Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations.

Despite the success of genome-wide association studies (GWASs) in identifying genetic variants associated with complex traits, understanding the mechanisms behind these statistical associations remains challenging. Several methods that integrate methylation, gene expression, and protein quantitative trait loci (QTLs) with GWAS data to determine their causal role in the path from genotype to phenotype have been proposed. Here, we developed and applied a multi-omics Mendelian randomization (MR) framework to study how metabolites mediate the effect of gene expression on complex traits. We identified 216 transcript-metabolite-trait causal triplets involving 26 medically relevant phenotypes. Among these associations, 58% were missed by classical transcriptome-wide MR, which only uses gene expression and GWAS data. This allowed the identification of biologically relevant pathways, such as between ANKH and calcium levels mediated by citrate levels and SLC6A12 and serum creatinine through modulation of the levels of the renal osmolyte betaine. We show that the signals missed by transcriptome-wide MR are found, thanks to the increase in power conferred by integrating multiple omics layer. Simulation analyses show that with larger molecular QTL studies and in case of mediated effects, our multi-omics MR framework outperforms classical MR approaches designed to detect causal relationships between single molecular traits and complex phenotypes

Service user, carer and provider perspectives on integrated care for older people with frailty, and factors perceived to facilitate and hinder implementation: A systematic review and narrative synthesis

© 2019 Sadler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Older people with frailty (OPF) can experience reduced quality of care and adverse outcomes due to poorly coordinated and fragmented care, making this patient population a key target group for integrated care. This systematic review explores service user, carer and provider perspectives on integrated care for OPF, and factors perceived to facilitate and hinder implementation, to draw out implications for policy, practice and research. Methods Systematic review and narrative synthesis of qualitative studies identified from MEDLINE, CINAHL, PsycINFO and Social Sciences Citation Index, hand-searching of reference lists and citation tracking of included studies, and review of experts’ online profiles. Quality of included studies was appraised with The Critical Appraisal Skills Programme tool for qualitative research. Results Eighteen studies were included in the synthesis. We identified four themes related to stakeholder perspectives on integrated care for OPF: different preferences for integrated care among service users, system and service organisation components, relational aspects of care and support, and stakeholder perceptions of outcomes. Service users and carers highlighted continuity of care with a professional they could trust, whereas providers emphasised improved coordination of care between providers in different care sectors as key strategies for integrated care. We identified three themes related to factors facilitating and hindering implementation: perceptions of the integrated care intervention and target population, service organisational factors and system level factors influencing implementation. Different stakeholder groups perceived the complexity of care needs of this patient population, difficulties with system navigation and access, and limited service user and carer involvement in care decisions as key factors hindering implementation. Providers mainly also highlighted other organisational and system factors perceived to facilitate and hinder implementation of integrated care for OPF

Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease.

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10 <sup>-10</sup> ) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10 <sup>-6</sup> ). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling

Dusty Nuclear Disks and Filaments in Early Type Galaxies

We examine the dust properties of a nearby distance-limited sample of early type galaxies using the WFPC2 of the Hubble Space Telescope. Dust is detected in 29 out of 67 galaxies (43%), including 12 with small nuclear dusty disks. In a separate sample of 40 galaxies biased for the detection of dust by virtue of their detection in the IRAS 100 micron band, dust is found in ~78% of the galaxies, 15 of which contain dusty disks. In those galaxies with detectable dust, the apparent mass of the dust correlates with radio and far infrared luminosity, becoming more significant for systems with filamentary dust. A majority of IRAS and radio detections are also associated with dusty galaxies rather than dustless galaxies. This indicates that thermal emission from clumpy, filamentary dust is the main source of the far-IR radiation in early type galaxies. Dust in small disk-like morphology tends to be well aligned with the major axis of the host galaxies, while filamentary dust appears to be more randomly distributed with no preference for alignment with any major galactic structure. This suggests that, if the dusty disks and filaments have a common origin, the dust originates externally and requires time to dynamically relax and settle in the galaxy potential in the form of compact disks. More galaxies with visible dust than without dust display emission lines, indicative of ionized gas, although such nuclear activity does not show a preference for dusty disk over filamentary dust. There appears to be a weak relationship between the mass of the dusty disks and central velocity dispersion of the galaxy, suggesting a connection with a similar recently recognized relationship between the latter and the black hole mass.Comment: 17 pages, including 10 figures & 7 tables, to be published in the Astronomical Journa

An ASKAP Search for a Radio Counterpart to the First High-significance Neutron Star-Black Hole Merger LIGO/Virgo S190814bv

We present results from a search for a radio transient associated with the LIGO/Virgo source S190814bv, a likely neutron star-black hole (NSBH) merger, with the Australian Square Kilometre Array Pathfinder. We imaged a 30 deg2 field at ΔT = 2, 9, and 33 days post-merger at a frequency of 944 MHz, comparing them to reference images from the Rapid ASKAP Continuum Survey observed 110 days prior to the event. Each epoch of our observations covers 89% of the LIGO/Virgo localization region. We conducted an untargeted search for radio transients in this field, resulting in 21 candidates. For one of these, AT2019osy, we performed multiwavelength follow-up and ultimately ruled out the association with S190814bv. All other candidates are likely unrelated variables, but we cannot conclusively rule them out. We discuss our results in the context of model predictions for radio emission from NSBH mergers and place constrains on the circum-merger density and inclination angle of the merger. This survey is simultaneously the first large-scale radio follow-up of an NSBH merger, and the most sensitive widefield radio transients search to-date

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

Measurement of Angular Distributions of Drell-Yan Dimuons in p + d Interaction at 800 GeV/c

We report a measurement of the angular distributions of Drell-Yan dimuons produced using an 800 GeV/c proton beam on a deuterium target. The muon angular distributions in polar angle $\theta$ and azimuthal angle $\phi$ have been measured over the kinematic range $4.5 < m_{\mu \mu} < 15$ GeV/c$^2$, $0 < p_T < 4$ GeV/c, and $0 < x_F < 0.8$. No significant cos$2\phi$ dependence is found in these proton-induced Drell-Yan data, in contrast to the situation for pion-induced Drell-Yan. The data are compared with expectations from models which attribute the cos$2\phi$ distribution to a QCD vacuum effect or to the presence of the transverse-momentum-dependent Boer-Mulders structure function $h_1^\perp$. Constraints on the magnitude of the sea-quark $h_1^\perp$ structure functions are obtained.Comment: 4 pages, 3 figure

Intracellular interferons in fish : a unique means to combat viral infection

Peer reviewedPublisher PD

Radio-Excess IRAS Galaxies: PMN/FSC Sample Selection

A sample of 178 extragalactic objects is defined by correlating the 60 micron IRAS FSC with the 5 GHz PMN catalog. Of these, 98 objects lie above the radio/far-infrared relation for radio-quiet objects. These radio-excess galaxies and quasars have a uniform distribution of radio excesses and appear to be a new population of active galaxies not present in previous radio/far-infrared samples. The radio-excess objects extend over the full range of far-infrared luminosities seen in extragalactic objects. Objects with small radio excesses are more likely to have far-infrared colors similar to starbursts, while objects with large radio excesses have far-infrared colors typical of pure AGN. Some of the most far-infrared luminous radio-excess objects have the highest far-infrared optical depths. These are good candidates to search for hidden broad line regions in polarized light or via near-infrared spectroscopy. Some low far-infrared luminosity radio-excess objects appear to derive a dominant fraction of their far-infrared emission from star formation, despite the dominance of the AGN at radio wavelengths. Many of the radio-excess objects have sizes likely to be smaller than the optical host, but show optically thin radio emission. We draw parallels between these objects and high radio luminosity Compact Steep-Spectrum (CSS) and GigaHertz Peaked-Spectrum (GPS) objects. Radio sources with these characteristics may be young AGN in which the radio activity has begun only recently. Alternatively, high central densities in the host galaxies may be confining the radio sources to compact sizes. We discuss future observations required to distinguish between these possibilities and determine the nature of radio-excess objects.Comment: Submitted to AJ. 44 pages, 11 figures. A version of the paper with higher quality figures is available from http://www.mso.anu.edu.au/~cdrake/PMNFSC/paperI

Improved catalytic activity of ruthenium–arene complexes in the reduction of NAD+

A series of neutral Ru-II half-sandwich complexes of the type [(eta(6)-arene)Ru(N,N')Cl] where the arene is para-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), or benzene (bn) and N,N' is N-(2-aminoethyl) -4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-4-toluenesulfonamide (TsEn), or N-(2-aminoethyl)-methylenesulfonamide (MsEn) were synthesized and characterized. X-ray crystal structures of [(p-cym)Ru(MsEn)Cl] (1), [(hmb)Ru(TsEn)Cl] (5), [(hmb)Ru(TfEn)Cl] (6), [(bip)Ru(MsEn)Cl] (7), and [(bip)Ru(TsEn)Cl] (8) have been determined. The complexes can regioselectively catalyze the transfer hydrogenation of NAD(+) to give 1,4-NADH in the presence of formate. The turnover frequencies (TOF) when the arene is varied decrease in the order bn > bip > p-cym > hmb for complexes with the same N,N' chelating ligand. The TOF decreased with variation in the N,N' chelating ligand in the order TfEn > TsEn > MsEn for a given arene. [(bn)Ru(TfEn)Cl] (12) was the most active, with a TOP of 10.4 h(-1). The effects of NAD(+) and formate concentration on the reaction rates were determined for [(p-cym)Ru(TsEn)Cl] (2). Isotope studies implicated the formation of [(arene)Ru(N,N')(H)] as the rate-limiting step. The coordination of formate and subsequent CO2 elimination to generate the hydride were modeled computationally by density functional theory (DFT). CO2 elimination occurs via a two-step process with the coordinated formate first twisting to present its hydrogen toward the metal center. The computed barriers for CO2 release for arene = benzene follow the order MsEn > TsEn > TfEn, and for the Ms En system the barrier followed bn < hmb, both consistent with the observed rates. The effect of methanol on transfer hydrogenation rates in aqueous solution was investigated. A study of pH dependence of the reaction in D2O gave the optimum pH* as 7.2 with a TOF of 1.58 h(-1) for 2. The series of compounds reported here show an improvement in the catalytic activity by an order of magnitude compared to the ethylenediamine analogues