Showing papers by "Mark E. Cooper published in 2017"

Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice

Abstract: Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr–/–) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.

Emerging pathogenic links between microbiota and the gut-lung axis

Abstract: The microbiota is vital for the development of the immune system and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the respiratory tract and the gut have recently been linked to alterations in immune responses and to disease development in the lungs. In this Opinion article, we review the microbial species that are usually found in healthy gastrointestinal and respiratory tracts, their dysbiosis in disease and interactions with the gut-lung axis. Although the gut-lung axis is only beginning to be understood, emerging evidence indicates that there is potential for manipulation of the gut microbiota in the treatment of lung diseases.

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice.

Abstract: Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.

Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.

Abstract: Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain–like receptor family, pyrin domain–containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection–mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including ele...

Antibiotics in the clinical pipeline at the end of 2015

Abstract: There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

Abstract: MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223(-/y) mice presented with exacerbated myeloid- driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1 beta was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2(+) inflammatory monocytes and pharmacologic blockade of IL-1 beta or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3'untranslated region, phenocopied the characteristics of miR-223(-/y) mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1 beta release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes

Abstract: NHMRC: 1083138, 1106154, 1021168, 1085752; NIH: HL092969, DK095684, R00HL122505; NHF: 100440; Diabetes Australia Research Trust

Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis

Abstract: The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE-/- mouse. In vitro platelet-derived growth factor (PDGF)- and tumor necrosis factor-α (TNF-α)-induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A4), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.

Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial.

Abstract: Aims The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48–86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 30–3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [CI], −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was −6.0% (95% CI, −15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.

NADPH Oxidase Nox5 Accelerates Renal Injury in Diabetic Nephropathy

Abstract: NADPH oxidase–derived excessive production of reactive oxygen species (ROS) in the kidney plays a key role in mediating renal injury in diabetes. Pathological changes in diabetes include mesangial expansion and accumulation of extracellular matrix (ECM) leading to glomerulosclerosis. There is a paucity of data about the role of the Nox5 isoform of NADPH oxidase in animal models of diabetic nephropathy since Nox5 is absent in the mouse genome. Thus, we examined the role of Nox5 in human diabetic nephropathy in human mesangial cells and in an inducible human Nox5 transgenic mouse exposed to streptozotocin-induced diabetes. In human kidney biopsies, Nox5 was identified to be expressed in glomeruli, which appeared to be increased in diabetes. Colocalization demonstrated Nox5 expression in mesangial cells. In vitro, silencing of Nox5 in human mesangial cells was associated with attenuation of the hyperglycemia and TGF-β1–induced enhanced ROS production, increased expression of profibrotic and proinflammatory mediators, and increased TRPC6, PKC-α, and PKC-β expression. In vivo, vascular smooth muscle cell/mesangial cell–specific overexpression of Nox5 in a mouse model of diabetic nephropathy showed enhanced glomerular ROS production, accelerated glomerulosclerosis, mesangial expansion, and ECM protein (collagen IV and fibronectin) accumulation as well as increased macrophage infiltration and expression of the proinflammatory chemokine MCP-1. Collectively, this study provides evidence of a role for Nox5 and its derived ROS in promoting progression of diabetic nephropathy.

Scaffolding and completing genome assemblies in real-time with nanopore sequencing

Abstract: Third generation sequencing technologies provide the opportunity to improve genome assemblies by generating long reads spanning most repeat sequences. However, current analysis methods require substantial amounts of sequence data and computational resources to overcome the high error rates. Furthermore, they can only perform analysis after sequencing has completed, resulting in either over-sequencing, or in a low quality assembly due to under-sequencing. Here we present npScarf, which can scaffold and complete short read assemblies while the long read sequencing run is in progress. It reports assembly metrics in real-time so the sequencing run can be terminated once an assembly of sufficient quality is obtained. In assembling four bacterial and one eukaryotic genomes, we show that npScarf can construct more complete and accurate assemblies while requiring less sequencing data and computational resources than existing methods. Our approach offers a time- and resource-effective strategy for completing short read assemblies.

Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases

Abstract: Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to examples undergoing preclinical or early stage development. The relatively "nonspecific" mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted.

Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

Abstract: Aims/hypothesis Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications.

Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation

Abstract: Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high NLRP3 expression was associated with peak inflammatory symptoms. Inhibition of NLRP3 activation using the small-molecule inhibitor MCC950 resulted in reduced CHIKV-induced inflammation and abrogated osteoclastogenic bone loss and myositis, but did not affect in vivo viral replication. Mice treated with MCC950 displayed lower expression levels of the cytokines interleukin-6, chemokine ligand 2 and tumour necrosis factor in joint tissue. Interestingly, MCC950 treatment abrogated disease signs in mice infected with a related arthritogenic alphavirus, Ross River virus, but not in mice infected with West Nile virus-a flavivirus. Here, using mouse models of alphavirus-induced musculoskeletal disease, we demonstrate that NLRP3 inhibition in vivo can reduce inflammatory pathology and that further development of therapeutic solutions targeting inflammasome function could help treat arboviral diseases.

Comparative effects of microvascular and macrovascular disease on the risk of major outcomes in patients with type 2 diabetes

Abstract: Microvascular disease is associated with a high risk of macrovascular events in patients with type 2 diabetes, but the impact of macrovascular disease on the risk of microvascular events remains unknown. We sought to evaluate the respective effects of prior microvascular and macrovascular disease on the risk of major outcomes, including microvascular events, in these patients. Participants in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial (n = 11,140) and the ADVANCE-ON post-trial study (n = 8494) were categorized into 4 groups at baseline: dual absence of microvascular or macrovascular disease (n = 6789), presence of microvascular disease alone (n = 761), macrovascular disease alone (n = 3196), and both (n = 394). Outcomes were all-cause mortality, major macrovascular events (MACE), and major clinical microvascular events. All-cause mortality, MACE, and major clinical microvascular events occurred in 2265 (20%), 2166 (19%), and 807 (7%) participants respectively, during a median follow-up of 9.9 (inter-quartile interval 5.6–10.9) years. The adjusted hazard ratios [95% CI] of death, MACE, and major clinical microvascular events were each greater in patients with baseline microvascular disease (1.43 [1.20–1.71], 1.64 [1.37–1.97], and 4.74 [3.86–5.82], respectively), macrovascular disease (1.43 [1.30–1.57], 2.04 [1.86–2.25], and 1.26 [1.06–1.51]) or both (2.01 [1.65–2.45], 2.92 [2.40–3.55], and 6.30 [4.93–8.06]) compared with those without these conditions. No interaction was observed between baseline microvascular and macrovascular disease for these events. The addition of microvascular disease (change in c-statistic [95% CI] 0.005 [0.002–0.008], p = 0.02) or macrovascular disease (0.005 [0.002–0.007], p < 0.0001) considered separately or together (0.011 [0.007–0.014], p < 0.0001) improved the discrimination and the classification (integrated discrimination improvement (IDI): 0.013 [0.010–0.016], p < 0.001; net reclassification improvement (NRI): 0.021 [0.011–0.032], p < 0.001) of the risk of all-cause mortality. Microvascular disease improved discrimination (0.009 [0.003–0.014]) and classification (IDI: 0.008 [0.006–0.010]; NRI: 0.011 [0.001–0.020]) of MACE. Baseline macrovascular disease modestly enhanced IDI (0.002 [0.001–0.002]) and NRI (0.041 [0.002–0.087]), but not discrimination, of major clinical microvascular events. Microvascular and macrovascular disease are independently associated with the 10-year risk of death, MACE, and major clinical microvascular events in patients with type 2 diabetes. The coexistence of these conditions was associated with the highest risks.

The behavior of iron and zinc stable isotopes accompanying the subduction of mafic oceanic crust: A case study from Western Alpine ophiolites

Abstract: Arc lavas display elevated Fe3+/ΣFe ratios relative to MORB. One mechanism to explain this is the mobilization and transfer of oxidized or oxidizing components from the subducting slab to the mantle wedge. Here we use iron and zinc isotopes, which are fractionated upon complexation by sulfide, chloride, and carbonate ligands, to remark on the chemistry and oxidation state of fluids released during prograde metamorphism of subducted oceanic crust. We present data for metagabbros and metabasalts from the Chenaillet massif, Queyras complex, and the Zermatt-Saas ophiolite (Western European Alps), which have been metamorphosed at typical subduction zone P-T conditions and preserve their prograde metamorphic history. There is no systematic, detectable fractionation of either Fe or Zn isotopes across metamorphic facies, rather the isotope composition of the eclogites overlaps with published data for MORB. The lack of resolvable Fe isotope fractionation with increasing prograde metamorphism likely reflects the mass balance of the system, and in this scenario Fe mobility is not traceable with Fe isotopes. Given that Zn isotopes are fractionated by S-bearing and C-bearing fluids, this suggests that relatively small amounts of Zn are mobilized from the mafic lithologies in within these types of dehydration fluids. Conversely, metagabbros from the Queyras that are in proximity to metasediments display a significant Fe isotope fractionation. The covariation of δ56Fe of these samples with selected fluid mobile elements suggests the infiltration of sediment derived fluids with an isotopically light signature during subduction.

The impact of racial discrimination on the health of Australian Indigenous children aged 5-10 years: analysis of national longitudinal data.

Abstract: A growing body of literature highlights that racial discrimination has negative impacts on child health, although most studies have been limited to an examination of direct forms of racism using cross-sectional data. We aim to provide further insights on the impact of early exposure to racism on child health using longitudinal data among Indigenous children in Australia and multiple indicators of racial discrimination. We used data on 1239 Indigenous children aged 5–10 years from Waves 1–6 (2008–2013) of Footprints in Time, a longitudinal study of Indigenous children across Australia. We examined associations between three dimensions of carer-reported racial discrimination (measuring the direct experiences of children and vicarious exposure by their primary carer and family) and a range of physical and mental health outcomes. Analysis was conducted using multivariate logistic regression within a multilevel framework. Two-fifths (40%) of primary carers, 45% of families and 14% of Indigenous children aged 5–10 years were reported to have experienced racial discrimination at some point in time, with 28–40% of these experiencing it persistently (reported at multiple time points). Primary carer and child experiences of racial discrimination were each associated with poor child mental health status (high risk of clinically significant emotional or behavioural difficulties), sleep difficulties, obesity and asthma, but not with child general health or injury. Children exposed to persistent vicarious racial discrimination were more likely to have sleep difficulties and asthma in multivariate models than those with a time-limited exposure. The findings indicate that direct and persistent vicarious racial discrimination are detrimental to the physical and mental health of Indigenous children in Australia, and suggest that prolonged and more frequent exposure to racial discrimination that starts in the early lifecourse can impact on multiple domains of health in later life. Tackling and reducing racism should be an integral part of policy and intervention aimed at improving the health of Australian Indigenous children and thereby reducing health disparities between Indigenous and non-Indigenous children.

Grain Yield and Nitrogen Accumulation in Maize Hybrids Released during 1934 to 2013 in the US Midwest

Abstract: Nitrogen (N) application in maize (Zea mays L.) reached a maximum of 145 kg N ha(-1) in the US Midwest in 1975. Grain yield has continued to increase at a rate of 111 kg ha(-1) yr(-1), implying an improvement in N efficiency. Our objective was to measure the rate of genetic gain and the traits that contributed to the observed N efficiency for a set of DuPont Pioneer hybrids released between the era decades (ERA) of 1934 to 2013. These hybrids represent the most widely sold hybrids (by volume) in each ERA. A randomized complete block experiment in a split-plot arrangement was conducted at Sciota, IL, and Marion, IA, during 2013 and 2014, with plant densities of 39,500 and 79,000 plants ha(-1) as the whole plot, respectively, and 47 ERA hybrids as the split plot. This experiment was grown in a low-N (56 kg N ha(-1)) block and in a high-N (> 200 kg N ha(-1)) block at each location. Grain yield increased at an average rate of 109 kg ha(-1) yr(-1) from 1934 to 2013. Partial factor productivity increased from 13.8 in 1934 to 55 kg grain kg applied N-1 in 2013 under high-N conditions and 79,000 plants ha(-1). Traits associated with yield improvement without increasing N application were (i) greater synchrony in floral development, (ii) reduced concentration of grain N, (iii) increased specific leaf nitrogen, (iv) increased kernel number per ear (KPE), and (v) increased kernel mass. Breeding efforts that select for increased KPE under increased plant density should increase yield, and this yield increase could partially be supported through greater postanthesis N remobilization from vegetative tissue without requiring greater N application.

Resveratrol inhibits growth of experimental abdominal aortic aneurysm associated with upregulation of angiotensin-converting enzyme 2

Abstract: Objective— Recent evidence suggests an important role for angiotensin-converting enzyme 2 (ACE2) in limiting abdominal aortic aneurysm (AAA) This study examined the effect of ACE2 deficiency on AAA development and the efficacy of resveratrol to upregulate ACE2 in experimental AAA Approach and Results— Ace2 deletion in apolipoprotein-deficient mice ( ApoE −/ − Ace2 −/y ) resulted in increased aortic diameter and spontaneous aneurysm of the suprarenal aorta associated with increased expression of inflammation and proteolytic enzyme markers In humans, serum ACE2 activity was negatively associated with AAA diagnosis ACE2 expression was lower in infrarenal biopsies of patients with AAA than organ donors AAA was more severe in ApoE −/− Ace2 −/y mice compared with controls in 2 experimental models Resveratrol (005/100-g chow) inhibited growth of pre-established AAAs in ApoE −/− mice fed high-fat chow and infused with angiotensin II continuously for 56 days Reduced suprarenal aorta dilatation in mice receiving resveratrol was associated with elevated serum ACE2 and increased suprarenal aorta tissue levels of ACE2 and sirtuin 1 activity In addition, the relative phosphorylation of Akt and ERK (extracellular signal-regulated kinase) 1/2 within suprarenal aorta tissue and gene expression for nuclear factor of kappa light polypeptide gene enhancer in B cells 1, angiotensin type-1 receptor, and metallopeptidase 2 and 9 were significantly reduced Upregulation of ACE2 in human aortic smooth muscle cells by resveratrol in vitro was sirtuin 1-dependent Conclusions— This study provides experimental evidence of an important role for ACE2 in limiting AAA development and growth Resveratrol upregulated ACE2 and inhibited AAA growth in a mouse model

Carbonate alteration of ophiolitic rocks in the Arabian–Nubian Shield of Egypt: sources and compositions of the carbonating fluid and implications for the formation of Au deposits

Abstract: Ultramafic portions of ophiolitic fragments in the Arabian–Nubian Shield (ANS) show pervasive carbonate alteration forming various degrees of carbonated serpentinites and listvenitic rocks. Notwithstanding the extent of the alteration, little is known about the processes that caused it, the source of the CO2 or the conditions of alteration. This study investigates the mineralogy, stable (O, C) and radiogenic (Sr) isotope composition, and geochemistry of suites of variably carbonate altered ultramafics from the Meatiq area of the Central Eastern Desert (CED) of Egypt. The samples investigated include least-altered lizardite (Lz) serpentinites, antigorite (Atg) serpentinites and listvenitic rocks with associated carbonate and quartz veins. The C, O and Sr isotopes of the vein samples cluster between −8.1‰ and −6.8‰ for δ13C, +6.4‰ and +10.5‰ for δ18O, and 87Sr/86Sr of 0.7028–0.70344, and plot within the depleted mantle compositional field. The serpentinites isotopic compositions plot on a mixing trend between the depleted-mantle and sedimentary carbonate fields. The carbonate veins contain abundant carbonic (CO2±CH4±N2) and aqueous-carbonic (H2O-NaCl-CO2±CH4±N2) low salinity fluid, with trapping conditions of 270–300°C and 0.7–1.1 kbar. The serpentinites are enriched in Au, As, S and other fluid-mobile elements relative to primitive and depleted mantle. The extensively carbonated Atg-serpentinites contain significantly lower concentrations of these elements than the Lz-serpentinites suggesting that they were depleted during carbonate alteration. Fluid inclusion and stable isotope compositions of Au deposits in the CED are similar to those from the carbonate veins investigated in the study and we suggest that carbonation of ANS ophiolitic rocks due to influx of mantle-derived CO2-bearing fluids caused break down of Au-bearing minerals such as pentlandite, releasing Au and S to the hydrothermal fluids that later formed the Au-deposits. This is the first time that gold has been observed to be remobilized from rocks during the lizardite–antigorite transition.

Structure-Activity and -Toxicity Relationships of the Antimicrobial Peptide Tachyplesin-1.

Abstract: Tachyplesin-1 (TP1; 1) is a cationic β-hairpin antimicrobial peptide with a membranolytic mechanism of action. While it possesses broad-spectrum, potent antimicrobial activity, 1 is highly hemolytic against mammalian erythrocytes, which precludes it from further development. In this study, we report a template-based approach to investigate the structure–function and structure–toxicity relationships of each amino acid of 1. We modulated charge and hydrophobicity by residue modification and truncation of the peptide. Antimicrobial activity was then assessed against six key bacterial pathogens and two fungi, with toxicity profiled against mammalian cells. The internal disulfide bridge Cys7-Cys12 of 1 was shown to play an important role in broad-spectrum antimicrobial activity against all pathogenic strains tested. Novel peptides based on the progenitor were then designed, including 5 (TP1[F4A]), 12 (TP1[I11A]), and 19 (TP1[C3A,C16A]). These had 26- to 64-fold improved activity/toxicity indices and show promi...

A randomised controlled trial of an iPad-based application to complement early behavioural intervention in Autism Spectrum Disorder.

Abstract: Background Technology-based interventions for Autism Spectrum Disorder (ASD) have proliferated, but few have been evaluated within the context of a randomised controlled trial (RCT). This RCT evaluated the efficacy of one technology-based early intervention programme (Therapy Outcomes By You; TOBY) in young children with ASD. Methods TOBY is an app-based learning curriculum designed for children and parents as a complement to early behavioural intervention. Eighty children (16 female) were recruited to this RCT within 12 months of receiving a diagnosis of ASD (M age = 3.38; SD = 0.69) and randomised to receive either treatment-as-usual (community-based intervention, n = 39) or the TOBY therapy (at least 20 min/day) plus treatment-as-usual (n = 41) for a period of 6 months. Outcomes were assessed at 3 and 6 months postbaseline. (Australian New Zealand Clinical Trials Registry: ACTRN12614000738628; www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365463). Results Children in the TOBY intervention group averaged 19 min/day engaging with the app in the first 3 months, but only 2 min/day during the second 3 months. There was no group difference in scores on the primary outcome, the Autism Treatment Evaluation Checklist, at either the 3- or 6-month follow-up. However, significant improvements at the 6-month follow-up were observed in the TOBY intervention group relative to the treatment-as-usual group on three secondary outcomes: the Fine Motor and Visual Reception subscales of the Mullen Scale of Early Learning and the Total Words Understood scale of the MacArthur-Bates Communicative Development Index. Statistical trends towards improvement in the TOBY intervention group were observed on measures of adaptive function, although these decreased in magnitude from the 3- to 6-month follow-up. Conclusions This study provides evidence that technology-based interventions may provide a relatively low-cost addition to existing therapist-delivered interventions for children with ASD. However, sustained use of the app over the full 6-month period was a challenge for most families.

Stability of dissolved and soluble Fe(II) in shelf sediment pore waters and release to an oxic water column.

Abstract: Shelf sediments underlying temperate and oxic waters of the Celtic Sea (NW European Shelf) were found to have shallow oxygen penetrations depths from late spring to late summer (2.2 to 5.8 mm below seafloor) with the shallowest during/after the spring-bloom (mid-April to mid-May) when the organic carbon content was highest. Sediment porewater dissolved iron (dFe, 85 %) consisted of reduced Fe(II) and gradually increased from 0.4 to 15 μM at the sediment surface to ~100 to 170 μM at about 6 cm depth. During the late spring this Fe(II) was found to be mainly present as soluble Fe(II) (> 85 % sFe, 7 hours. Iron(II) oxidation experiments in core top and bottom waters also showed removal from solution but at rates up to 5-times slower than predicted from theoretical reaction kinetics. These data imply the presence of ligands capable of complexing Fe(II) and supressing oxidation rates. The lower oxidation rate allows more time for the diffusion of Fe(II) from the sediments into the overlying water column. Modelling indicates significant diffusive fluxes of Fe(II) (on the order of 23-31 μmol m-2 d-1) are possible during late spring when oxygen penetration depths are shallow, and pore water Fe(II) concentrations are highest. In the water column this stabilised Fe(II) will gradually be oxidised and become part of the dFe(III) pool. Thus oxic continental shelves can supply dFe to the water column, which is enhanced during a small period of the year after phytoplankton bloom events when organic matter is transferred to the seafloor. This input is based on conservative assumptions for solute exchange (diffusionreaction), whereas (bio)physical advection and resuspension events are likely to accelerate these solute exchanges in shelf-seas.

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

Abstract: Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.

NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction.

Abstract: The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.

The impact of racial discrimination on the health of Australian Indigenous children aged 5-10 years: analysis of national longitudinal data

Abstract: [Background:] A growing body of literature highlights that racial discrimination has negative impacts on child health, although most studies have been limited to an examination of direct forms of racism using cross-sectional data. We aim to provide further insights on the impact of early exposure to racism on child health using longitudinal data among Indigenous children in Australia and multiple indicators of racial discrimination. [Methods:] We used data on 1239 Indigenous children aged 5–10 years from Waves 1–6 (2008–2013) of Footprints in Time, a longitudinal study of Indigenous children across Australia. We examined associations between three dimensions of carer-reported racial discrimination (measuring the direct experiences of children and vicarious exposure by their primary carer and family) and a range of physical and mental health outcomes. Analysis was conducted using multivariate logistic regression within a multilevel framework. [Results:] Two-fifths (40%) of primary carers, 45% of families and 14% of Indigenous children aged 5–10 years were reported to have experienced racial discrimination at some point in time, with 28–40% of these experiencing it persistently (reported at multiple time points). Primary carer and child experiences of racial discrimination were each associated with poor child mental health status (high risk of clinically significant emotional or behavioural difficulties), sleep difficulties, obesity and asthma, but not with child general health or injury. Children exposed to persistent vicarious racial discrimination were more likely to have sleep difficulties and asthma in multivariate models than those with a time-limited exposure. [Conclusions:] The findings indicate that direct and persistent vicarious racial discrimination are detrimental to the physical and mental health of Indigenous children in Australia, and suggest that prolonged and more frequent exposure to racial discrimination that starts in the early lifecourse can impact on multiple domains of health in later life. Tackling and reducing racism should be an integral part of policy and intervention aimed at improving the health of Australian Indigenous children and thereby reducing health disparities between Indigenous and non-Indigenous children.

Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress.

Abstract: Aging is commonly associated with chronic low-grade inflammation and hypertension but it is unknown whether a cause-effect relationship exists between them. We compared the sensitivity of young adult (8-12 w) and aged (23-31 mo) male C57Bl6J mice to develop hypertension in response to a slow-pressor dose of angiotensin II (Ang II; 0.28 mg/kg/d; 28 d). In young mice, the pressor response to Ang II was gradual and increased to 142±8 mmHg over 28 d. However, in aged mice, Ang II promptly increased SBP and reached 155±12 mmHg by 28 d. Aging increased renal but not brain expression of Ang II receptors (At1ar and At2r) and elevated AT1R:AT2R expression ratio in mesenteric artery. Maximal contractile responses of mesenteric arteries to Ang II were enhanced in aged mice and were not affected by L-NAME, indomethacin or tempol. Mesenteric arteries and thoracic aortae from aged mice exhibited higher Nox2-dependent superoxide production. Despite having higher renal expression of Nlrp3, Casp-1 and Il-1β, Ang II-induced hypertension (SBP: 139±7 mmHg) was unaffected by co-infusion of the NLRP3 inflammasome inhibitor, MCC950 (10 mg/kg/d; SBP: 145±10 mmHg). Thus, increased vascular AT1R:AT2R expression, rather than NLRP3 inflammasome activation, may contribute to enhanced responses to Ang II in aging.