Exosome membrane bound TNF-receptor for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that causes painful inflammation of the synovium of the patient’s joints. However, current treatments for RA have a variety of drawbacks. They often are ineffective, expensive, invasive, risky, cause an immune response, and/ or only provide short term relief. Thus, we developed a new treatment for preventing inflammation: TNF-receptors anchored onto exosome surfaces. Exosomes are nanovesicles that are naturally secreted by most of the cells in our bodies. The many benefits of using exosomes include non-immunogenicity, natural stability in the body, and non-invasiveness. We have demonstrated that exosome membrane bound TNF-receptors have the ability to prevent inflammation in mammalian cells. The success of this project could lead to a clinically effective treatment of rheumatoid arthritis as well as other inflammatory diseases by opening the doors to further research and development of exosomal therapies

A Novel Genetic Circuit Supports Laboratory Automation and High Throughput Monitoring of Inflammation in Living Human Cells

Genetically encoded reporter circuits have been revolutionizing our ability to monitor, manipulate, and visualize specific cellular responses to a variety of environmental stimuli. However, the development of genetic circuits that enable both high throughput (HTP) application and laboratory automation remains challenging. In this report, we describe a novel dual-reporter circuit that utilizes a secretory Gaussia luciferase (Gluc) and a green fluorescent protein (GFP) for monitoring inflammatory signaling, a fundamental process in many life events. We designed and built this genetic circuit into a simple adeno-associated viral (AAV) vector, which is suitable for both simple transfection and efficient transduction protocols. We demonstrated high sensitivity and specificity of this new circuit and its ability to monitor a broad range of inflammatory response in various human cell models. Importantly, this novel system is simple, robust, and readily adaptable to HTP applications and laboratory automation including fluorescence activated cell sorting (FACS) and microplate reader analysis. By combining both GFP and Gluc in one genetic circuit, our new dual-reporter circuit provides an easy and powerful tool for monitoring and quantifying inflammatory signals in various mammalian cells

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P \u3c 1 × 10−3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases

Scary Barbie: An Extremely Energetic, Long-Duration Tidal Disruption Event Candidate Without a Detected Host Galaxy at z = 0.995

We report multi-wavelength observations and characterization of the ultraluminous transient AT 2021lwx (ZTF20abrbeie; aka ``Barbie'') identified in the alert stream of the Zwicky Transient Facility (ZTF) using a Recommender Engine For Intelligent Transient Tracking (REFITT) filter on the ANTARES alert broker. From a spectroscopically measured redshift of 0.995, we estimate a peak observed pseudo-bolometric luminosity of log (L$_{\text{max}} / [\text{erg}/\text{s}]$) = 45.7 from slowly fading ztf-$\it{g}$ and ztf-$r$ light curves spanning over 1000 observer-frame days. The host galaxy is not detected in archival Pan-STARRS observations ($g > 23.3$ mag), implying a lower limit to the outburst amplitude of more than 5 mag relative to the quiescent host galaxy. Optical spectra from Lick and Keck Observatories exhibit strong emission lines with narrow cores from the H Balmer series and ultraviolet semi-forbidden lines of Si III] $\lambda$1892, C III] $\lambda$1909, and C II] $\lambda$2325. Typical nebular lines in AGN spectra from ions such as [O II] and [O III] are not detected. These spectral features, along with the smooth light curve that is unlike most AGN flaring activity, and the luminosity that exceeds any observed or theorized supernova, lead us to conclude that AT 2021lwx is most likely an extreme tidal disruption event (TDE). Modeling of ZTF photometry with MOSFiT suggests that the TDE was between a $\approx 14 M_{\odot}$ star and a supermassive black hole of mass $M_{\text{BH}} \sim$ $10^{8} M_{\odot}$. Continued monitoring of the still-evolving light curve along with deep imaging of the field once AT 2021lwx has faded can test this hypothesis and potentially detect the host galaxy.Comment: 15 pages, 4 figures, 1 Table; Version as published in The Astrophysical Journal Letters. Observations of AT 2021lwx published in the paper can be found at https://bsubraya.github.io/research

APOE ε2 resilience for Alzheimer’s disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Introduction The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer\u27s disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer\u27s Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer\u27s disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer\u27s disease and as such represent a potential therapeutic target

The GALAH Survey: Using galactic archaeology to refine our knowledge of TESS target stars

An unprecedented number of exoplanets are being discovered by the Transiting Exoplanet Survey Satellite (TESS). Determining the orbital parameters of these exoplanets, and especially their mass and radius, will depend heavily upon the measured physical characteristics of their host stars. We have cross-matched spectroscopic, photometric, and astrometric data from GALAH Data Release 2, the TESS Input Catalog and Gaia Data Release 2, to create a curated, self-consistent catalogue of physical and chemical properties for 47 285 stars. Using these data, we have derived isochrone masses and radii that are precise to within 5 per cent. We have revised the parameters of three confirmed, and twelve candidate, TESS planetary systems. These results cast doubt on whether CTOI-20125677 is indeed a planetary system, since the revised planetary radii are now comparable to stellar sizes. Our GALAH-TESS catalogue contains abundances for up to 23 elements. We have specifically analysed the molar ratios for C/O, Mg/Si, Fe/Si, and Fe/Mg, to assist in determining the composition and structure of planets with Rp < 4R⊕. From these ratios, 36 per cent fall within 2$\sigma$ sigma of the Sun/Earth values, suggesting that these stars may host rocky exoplanets with geological compositions similar to planets found within our own Solar system.JTC would like to thank SW, BC, and DN, and is supported by the Australian Government Research Training Program (RTP) Scholarship. JTC would also like to thank Vardan Adibekyan for their valuable comments which have significantly improved the science of this manuscript. JDS and SM acknowledges the support of the Australian Research Council through Discovery Project grant DP180101791. SB acknowledges funds from the Australian Research Council (grants DP150100250 and DP160103747). Parts of this research were supported by the Australian Research Council (ARC) Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D), through project number CE170100013. YST is grateful to be supported by the NASA Hubble Fellowship grant HSTHF2-51425.001 awarded by the Space Telescope Science Institute

Asian Pacific Society of Cardiology Consensus Statements on the Diagnosis and Management of Obstructive Sleep Apnoea in Patients with Cardiovascular Disease

Obstructive sleep apnoea (OSA) is strongly associated with cardiovascular disease (CVD). However, evidence supporting this association in the Asian population is scarce. Given the differences in the epidemiology of CVD and cardiovascular risk factors, as well as differences in the availability of healthcare resources between Asian and Western countries, an Asian Pacific Society of Cardiology (APSC) working group developed consensus recommendations on the management of OSA in patients with CVD in the Asia-Pacific region. The APSC expert panel reviewed and appraised the available evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed and put to an online vote. Consensus was reached when 80% of votes for a given recommendation were in support of ‘agree’ or ‘neutral.’ The resulting statements provide guidance on the assessment and treatment of OSA in patients with CVD in the Asia-Pacific region. The APSC hopes for these recommendations to pave the way for screening, early diagnosis and treatment of OSA in the Asia-Pacific region

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼ 456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P \u3c 1 × 10−3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases

Evaluating Natural History and Follow Up Strategies for Non-obstructive Urolithiasis in Pediatric Population

Objective: While small non-obstructive stones in the adult population are usually observed with minimal follow-up, the same guidelines for management in the pediatric population have not been well-studied. We evaluate the clinical outcomes of small non-obstructing kidney stones in the pediatric population to better define the natural history of the disease.Methods: In this IRB-approved retrospective study, patients with a diagnosis of kidney stones from January 2011 to March 2017 were identified using ICD9 and ICD10 codes. Patients with ureteral stones, obstruction, or stones &gt;5 mm in size were excluded. Patients with no follow-up after initial imaging were also excluded. Patients with a history of stones or prior stone interventions were included in our population. Frequency of follow-up ultrasounds while on observation were noted and any ER visits, stone passage episodes, infections, and surgical interventions were documented.Results: Over the 6-year study period, 106 patients with non-obstructing kidney stones were identified. The average age at diagnosis was 12.5 years and the average stone size was 3.6 mm. Average follow-up was 17 months. About half of the patients had spontaneous passage of stones (54/106) at an average time of 13 months after diagnosis. Stone location did not correlate with spontaneous passage rates. Only 6/106 (5.7%) patients required stone surgery with ureteroscopy and/or PCNL at an average time of 12 months after initial diagnosis. The indication for surgery in all 6 cases was pain. 17/106 (16%) patients developed febrile UTIs and a total of 43 ER visits for stone-related issues were noted, but no patients required urgent intervention for an infected obstructing stone. Median interval for follow-up was every 6 months with renal ultrasounds, which then was prolonged to annual follow up in most cases.Conclusions: The observation of pediatric patients with small non-obstructing stones is safe with no episodes of acute obstructive pyelonephritis occurring in these patients. The sole indication for intervention in our patient population was pain, which suggests that routine follow-up ultrasounds may not be necessary for the follow-up of pediatric non-obstructive renal stones ≤5 mm in size