Repurposing Statins for Renal Protection: Is It a Class Effect?

There has been a great deal of excitement regarding the potential benefits of statins beyond their lipid-lowering effect, and repurposing them for other indications. In this commentary, we evaluate the role of statins in protecting the kidneys, with a focus on three areas: cardiac surgery, contrast-induced nephropathy, and aminoglycoside-induced nephrotoxicity

Genomic alterations in primary gastric adenocarcinomas correlate with clinicopathological characteristics and survival.

Background & aimsPathogenesis of gastric cancer is driven by an accumulation of genetic changes that to a large extent occur at the chromosomal level. In order to investigate the patterns of chromosomal aberrations in gastric carcinomas, we performed genome-wide microarray based comparative genomic hybridisation (microarray CGH). With this recently developed technique chromosomal aberrations can be studied with high resolution and sensitivity.MethodsArray CGH was applied to a series of 35 gastric adenocarcinomas using a genome-wide scanning array with 2275 BAC and P1 clones spotted in triplicate. Each clone contains at least one STS for linkage to the sequence of the human genome. These arrays provide an average resolution of 1.4 Mb across the genome. DNA copy number changes were correlated with clinicopathological tumour characteristics as well as survival.ResultsAll thirty-five cancers showed chromosomal aberrations and 16 of the 35 tumours showed one or more amplifications. The most frequent aberrations are gains of 8q24.2, 8q24.1, 20q13.12, 20q13.2, 7p11.2, 1q32.3, 8p23.1-p23.3, losses of 5q14.1, 18q22.1, 19p13.12-p13.3, 9p21.3-p24.3, 17p13.1-p13.3, 13q31.1, 16q22.1, 21q21.3, and amplifications of 7q21-q22, and 12q14.1-q21.1. These aberrations were correlated to clinicopathological characteristics and survival. Gain of 1q32.3 was significantly correlated with lymph node status (p=0.007). Tumours with loss of 18q22.1, as well as tumours with amplifications were associated with poor survival (p=0.02, both).ConclusionsMicroarray CGH has revealed several chromosomal regions that have not been described before in gastric cancer at this frequency and resolution, such as amplification of at 7q21-q22 and 12q14.1-q21.1, as well gains at 1q32.3, 7p11.2, and losses at 13q13.1. Interestingly, gain of 1q32.3 and loss of 18q22.1 are associated with a bad prognosis indicating that these regions could harbour gene(s) that may determine aggressive tumour behaviour and poor clinical outcome

Discovering neutron stars with LISA via measurements of orbital eccentricity in Galactic binaries

LISA will detect $\sim \! 10^4$ Galactic binaries, the majority being double white dwarfs. However, approximately $\sim \! 1 \textrm{--} 5 \%$ of these systems will contain neutron stars which, if they can be correctly identified, will provide new opportunities for studying binary evolution pathways involving mass reversal and supernovae as well as being promising targets for multi-messenger observations. Eccentricity, expected from neutron star natal kicks, will be a key identifying signature for binaries containing a neutron star. Eccentric binaries radiate at widely-spaced frequency harmonics that must first be identified as originating from a single source and then analysed coherently. A multi-harmonic heterodyning approach for this type of data analysis is used to perform Bayesian parameter estimation on a range of simulated eccentric LISA signals. This is used to: (i) investigate LISA's ability to measure orbital eccentricity and to quantify the minimum detectable eccentricity; (ii) demonstrate how eccentricity and periastron precession help to break the mass degeneracy allowing the individual component masses to be inferred, potentially confirming the presence of a neutron star; (iii) investigate the possibility of source misidentification when the individual harmonics of an eccentric binary masquerade as separate circular binaries; and (iv) investigate the possibility of source reclassification, where parameter estimation results of multiple circular analyses are combined in postprocessing to quickly infer the parameters of an eccentric source. The broader implications of this for the ongoing design of the LISA global fit are also discussed.Comment: 10 pages + appendices, 9 figures, submitted to MNRA

Applications of Blockchain for the Governance of Integrated Project Delivery: A Crypto Commons Approach

This paper outlines why and how blockchain can digitally support and evolve the governance of collaborative project deliveries, such as integrated project deliveries (IPDs), to provide the foundation for novel and disruptive forms of organizational collaboration in the construction industry. Previous work has conceptualized IPDs as a common pool resource (CPR) scenario, where shared resources are collectively governed. Through the use of blockchain and smart contracts for trustworthy peer-to-peer transactions and execution logic, Ostrom's design principles can be digitally encoded to scale CPR scenarios. Building on the identified connections, the paper 1) synthesizes fourteen blockchain-based mechanisms to govern CPRs, 2) identifies twenty-two applications of these mechanisms to govern IPDs, and 3) introduces a conceptualization of the above relationships towards a holistic understanding of collaborative project deliveries on the crypto commons for novel collective organization of construction project delivery between both humans and machines

Activation of Flucloxacillin-Specific CD8+ T-Cells With the Potential to Promote Hepatocyte Cytotoxicity in a Mouse Model

There are currently no animal models of drug-induced liver injury (DILI) where the adaptive immune system has been shown to damage the liver. Thus, it is difficult to explore the mechanistic basis of the tissue injury. The aim of this study was to use C57BL/6 CD4+-deficient mice with a mutation in the αβ gene encoding for Major histocompatibilty complex (MHC) class II molecules to (1) develop a mouse model of flucloxacillin sensitization, (2) explore whether drug-specific CD8+ kill primary hepatocytes, and (3) analyze perturbations in liver integrity following oral exposure to flucloxacillin. CD8+ T-cells from lymph nodes of flucloxacillin-sensitized mice were stimulated to proliferate, secrete interferon (IFN-γ) and granzyme B, and induce hepatocyte apoptosis in a concentration-dependent manner following ex vivo stimulation. The T-cell response was antigen-specific; T-cells were not activated with other β-lactam antibiotics. Furthermore, T-cell responses only occurred in the presence of flucloxacillin-pulsed antigen presenting cells. In separate experiments, flucloxacillin-specific T-cells were induced to migrate to the mesenteric lymph nodes using retinoic acid, prior to administration of oral flucloxacillin, and analysis of plasma biomarkers of liver injury. Oral exposure to flucloxacillin resulted in mild elevations in alanine aminotransferase, liver, and gall bladder leukocyte infiltration and a marked swelling of the gall bladder. Thus, CD4+-deficient mice represent a promising model to study the role of the adaptive immune system in DIL

Quantification of Urinary Mevalonic Acid as a Biomarker of HMG-CoA Reductase Activity by a Novel Translational LC-MS/MS Method

Background: Mevalonic acid (MVA), as a product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, represents a potential multipurpose biomarker in health and disease. A translational urinary MVA quantification method was developed, validated and used to demonstrate the diurnal variation of urinary MVA excretion in rats and healthy children. Methods: Urinary MVA was converted to mevalonolactone at pH 2, extracted with ethyl acetate and quantified by reversed-phase liquid chromatography-tandem mass spectrometry. Results: The assay had a dynamic range of 0.0156-10 µg/ml with precision <15% CV, accuracy 85-115% and was transferred between laboratories. Urinary MVA excretion in rats and healthy children displayed a diurnal variation consistent with the known diurnal variation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Conclusion: Urinary MVA can be quantified accurately over a wide dynamic range by a validated translational and transferable method with biomarker capability

The True Identity of Putative Tooth Alveoli in a Cenozoic Crown Bird, the Gastornithid Omorhamphus

All extant birds are toothless, and recent molecular evidence suggests that edentulism in extant birds is the product of a single evolutionary transition to toothlessness on the line to crown birds in the Cretaceous. However, a fossil crown bird premaxilla from the Palaeogene of North America (assigned to the gastornithid Omorhamphus storchii) has been interpreted as bearing alveoli for teeth, an observation that would cast doubt on a single loss of teeth preceding the extant avian radiation. However, the identity of these putative alveoli has never been reinvestigated in detail. Here, we re-examine this problematic juvenile specimen, using non-invasive x-ray microtomography, enabling the assessment of the true identity of the large, alveolus-like pits on the ventral side of this premaxilla. Although superficially alveolus-like, we illustrate that these pits represent openings of large neurovascular canals communicating with both the medullary cavity as well as other canals opening along the dorsal and lateral surfaces of the upper jaw, and that none of these openings appear to represent tooth alveoli. Further, we demonstrate that claims of an adult gastornithid specimen (Gastornis parisiensis) exhibiting tooth alveoli are similarly unfounded. By rejecting the hypothesis of dentition in these gastornithids, we eliminate any lingering uncertainty regarding the persistence of teeth within the avian crown group. We illustrate the presence of similar large vascular openings along the ventral surface of the beak of juvenile Gastornis russelli/parisiensis, and smaller versions in the juvenile premaxillae of Sylviornis neocaledoniae. We suggest that the large vascular canals in gastornithid specimens such as O. storchii are a feature associated with rapid growth of the juvenile beak, allowing the attainment of a large and dorsoventrally deep beak early in ontogeny. This may have enabled young gastornithids to become autonomous early, consistent with a presumably precocial developmental strategy