 8.1‐fold at 8 weeks (p = 0.04) following TT injury, but returned to baseline by 14 weeks (p = 0.91). Myod1 remained upregulated 3.3‐fold at 3 weeks (p = 0.03) and 2.0‐fold at 14 weeks (p = 0.0003), respectively. Myofiber cross‐sectional area was decreased at both 3 and 14 weeks after injury, but the number of MuSCs per fiber remained relatively constant at 3 (p = 0.3) and 14 (p = 0.6) weeks after TT. In this study, we characterized the longitudinal effect of RC tendon injury on the MuSC population in supraspinatus and infraspinatus muscles. MuSCs are transiently activated, and are not depleted, in spite of persistent muscle atrophy. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1370–1376, 2018. [ABSTRACT FROM AUTHOR]

BackgroundDespite decades of research on family adaptation in relation to caring for a child with an autism spectrum disorder (ASD), the wellbeing of fathers remains poorly understood. MethodThe present study sought to investigate experiences of fathers of young children with ASD aged between 2½ and 6 years attending an ASD-specific early intervention centre. Eighteen fathers initially completed a mailed questionnaire and 8 of these fathers were then interviewed by telephone. The questionnaire included standardised measures assessing constructs of the double ABCX model of family adaptation. The interview used open-ended questions to understand the experiences of fathers’ involvement in caring, sources of support, and coping strategies. ResultsFathers experienced elevated levels of parental stress and elevated depressive symptoms. Interviews deepened understanding of fathers’ personal experiences of each component of the double ABCX model. ConclusionsFindings from this study provide further insight into the fathering role and demonstrate the utility of the double ABCX model as a framework for exploring their experiences. The need for further research to explore practical implications to better support fathers is discussed. [ABSTRACT FROM PUBLISHER]

Drug delivery to the body via the inhaled route is dependent upon patient status, device use, and respirable formulation characteristics. Further to inhalation, drug‐containing particles interact and dissolve within pulmonary fluid leading to the desired pharmacological response. Pulmonary surfactant stabilises the alveolar air‐liquid interface and permits optimal respiratory mechanics. This material represents the initial contacting surface for all inhaled matter. On dissolution, the fate of a drug substance can include receptor activation, membrane partitioning and cellular penetration. Here, we consider the partitioning behaviour of salbutamol when located in proximity to a simulated pulmonary surfactant monolayer at pH 7. The administration of salbutamol to the underside of the surfactant film resulted in an expanded character for the 2‐dimensional ensemble and a decrease in the compressibility term. The rate of drug partitioning was greater when the monolayer was in the expanded state (ie, inhalation end‐point), which was ascribed to more accessible areas for molecular insertion. Quantum mechanics protocols, executed via Gaussian 09, indicated that constructive interactions between salbutamol and integral components of the model surfactant film took the form of electrostatic and hydrophobic associations. The favourable interactions are thought to promote drug insertion into the monolayer structure leading to the observed expanded character. The data presented herein confirm that drug partitioning into pulmonary surfactant monolayers is a likely prospect further to the inhalation of respirable formulations. As such, this process holds potential to reduce drug‐receptor activation and/or increase the residence time of drug within the pulmonary space. [ABSTRACT FROM AUTHOR]

The principal site for gaseous exchange within the lung is the alveolar space, which is bathed in a lipid‐protein blend called pulmonary surfactant. This material is the initial contacting site for orally inhaled products and environmental toxins. Using the lung biosimulator, this study investigates the influence of cannabis smoke on the activity of the lung surfactant replacement product, Curosurf. Initially, 50‐mg cannabis material was pyrolysed and the smoke collected. Cannabis smoke profiling was conducted via gas chromatography–mass spectroscopy, with a mean concentration of 1% Δ9‐tetrahydrocannabinol determined. The smoke aliquots were transferred to the lung biosimulator and expansion—contraction cycles were then initiated to mimic tidal breathing. Baseline data confirmed that Curosurf works effectively under physiologically relevant conditions. Exposure to cannabis smoke from 2 independent batches reduced the Langmuir maximum surface pressure values by approximately 20% and increased the compressibility term; interbatch variation was detected. Cannabis smoke impaired the ability of Curosurf to lower the surface tension term. This was ascribed to the penetration of the planar, hydrophobic drug into the two‐dimensional film, and destructive interaction with polar functionalities. The net effect would be increased work of breathing for the individual. [ABSTRACT FROM AUTHOR]

Objective: In addition to achieving glycemic control, weight loss and blood pressure (BP) reduction are important components of type 2 diabetes mellitus (T2DM) management, as many patients with T2DM are overweight/obese and/or have hypertension. Canagliflozin, an SGLT2 inhibitor, has demonstrated improvements in HbA1c, body weight (BW), and systolic BP across a broad range of patients with T2DM. This analysis evaluated achievement of composite endpoints of HbA1c, BW, and systolic BP targets with canagliflozin versus placebo.Methods: This post hoc analysis evaluated the proportion of T2DM patients achieving the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4mmHg with canagliflozin 100 and 300mg compared with placebo using pooled data from four 26-week, phase 3 studies (N = 2313; NCT01081834, NCT01106677, NCT01106625, NCT01106690). The proportion of patients achieving the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg was also evaluated.Results: At week 26, greater proportions of patients met individual HbA1c, BW, and systolic BP targets with canagliflozin versus placebo. A greater proportion of patients treated with canagliflozin 100 or 300 mg versus placebo also achieved the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4 mmHg at week 26 (21.1%, 25.3%, and 5.7%, respectively; odds ratios [95% CI] of 4.5 [3.1, 6.5] and 5.6 [3.8, 8.2]). A greater proportion of patients also achieved the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg with canagliflozin 100 and 300 mg versus placebo (14.7%, 20.9%, and 3.3%, respectively; odds ratios [95% CI] of 5.2 [3.2, 8.4] and 8.4 [5.2, 13.5]). Canagliflozin was generally well tolerated, with a safety profile similar to that seen in other phase 3 studies.Conclusions: Patients with T2DM were more likely to achieve clinically important reductions in HbA1c, BW, and systolic BP with canagliflozin versus placebo. [ABSTRACT FROM AUTHOR]

Background: Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737).Methods: Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions.Results: Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure.Conclusions: SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Adjustments are considered necessary for students with disabilities to be fully included in classroom instruction, classroom assessment and external accountability tests. The 67 item Checklist of Learning and Assessment Adjustments for Students (CLAAS), translated for the Chinese community, was used by 74 teachers from Macau and Mainland China to document their application of adjustments for 319 students with special educational needs across these three settings. Results indicated consistently large gaps between adjustment use in classrooms compared with national tests, with the allowable adjustments for public testing reportedly used very little. Findings also provided evidence for the content validity of the checklist for teachers of students with disabilities in China and its utility in documenting applied adjustments. This study also indicates the potential for CLAAS to provide teachers across China with a comprehensive list of adjustments, to reflect on and review adjustment decision-making and assessment protocols for all students. [ABSTRACT FROM AUTHOR]

Problem In molecular analysis of tissue biopsy specimens, one crucial aspect is characterization of immune cell populations. This is especially important for evaluation of uterine receptivity by assessing levels of lymphocyte populations including CD56bright CD16- uterine NK cells and CD56dim CD16+ conventional NK cells. Our objective was to investigate whether measuring total RNA transcripts from a tissue specimen would accurately reflect immune cell levels and be a new technique to assess immune cell subsets. Method of Study Peripheral blood mononuclear cells ( PBMCs) and endometrial tissues were used. Flow cytometry was utilized for the analysis of lymphocyte subsets in PBMCs, and RT- qPCR was applied to quantify RNA transcripts indicative of lymphocyte and granulocyte populations. Results In PBMC specimens, there were significant correlations between gene expression levels and cell subsets. NK cells correlated with CD16A, NKp46, and CD56 transcripts, B cells correlated with EBF1, and CD8+ T cells correlated with CD8β. Finally, endometrial tissues displayed high CD56 expression and very low CD3ε, CD16A, and NKp30, reflecting the characteristic endometrial NK cell subsets. Conclusion Strong correlations between RT- qPCR data and levels of lymphocyte subsets indicate that gene expression analysis will be a useful technique for characterizing levels of CD56+ cells in endometrial tissues. [ABSTRACT FROM AUTHOR]

Pain is a prevalent condition that can have a serious impact upon the socioeconomic function of a population. Numerous methods exist to administer analgesic medication (e.g. aspirin) to the body however inherent drawbacks limit patient acceptability. The inhaled route offers promise to facilitate the administration of medication to the body. Here, we consider the crystallisation behaviour of aspirin, our model therapeutic agent, when in contact with material of relevance to the lung. Thus, our approach aims to better understand the interaction between drug substances and the respiratory tract. Langmuir monolayers composed of a mixed surfactant system were supported on an aqueous subphase containing aspirin (7.5 mg/ml). The surfactant film was compressed to either 5mN/m (i.e. inhalation end point) or 50 mN/m (i.e. exhalation end point), whilst located within a humid environment for 16 h. Standard cooling crystallisation procedures were employed to produce control samples. Antisolvent crystallisation in the presence or absence of lung-specific additives was conducted. All samples were analysed via scanning electron microscopy and X-ray diffraction. Drug-surfactant interactions were confirmed via condensed Langmuir isotherms. Scanning electron microscopy analysis revealed plate-like morphology. The crystallisation route dictated both the crystal habit and particle size distribution. Dominant reflections were the (100) and (200) aspects. The main modes of interaction were hydrogen bonding, hydrophobic associations, and van der Waals forces. Here, we have demonstrated the potential of antisolvent crystallisation with lung-specific additives to achieve control over drug crystal morphology. The approach taken can be applied in respirable formulation engineering. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant is an endogenous material that lines and stabilises the alveolar air-liquid interface. Respiratory mechanics can be compromised by exposure to environmental toxins such as cigarette smoke, which contains nicotine. This study aims to determine the influence of nicotine on the activity of simulated lung surfactant at pH 7 and pH 9. In all cases, the addition of nicotine to the test zone caused deviation in surfactant film performance. Importantly, the maximum surface pressure was reduced for each system. Computational modelling was applied to assess key interactions between each species, with the Gaussian 09 software platform used to calculate electrostatic potential surfaces. Modelling data confirmed either nicotine penetration into the two-dimensional structure or interfacial/electrostatic interactions across the underside. The results obtained from this study suggest that nicotine can impair the ability of pulmonary surfactant to reduce the surface tension term, which can increase the work of breathing. When extrapolated to gross lung function, alveolar collapse and respiratory disease (e.g. chronic airway obstruction) may result. The delivery of nicotine to the (deep) lung can cause a deterioration in lung function and lead to reduced quality of life. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Neutrophils are innate immune cells that play a key role in pathogen clearance. They contribute to inflammatory diseases, including diabetes, by releasing pro-inflammatory cytokines, reactive oxygen species, and extracellular traps (NETs). NETs contain a DNA backbone and catalytically active myeloperoxidase (MPO), which produces hypochlorous acid (HOCl). Chlorination of the DNA nucleoside 8-chloro-deoxyguanosine has been reported as an early marker of inflammation in diabetes. In this study, we examined the reactivity of different chlorinated nucleosides, including 5-chloro-(deoxy)cytidine (5ClC, 5CldC), 8-chloro-(deoxy)adenosine (8ClA, 8CldA) and 8-chloro-(deoxy)guanosine (8ClG, 8CldG), with the INS-1E β-cell line. Exposure of INS-1E cells to 5CldC, 8CldA, 8ClA, and 8CldG decreased metabolic activity and intracellular ATP, and, together with 8ClG, induced apoptotic cell death. Exposure to 8ClA, but not the other nucleosides, resulted in sustained endoplasmic reticulum stress, activation of the unfolded protein response, and increased expression of thioredoxin-interacting protein (TXNIP) and heme oxygenase 1 (HO-1). Exposure of INS-1E cells to 5CldC also increased TXNIP and NAD(P)H dehydrogenase quinone 1 (NQO1) expression. In addition, a significant increase in the mRNA expression of NQO1 and GPx4 was seen in INS-1E cells exposed to 8ClG and 8CldA, respectively. However, a significant decrease in intracellular thiols was only observed in INS-1E cells exposed to 8ClG and 8CldG. Finally, a significant decrease in the insulin stimulation index was observed in experiments with all the chlorinated nucleosides, except for 8ClA and 8ClG. Together, these results suggest that increased formation of chlorinated nucleosides during inflammation in diabetes could influence β-cell function and may contribute to disease progression. [ABSTRACT FROM AUTHOR]

Deviation in pulmonary surfactant structure-function activity can impair airway patency and lead to respiratory disorders. This novel study aims to evaluate the influence cigarette/e-cigarette vapour has on model surfactant films located within a simulated pulmonary environment using a lung biosimulator. Chromatographic analysis confirmed that nicotine levels were consistent with the sampling regimen employed. On exposure to smoke vapour, Langmuir isotherms exhibited condensed character and a significant reduction in maximum surface pressure was noted in all cases. Langmuir isocycles, reflective of the human breathing cycle, demonstrated condensed character on smoke vapour delivery. A reduction in the maximum surface pressure was clear only in the case of cigarette vapour application. The components of cigarette vapour can cause oxidative damage to pulmonary surfactant and impair recycling. Neutral nicotine molecules can weaken the structure of the monolayer and cause destabilisation. A protective effect was evident in the case of repeated surfactant compression - relaxation cycles (i.e. the ability to reduce the surface tension term was impaired less), demonstrating a likely innate biological defensive mechanism of the lung. E-cigarette vapour appeared to have a reduced impact on surfactant performance, which may hold value in harm reduction over the longer term. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Dabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases.Methods: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947.Findings: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).Interpretation: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases.Funding: Novartis. [ABSTRACT FROM AUTHOR]

ABSTRACT Previous studies have suggested that macrophage-mediated chronic inflammation is involved in the development of rotator cuff muscle atrophy and degeneration following massive tendon tears. Increased RhoA signaling has been reported in chronic muscle degeneration, such as muscular dystrophy. However, the role of RhoA signaling in macrophage infiltration and rotator muscle degeneration remains unknown. Using a previously established rat model of massive rotator cuff tears, we found RhoA signaling is upregulated in rotator cuff muscle following a massive tendon-nerve injury. This increase in RhoA expression is greatly potentiated by the administration of a potent RhoA activator, lysophosphatidic acid (LPA), and is accompanied by increased TNFα and TGF-β1 expression in rotator cuff muscle. Boosting RhoA signaling with LPA significantly worsened rotator cuff muscle atrophy, fibrosis, and fatty infiltration, accompanied with massive monocytic infiltration of rotator cuff muscles. Co-staining of RhoA and the tissue macrophage marker CD68 showed that CD68+ tissue macrophages are the dominant cell source of increased RhoA signaling in rotator cuff muscles after tendon tears. Taken together, our findings suggest that LPA-mediated RhoA signaling in injured muscle worsens the outcomes of atrophy, fibrosis, and fatty infiltration by increasing macrophage infiltraion in rotator cuff muscle. Clinically, inhibiting RhoA signaling may represent a future direction for developing new treatments to improve muscle quality following massive rotator cuff tears. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1539-1547, 2017. [ABSTRACT FROM AUTHOR]

The goal of the innate immune system is to reduce pathogen spread prior to the initiation of an effective adaptive immune response. Following an infection at a peripheral site, virus typically drains through the lymph to the lymph node prior to entering the blood stream and being systemically disseminated. Therefore, there are three distinct spatial checkpoints at which intervention to prevent systemic spread of virus can occur, namely: 1) the site of infection, 2) the draining lymph node via filtration of lymph or 3) the systemic level via organs that filter the blood. We have previously shown that systemic depletion of phagocytic cells allows viral spread after dermal infection with Vaccinia virus (VACV), which infects naturally through the skin. Here we use multiple depletion methodologies to define both the spatial checkpoint and the identity of the cells that prevent systemic spread of VACV. Subcapsular sinus macrophages of the draining lymph node have been implicated as critical effectors in clearance of lymph borne viruses following peripheral infection. We find that monocyte populations recruited to the site of VACV infection play a critical role in control of local pathogenesis and tissue damage, but do not prevent dissemination of virus. Following infection with virulent VACV, the subcapsular sinus macrophages within the draining lymph node become infected, but are not exclusively required to prevent systemic spread. Rather, small doses of VACV enter the bloodstream and the function of systemic macrophages, but not dendritic cells, is required to prevent further spread. The results illustrate that a systemic innate response to a peripheral virus infection may be required to prevent widespread infection and pathology following infection with virulent viruses, such as poxviruses. [ABSTRACT FROM AUTHOR]

Background: Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors. Methods: Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports. Results: At week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (-0.95 and -1.07%) versus no history of CV disease (-0.71 and -0.90%), history of hypertension (-0.72 and -0.89%) versus no history of hypertension (-0.73 and -0.95%), baseline statin use (-0.77 and -0.99%) versus no statin use (-0.69 and -0.85%), and 0-1 CV risk factor (-0.72 and -0.87%) versus ≥2 CV risk factors (-0.74 and -1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups. Conclusions: The efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors. [ABSTRACT FROM AUTHOR]

Oxidation of critical signaling protein cysteines regulated by H 2 O 2 has been considered to involve sulfenic acid (RSOH) formation. RSOH may subsequently form either a sulfenyl amide (RSNHR′) with a neighboring amide, or a mixed disulfide (RSSR′) with another protein cysteine or glutathione. Previous studies have claimed that RSOH can be detected as an adduct (e.g., with 5,5-dimethylcyclohexane-1,3-dione; dimedone). Here, kinetic data are discussed which indicate that few proteins can form RSOH under physiological signaling conditions. We also present experimental evidence that indicates that (1) dimedone reacts rapidly with sulfenyl amides, and more rapidly than with sulfenic acids, and (2) that disulfides can react reversibly with amides to form sulfenyl amides. As some proteins are more stable as the sulfenyl amide than as a glutathionylated species, the former may account for some of the species previously identified as the “sulfenome” - the cellular complement of reversibly-oxidized thiol proteins generated via sulfenic acids. [ABSTRACT FROM AUTHOR]