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Background and objectives: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitialfibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

We present deep 1.4 GHz source counts from $\sim$5 deg$^2$ of the continuum Early Science data release of the MeerKAT International Gigahertz Tiered Extragalactic Exploration (MIGHTEE) survey down to $S_{1.4\textrm{GHz}}\sim$15 $\mu$Jy. Using observations over two extragalactic fields (COSMOS and XMM-LSS), we provide a comprehensive investigation into correcting the incompleteness of the raw source counts within the survey to understand the true underlying source count population. We use a variety of simulations that account for: errors in source detection and characterisation, clustering, and variations in the assumed source model used to simulate sources within the field and characterise source count incompleteness. We present these deep source count distributions and use them to investigate the contribution of extragalactic sources to the sky background temperature at 1.4 GHz using a relatively large sky area. We then use the wealth of ancillary data covering{a subset of the COSMOS field to investigate the specific contributions from both active galactic nuclei (AGN) and star forming galaxies (SFGs) to the source counts and sky background temperature. We find, similar to previous deep studies, that we are unable to reconcile the sky temperature observed by the ARCADE 2 experiment. We show that AGN provide the majority contribution to the sky temperature contribution from radio sources, but the relative contribution of SFGs rises sharply below 1 mJy, reaching an approximate 15-25% contribution to the total sky background temperature ($T_b\sim$100 mK) at $\sim$15 $\mu$Jy., Comment: 24 pages, 12 figures; Accepted for publication in MNRAS

Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and −0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = −0.83 and −0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = −0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = −0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

We present the evolution of the star formation dispersion–stellar mass relation (σSFR–M⋆) in the DEVILS D10 region using new measurements derived using thePROSPECTspectral energy distribution fitting code. We find that σSFR–M⋆shows the characteristic ‘U-shape’ at intermediate stellar masses from 0.1 z< 0.7 for a number of metrics, including using the deconvolved intrinsic dispersion. A physical interpretation of this relation is the combination of stochastic star formation and stellar feedback causing large scatter at low stellar masses and AGN feedback causing asymmetric scatter at high stellar masses. As such, the shape of this distribution and its evolution encodes detailed information about the astrophysical processes affecting star formation, feedback and the lifecycle of galaxies. We find that the stellar mass that the minimum σSFRoccurs evolves linearly with redshift, moving to higher stellar masses with increasing lookback time and traces the turnover in the star-forming sequence. This minimum σSFRpoint is also found to occur at a fixed specific star formation rate (sSFR) at all epochs (sSFR ∼ 10−9.6 Gyr−1). The physical interpretation of this is that there exists a maximum sSFR at which galaxies can internally self-regulate on the tight sequence of star formation. At higher sSFRs, stochastic stellar processes begin to cause galaxies to be pushed both above and below the star-forming sequence leading to increased SFR dispersion. As the Universe evolves, a higher fraction of galaxies will drop below this sSFR threshold, causing the dispersion of the low stellar mass end of the star-forming sequence to decrease with time.

We present the first measurements of HI galaxy scaling relations from a blind survey at $z>0.15$. We perform spectral stacking of 9023 spectra of star-forming galaxies undetected in HI at $0.23, Comment: 12 pages, 5 figures. Accepted for publication in ApJ Letters on 30 July 2022

Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved.

English learners (ELs) comprise approximately 10% of kindergarten to Grade 12 students in US public schools, with about 15% of ELs identified as having disabilities. English language proficiency (ELP) assessments must adhere to universal design principles and incorporate universal tools, designed to increase accessibility for all ELs, including those with disabilities. This two-phase mixed methods study examined the extent Grades 1–12 ELs with and without disabilities activated universal tools during an online ELP assessment: Color Overlay, Color Contrast, Help Tools, Line Guide, Highlighter, Magnifier, and Sticky Notes. In Phase 1, analyses were conducted on 1.25 million students’ test and telemetry data (record of keystrokes and clicks). Phase 2 involved interviewing 55 ELs after test administration. Findings show that ELs activated the Line Guide, Highlighter, and Magnifier more frequently than others. The tool activation rate was higher in listening and reading domains than in speaking and writing. A significantly higher percentage of ELs with disabilities activated the tools than ELs without disabilities, but effect sizes were small; interview findings further revealed students’ rationale for tool use. Results indicate differences in ELs’ activation of universal tools depending on their disability category and language domain, providing evidence for the usefulness of these tools.

ObjectiveThe International Society of Nephrology/Renal Pathology Society classification is the gold standard for the characterisation of lupus nephritis (LN) on renal biopsy, with therapeutic repercussions. Its recent revision simplified the current class subdivisions, eliminating the S/G forms of class IV, although data on a possible pathogenetic/clinical value of this subdivision are still contradictory.Methods353 renal biopsies from Belimumab International Study in LN were assessed through central pathology review. Univariate logistic models and a decision tree were performed on 314 adequate biopsies to evaluate the impact of histological features on focal/diffuse classes. Removing class I/II (n=6) and ‘pure’ class V (n=34), principal component analysis (PCA) and heatmap were used to explore similarities among III, IVS and IVG biopsies either incorporating or not the mixed classes (+V, n=274). Finally, a method aimed at partitioning the cases into k clusters based on their similarity (KMeans), was used to study features from the cohort of ‘pure’ class III/IVS/IVG cases (n=214) to determine alternative subdivisions based on phenotypic data.ResultsSegmental endocapillary hypercellularity (EH) was prevalent in class III, global EH, wire loops, hyaline thrombi and double contours were hallmarks of class IVG, with IVS cases showing intermediate characteristics. Heatmap and PCA confirmed the segregation of these features among classes, showing better segregation for focal/diffuse LN as compared with the mixed classes (+V). KMeans revealed the presence of two main clusters, membranoproliferative-like (n=83) or vasculitis-like (n=131).ConclusionsThis study reveals new phenotypic forms of LN surpassing the traditional classes as determined by the current classification. Future validation and confirmation are required to confirm these findings.

Gas-phase metallicities of galaxies are typically measured through auroral or nebular emission lines, but metallicity also leaves an imprint on the overall spectral energy distribution (SED) of a galaxy and can be estimated through SED fitting. We use the PROSPECT SED fitting code with a flexible parametric star formation history and an evolving metallicity history to self-consistently measure metallicities, stellar mass, and other galaxy properties for ∼90000 galaxies from the Deep Extragalactic VIsible Legacy Survey (DEVILS) and Galaxy and Mass Assembly (GAMA) survey. We use these to trace the evolution of the mass–metallicity relation (MZR) and show that the MZR only evolves in normalization by ∼0.1dex at stellar mass M⋆=1010.5M⊙⁠. We find no difference in the MZR between galaxies with and without SED evidence of active galactic nuclei emission at low redshifts (⁠z < 0.3). Our results suggest an anticorrelation between metallicity and star formation activity at fixed stellar mass for galaxies with M⋆>1010.5M⊙ for z < 0.3. Using the star formation histories extracted using PROSPECT we explore higher order correlations of the MZR with properties of the star formation history including age, width, and shape. We find that at a given stellar mass, galaxies with higher metallicities formed most of their mass over shorter time-scales, and before their peak star formation rate. This work highlights the value of exploring the connection of a galaxy’s current gas-phase metallicity to its star formation history in order to understand the physical processes shaping the MZR., JET is supported by the Australian Government Research Training Program (RTP) Scholarship. ASGR and LJMD acknowledge support from the Australian Research Council’s Future Fellowship scheme (FT200100375 and FT200100055, respectively). SB acknowledges support from the Australian Research Council’s Discovery Project and Future Fellowship funding schemes (DP180103740, FT200100375). LC acknowledges support from the Australian Research Council Discovery Project and Future Fellowship funding schemes (DP210100337, FT180100066). This work was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. We gratefully acknowledge DUG Technology for their support and HPC services.