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Management of RA patients has significantly improved over the past decades. However, a substantial proportion of patients is difficult-to-treat (D2T), remaining symptomatic after failing biological and/or targeted synthetic DMARDs. Multiple factors can contribute to D2T RA, including treatment non-adherence, comorbidities and co-existing mimicking diseases (e.g. fibromyalgia). Additionally, currently available biological and/or targeted synthetic DMARDs may be truly ineffective (‘true’ refractory RA) and/or lead to unacceptable side effects. In this narrative review based on a systematic literature search, an overview of underlying (immune) mechanisms is presented. Potential scenarios are discussed including the influence of different levels of gene expression and clinical characteristics. Although the exact underlying mechanisms remain largely unknown, the heterogeneity between individual patients supports the assumption that D2T RA is a syndrome involving different pathogenic mechanisms.

Age-related Macular Degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. We present a comprehensive molecular atlas for different stages of AMD.

Objective Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study. Methods Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48. Results Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. Conclusion While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition.

Predicting the effects of invasive ecosystem engineering species in new bioregions has proved elusive. In part this is because separating biological effects from purely physical mechanisms has been little studied and yet could help predict potentially damaging bioinvasions. Here we tested the effects of a large bio-engineering fanworm Sabella spallanzanii (Sabella) versus worm-like structures (mimics) on gas and nutrient fluxes in a marine soft bottom sediment. Experimental plots of sediment in Hauraki Gulf (New Zealand) were used to test the hypothesis that ecosystem engineers negatively influence benthic ecosystem function through autogenic mechanisms, facilitating activity by biofouling organisms and competitive exclusion of native infauna. Enhanced physical structure associated with Sabella and mimics increased nitrogen fluxes, community metabolism and reduced denitrification from 23 μmol m−2 h−1 to zero at densities greater than 25 m2. Sabella plots on average had greater respiration (29%), NH4 release (33%), and greater NO3 release (52%) compared to mimics, suggesting allogenic (biological) mechanisms occur, but play a secondary role to autogenic (physical) mechanisms. The dominance of autogenic mechanisms indicates that bio-engineers are likely to cause significant impacts when established, regardless of fundamental differences in recipient regions or identity of the introduced bio-engineer. In the case of Sabella spallanzanii, compromised denitrification has the potential to tip the balance of net solute and gas exchanges and cause further ecological degradation in an already eutrophic system.

A key challenge in environmental management is determining how to manage multiple ecosystem services (ES) simultaneously, to ensure efficient and sustainable use of the environment and its resources. In marine environments, the spatial assessment of ES is lagging as a result of data-scarcity and modelling complexity. Applying mechanistic models to link ecological processes with ecosystem functions and services to assess areas of high ES potential can bridge this gap and accommodate assessments of functional differences between service providers. Here, we applied an ecosystem principles approach to assess ES potential for food provision, water quality regulation, nitrogen removal, and sediment stabilisation, provided by two estuarine bivalves (Austrovenus stutchburyi and Paphies australis) that differ in habitat association (broad and narrow distributions), to gain insight into the utility of these models for local-scale management. Maps of individual ES displayed differing patterns related to habitat associations of the species providing them, with variation in the quantities of services being delivered and locations of importance. Areas of importance for the provision of multiple services (number of services provided and their combined intensity per species) were assessed using hotspot analyses, which suggested that areas of high shellfish density at the harbour entrances were important for ES multifunctionality. A targeted management approach that includes environmental context, rather than a focus solely on the protection of high-density shellfish areas, is required to sustain the provision of individual ES.

Particle mixing and irrigation of the seabed by benthic fauna (bioturbation) have major impacts on ecosystem functions such as remineralization of organic matter and sediment-water exchange. As a tribute to Prof. Gaston Desrosiers by the Nereis Park association, eighteen laboratories carried out a collaborative experiment to acquire a global snapshot of particle reworking by the polychaete Hediste diversicolor at 16 sites surrounding the Northern Atlantic. Organisms and soft sediments were collected during May – July at different geographical locations and, using a common laboratory protocol, particulate fluorescent tracers (‘luminophores’) were used to quantify particle transport over a 10-day period. Particle mixing was quantified using the maximum penetration depth of tracers (MPD), particle diffusive coefficients (Db), and non-local transport coefficients (r). Non-local coefficients (reflecting centimeter scale transport steps) ranged from 0.4 to 15 yr−1, and were not correlated across sites with any measured biological (biomass, biovolume) or environmental parameters (temperature, grain size, organic matter). Maximum penetration depths (MPD) averaged ~10.7 cm (6.5–14.5 cm), and were similar to the global average bioturbation depth inferred from short-lived radiochemical tracers. MPD was also not correlated with measures of size (individual biomass), but increased with grain size and decreased with temperature. Biodiffusion (Db) correlated inversely with individual biomass (size) and directly with temperature over the environmental range (Q10 ~ 1.7; 5–21 °C). The transport data were comparable in magnitude to rates reported for localized H. diversicolor populations of similar size, and confirmed some but not all correlations between sediment reworking and biological and environmental variables found in previous studies. The results imply that measures of particle reworking activities of a species from a single location can be generally extrapolated to different populations at similar conditions.

Summary There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage., Graphical Abstract, Highlights • Deep phenotyping and RNA-seq of early rheumatoid arthritis individuals pre-treatment • Synovial plasma cell gene expression predicts future progressive joint damage on X-ray • Blood interferon gene signature associates with synovial B and plasma cell infiltration • Interactive website enables RNA-seq and clinical data to be fully explored, Lewis et al. use histology and RNA-seq of synovial biopsies from a cohort of early rheumatoid arthritis individuals to identify three histological pathotypes and reveal gene modules associated with disease severity and clinical response.

Background: Neurofilament light (NfL) chain is an established cerebrospinal fluid (CSF) biomarker for neuroaxonal injury. The highly sensitive Quanterix Simoa™ platform is evaluated for NfL measurement in both CSF and blood. There is a need to link historical ELISA data that use bovine NfL to that of Simoa using a recombinant human (rhuman) NfL standard. Results/Methodology: The Simoa NF-light® Advantage Kit was validated for CSF and qualified for serum and plasma, using both rhuman and bovine NfL calibrators. Matched CSF, serum and plasma samples from 112 multiple sclerosis patients were analyzed using both calibrators. Conclusion: In multiple sclerosis, there is a good correlation between blood and CSF NfL levels. A conversion factor of approximately 5:1 was established between bovine and rhuman NfL calibrators.

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4 + T cells, prior activation via the T cell antigen receptor limits IL-6’s control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4 + T cells. Transcriptomics and chromatin immunoprecipitation–sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4 + T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4 + T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4 + T cells sense and interpret cytokine signals.

Genetic variants in C5orf30 have been associated with development of the autoimmune conditions primary biliary cirrhosis and rheumatoid arthritis. In rheumatoid arthritis, C5orf30 expression is cell-specific, with highest expression found in macrophages and synovial fibroblasts. C5orf30 is highly expressed in inflamed joints and is a negative regulator of tissue damage in a mouse model of inflammatory arthritis. Transcriptomic analysis from ultrasound-guided synovial biopsy of inflamed joints in a well characterized clinical cohort of newly diagnosed, disease-modifying antirheumatic drugs–naive rheumatoid arthritis patients was used to determine the clinical association of C5orf30 expression with disease activity. A combined molecular and computational biology approach was used to elucidate C5orf30 function in macrophages both in vitro and in vivo. Synovial expression of C5orf30 is inversely correlated with both clinical measures of rheumatoid arthritis disease activity and with synovial TNF mRNA expression. C5orf30 plays a role in regulating macrophage phenotype and is differentially turned over in inflammatory and anti-inflammatory macrophages. Inhibition of C5orf30 reduces wound healing/repair–associated functions of macrophages, reduces signaling required for resolution of inflammation, and decreases secretion of anti-inflammatory mediators. In an animal model of wound healing (zebrafish), C5orf30 inhibition increases the recruitment of macrophages to the wound site. Finally, we demonstrate that C5orf30 skews macrophage immunometabolism, demonstrating a mechanism for C5orf30-mediated immune regulation.

The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Bruton's tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex- and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)-responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.

Blue carbon ecosystems (including saltmarsh, mangrove, seagrass meadows, and other soft sediment habitats) play a valuable role in aquatic carbon dynamics and contribute significantly to global climate change mitigation. However, these habitats are undergoing rapid and accelerating shifts in extent due to climate change and anthropogenic impactsstressors. Here, we demonstrate that blue carbon stocks vary across habitats and that cross-habitat subsidies of carbon contribute significantly to blue carbon stocks. Using a case study estuary from New Zealand, organic carbon stocks in above ground biomass and sediment to 100 cm varied significantly between habitat types, from saltmarsh (90 t ha-1), to mangrove (46 t ha-1), to seagrass (27 t ha-1) and unvegetated habitats (26 t ha-1). Despite being typically overlooked in blue carbon literature, unvegetated habitats contained the majority of estuarine carbon stocks when adjusted for their large extent within the estuary (occupying 68.4% of the estuarine area and containing 57% of carbon stocks). When carbon stocks were further refined based on δ13C and δ15N mixing model results, coastal vegetation (saltmarsh, mangrove, seagrass) was found to provide important cross-habitat subsidies exchanges of carbon throughout the estuary, including contributing an estimated 41% of organic carbon within unvegetated sediments, and 51% of the total carbon stock throughout the estuary (yet occupying only 31.6% of the estuary). Given the connected nature of blue carbon ecosystems these findings illustrate the importance of considering the contribution and cross habitat subsidies of both vegetated and unvegetated habitats to blue carbon stocks in estuaries. This provides critical context when assessing the impact of shifts in habitat distributions due to impacts from climate change and anthropogenic stressors.

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

BackgroundTubulointerstitial inflammation (TII) in lupus nephritis is associated with a worse prognosis. Vimentin, a filamental antigen, is commonly targeted by in situ activated B-cells in TII. The prognostic importance of high serum anti-vimentin antibodies (AVAs) in lupus nephritis and their relationship with common lupus autoantibody specificities is unknown. Herein we investigated associations between AVA isotypes, other autoantibodies, and response to mycophenolate mofetil (MMF) in the presence or absence of rituximab.MethodsThe Translational Research Initiative in the Department of Medicine (TRIDOM) cross-sectional cohort of 99 lupus patients was assayed for IgG-, IgA- and IgM- AVAs, lupus-associated and rheumatoid arthritis-associated antibodies, and hierarchically clustered. Serum from baseline, 26 and 52 weeks from 132 Lupus Nephritis Assessment with Rituximab (LUNAR) trial enrolled lupus nephritis patients was also analysed and correlated with renal function up to week 78.ResultsIn TRIDOM, AVAs, especially IgM AVAs, clustered with IgG anti-dsDNA and away from anti-Sm and -RNP and rheumatoid arthritis-associated antibodies. In LUNAR at baseline, AVAs correlated weakly with anti-dsDNA and more strongly with anticardiolipin titers. Regardless of treatment, IgG-, but not IgM- or IgA-, AVAs were higher at week 52 than at baseline. In contrast, anti-dsDNA titers declined, regardless of therapeutic regime. High IgG AVA titers at entry predicted less response to therapy.ConclusionAVAs, especially IgG AVAs, are unique in distribution and response to therapy compared with other commonly measured autoantibody specificities. Furthermore, high-titer IgG AVAs identify lupus nephritis patients resistant to conventional therapies. These data suggest that AVAs represent an independent class of prognostic autoantibodies.

Background Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, has been proven to be a safe and effective treatment for rheumatoid arthritis (RA). Because RA is a heterogenous disease and patient response to treatments can vary, identifying characteristics that predict which patients are more likely to respond to TCZ is important for optimal patient care. Serum levels of C-X-C motif chemokine ligand 13 (CXCL13) and soluble intercellular adhesion molecule-1 (sICAM-1) have been associated with response to TCZ in patients with RA. Objectives To evaluate the association of CXCL13 and sICAM-1 with disease activity and response to TCZ in patients with early RA and those with inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). Methods Baseline and week 24 serum CXCL13 and sICAM-1 levels were measured using available patient samples from the FUNCTION (early RA) and LITHE (DMARD-IR) trials. Correlations between CXCL13 and sICAM-1 levels and Disease Activity Score in 28 joints calculated with erythrocyte sedimentation rate (DAS28-ESR) at baseline and between change in CXCL13 and sICAM-1 and change in DAS28-ESR at week 24 were estimated. CXCL13 and sICAM-1 changes from baseline to week 24 were compared between treatment arms. The effects of TCZ treatment and baseline DAS28-ESR, CXCL13 and sICAM-1 levels on DAS28-ESR remission and 50% improvement per the American College of Rheumatology (ACR50) response at week 24 were determined. Results Overall, 458 patients from FUNCTION and 287 patients from LITHE were included. Correlation of baseline serum CXCL13 and sICAM-1 levels with DAS28-ESR was weak to moderate. CXCL13 and sICAM-1 levels decreased significantly at week 24 in TCZ-treated patients in both the early-RA and DMARD-IR populations. CXCL13 and sICAM-1 changes correlated moderately to weakly with DAS28-ESR changes at week 24 in both populations. The treatment regimen, but not baseline CXCL13 and sICAM-1 levels, had a significant effect on the likelihood of DAS28-ESR remission and ACR50 response. Conclusions Although CXCL13 and sICAM-1 are modestly associated with RA disease activity, they do not predict response to TCZ in all RA populations.

The Mediterranean fanworm, Sabella spallanzanii, is listed as an introduced and established “unwanted species” in New Zealand, subject to nationwide targeted surveillance in port, marina, urban and natural environments. Sabella spallanzanii has the potential to change soft-sediment benthic habitats due to the physical presence of the fanworm's tube and associated biological activities, particularly suspension feeding and bio-deposition. A 6-month field experiment was conducted to investigate the impacts of S. spallanzanii on the structure and diversity of existing communities within invaded soft-sediment habitats. Macrofaunal communities were assessed using traditional sampling and identification via microscopy, while microbial and eukaryotic communities were characterized using metabarcoding of 16S and 18S ribosomal genes, respectively. Live and mimic S. spallanzanii were transplanted at different densities (10–50 individuals per m2) into experimental plots with existing assemblages, to test for potential biological and/or physical effects on benthic communities. Analyses revealed significant differences in macrofaunal, eukaryote, and bacterial assemblages in the presence of live S. spallanzanii and mimics, underpinned by changes in the relative abundance of several taxa, indicating that these effects are brought about by biological and physical functions. The presence of S. spallanzanii did not alter total abundance and taxa richness of benthic assemblages but resulted in compositional differences. We found no effect of live or mimic worm density on the structure and diversity of the studied communities. Changes in the structure of native benthic communities, as indicated by this study, can potentially impact functioning of soft-sediment habitats, through alterations to nutrient cycling, bioturbation and benthic-pelagic coupling. Quantitative measurements of impacts are crucial to understand the trajectory of marine invasions, their roles in re-structuring communities, and to guide management efforts.

NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE., Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.

Spatial information on the distribution and densities of key species is an important prerequisite for understanding the functioning and management of ecosystem services. Species distribution models (SDMs) are increasingly used in marine environments to assist with spatial management; however, most SDMs only predict occurrence and not density. Here, we use SDMs to predict probability of occurrence and density of two key estuarine bivalve species (Austrovenus stutchburyi and Paphies australis) that differ in habitat usage and distribution, to gain insight into the utility of these methods for management. Boosted regression trees (BRTs) were used to predict occurrence, density, and uncertainty at a fine spatial scale (100 m resolution). Results showed high probability of occurrence for Paphies near the estuary mouth (up to 0.83), where high densities, exceeding 4000 ind m−2, were also predicted. For Austrovenus, predicted occurrence was high throughout the intertidal area, ranging from 0.5 to 0.87, with no clear spatial patterns. Instead, density models clearly identified spatial patterns for Austrovenus, with high densities exceeding 1000 ind m−2. Spatially explicit uncertainty was low throughout the estuary for both species, providing confidence in model outcomes. Our study demonstrates that a high probability of occurrence does not necessarily equate to high density and illustrates the need for the transition to more informative species density models. Management that simultaneously considers both density and occurrence probabilities will enable targeted protection of areas that are of greatest ecological value to species of interest.

A laboratory experiment was conducted, to examine how feeding, siphon activity and movement behaviours of a tellinid bivalve, Macomona liliana (Iredale, 1915), were affected by thin surface layers of mud (1–4 mm) and the incorporation of mud into surface (0–2 cm) sediment. Time-lapse photography and porewater pressure sensors were used to characterise changes in behaviour before and after mud addition. Mud addition modified the sediment matrix which had an immediate effect on M. liliana behaviour; significantly affecting the rates of feeding and the degree of porewater pressurisation during feeding events. Surface activity indicated maintenance and clearance of established burrow structures and increased ventilation. Ultimately, subtle modifications in behaviour and sediment hydraulic conductivity may have consequences for nutrient exchange and benthic-pelagic coupling. Our results emphasise the need to consider the impacts of low level stressors when they affect the behaviour of structurally impo...

Neutrophil activation and the formation of neutrophil extracellular trap (NET) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE) and contribute to the systemic interferon signature. Here we report that the expression of an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and was correlated with higher interferon status. Induction of ERV-K102 expression most strongly correlated with reduced transcript levels of epigenetic silencing factors. SLE IgG promoted phagocytosis of ERV-K102 envelope protein by neutrophils through immune complex formation. ERV immune complex phagocytosis resulted in subsequent NET formation consisting of DNA, neutrophil elastase, and citrullinated histone H3. Finally, analysis of anti-ERV-K102 IgG in SLE patients showed that IgG2 likely mediates this effect. Together, we identified an immunostimulatory ERV-K envelope protein elevated in SLE that may be a target of SLE IgG and able to promote neutrophil activation.eTOC summaryUsing ERVmap, the authors determined that the expression of ERV-K102 locus was elevated in SLE patient blood and correlated with the interferon signature. The envelope protein encoded by this locus activates human neutrophils through immune complex formation with SLE IgG.

Using ERVmap, the authors determined that ERV-K102 expression was elevated in SLE patients’ peripheral blood cells and correlated with the interferon signature. IgG antibodies from SLE patients complexed with the K102 envelope protein activate neutrophils and induce NETs., Neutrophil activation and the formation of neutrophil extracellular traps (NETs) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE). Here we report that the expression of an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and correlated with autoantibody levels and higher interferon status. Induction of ERV-K102 in SLE negatively correlated with the expression of epigenetic silencing factors. Anti-ERV-K102 IgG levels in SLE plasma correlated with higher interferon stimulated gene expression, and further promoted enhanced neutrophil phagocytosis of ERV-K102 envelope protein through immune complex formation. Finally, phagocytosis of ERV-K102 immune complexes resulted in the formation of NETs consisting of DNA, neutrophil elastase, and citrullinated histone H3. Together, we identified an immunostimulatory ERV-K envelope protein that in an immune complex with SLE IgG is capable of activating neutrophils.

The supply of ecosystem services (ES) that benefit humanity are derived from multiple, interacting ecological functions and processes. Focusing on the ecological mechanisms that underpin ES delivery allows bundles of services to be identified, bridging a critical gap with management. Work in marine systems has not yet progressed to the identification of ES bundles, as a result of data scarcity and complications arising from system complexity and connectivity, as opposed to terrestrial systems where ES bundles have been more widely applied based on spatial clustering. To demonstrate the approach, identification of ES bundles provided by shellfish is used as a case-study. Shellfish provide a number of known ES that need to be strategically managed to ensure sustainable use. As a result of global degradations in shellfish beds ES have been lost, and restoration efforts emphasize the importance in regaining these services. A literature review, including 146 papers aimed specifically at linking shellfish to either ecosystem functions or ecosystem services, was conducted to establish key linkages between processes, functions and services. Based on co-occurrence of services and shared linkages, four bundles of services are identified, including Marine resources, Coastal health and quality, Habitat modification, and Biological structuring. Our study emphasizes the underpinning ecological mechanisms and the importance of interactions between services, expressed in the formation of bundles by mutual drivers and processes, as well as between services in different bundles, as either synergies or trade-offs. The approach enables the translation of ecological knowledge and creates generality to inform policy making and management, thereby providing a format useful for ecologists, managers and other stakeholders.

We would like to thank Professor Buch and colleagues for their interest and thoughtful comments regarding our manuscript,1 and we are grateful for the opportunity to provide further clarification on the clinical phenotype displayed by the rheumatoid arthritis (RA) patients with a pauci-immune pathotype analysed in our early arthritis cohort.2 We have segregated this group into anti-citrullinated peptide antibodies (ACPA) +ve and -ve subsets and analysed age distribution, disease activity score (DAS28) components, ultrasound (US) scores, joint biopsied and modified Sharp van der Heijde score (SHSS) components, as indicated by Buch and colleagues to evaluate whether significant differences in clinical parameters could be identified (table 1). …

Background Serum levels of C-X-C motif chemokine ligand 13 (CXCL13) and soluble intercellular adhesion molecule-1 (sICAM-1) have been associated with response to tocilizumab (TCZ) in patients with rheumatoid arthritis (RA); levels of matrix metalloproteinase-3 (MMP-3) and S100A8/A9 have also been associated with RA disease activity and joint damage. Objectives To evaluate the association of CXCL13, sICAM-1, MMP-3 and s100A8/A9 levels with disease activity and response to TCZ in patients with RA who achieved low disease activity with 24 weeks of TCZ + methotrexate (MTX) treatment and were subsequently randomized to TCZ monotherapy (mono) or TCZ + MTX in the COMP-ACT trial (NCT01855789). Methods US patients with RA who had an inadequate response to MTX received initial combination therapy of MTX plus TCZ 162 mg subcutaneous for 24 weeks. Patients who achieved Disease Activity Score in 28 joints calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to receive either TCZ mono or continue TCZ + MTX until Week 52. Randomized patients were included in the present study based on baseline, Week 24 and Week 40 sample availability; serum levels of CXCL13, sICAM-1, MMP-3 and S100A8/A9 were measured by immunoassay. Correlations between CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels and DAS28-ESR at baseline, Week 24 and Week 40 were determined according to Spearman correlation coefficient. Changes in CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels from baseline to Week 24 (open-label period) were determined using Wilcoxon test. Mean changes in CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels from Week 24 to Week 40 (randomized period) were compared between treatment arms using analysis of covariance. Results Of 296 randomized patients, 249 were included (TCZ mono, n = 126; TCZ + MTX, n = 123). Biomarker levels were well balanced across treatment arms at baseline and Week 24 (randomization). At baseline, there were weak to mild correlations between DAS28-ESR and biomarker levels (CXCL13 [r = 0.13, P = 0.0411], sICAM-1 [r = 0.20, P = 0.0015], MMP-3 [r = 0.19, P = 0.0021], S100A8/A9 [r = 0.25, P = 0.0001]). Significant reductions in mean biomarker levels were observed from baseline to Week 24 (open-label period) among the total randomized patients (P Conclusion In agreement with previous studies, the association between baseline disease activity and CXCL13, sICAM-1, MMP-3 and S100A8/A9 levels was weak to mild; TCZ + MTX treatment from baseline to Week 24 (open-label period) resulted in significant reductions in all biomarkers. Changes in levels of CXCL13, sICAM-1, MMP-3 and S100A8/A9 from Week 24 to 40 (randomized period) were similar between treatment groups, consistent with the finding of non-inferiority of TCZ mono compared with TCZ + MTX in patients with RA who achieve low disease activity with TCZ + MTX. Acknowledgement This study was funded by Genentech, Inc. Disclosure of Interests D. James Haddon Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Thierry Sornasse Employee of: Genentech, Inc., Michael J. Townsend Shareholder of: Stockholder of Genentech/Roche, Employee of: Genentech/Roche, Jinglan Pei Employee of: Genentech, Margaret Michalska Employee of: Genentech, Inc.

Background: Bruton’s tyrosine kinase (BTK) plays an essential role in B cell development. BTK acts downstream of the B cell receptor in B cells, and Fc receptor signaling in myeloid cells, pathways thought to be involved in the pathogenesis of RA. Fenebrutinib (FEN) is a non-covalent small molecule inhibitor of BTK with greater than 100-fold selectivity relative to other kinases1. Objectives: To characterize the mechanistic effects of FEN on B and myeloid cell biology and determine the potential of biomarkers to predict response to FEN treatment in patients with RA. Methods: The ANDES study included RA patients (pts) on background methotrexate (MTX) with inadequate response to prior MTX (n=480, Cohort 1, MTX-IR) or anti-TNFs (n=98, Cohort 2, TNF-IR). Cohort 1 pts were randomized to receive PBO, adalimumab (ADA) 40 mg Q2W, or FEN 50 mg QD, 150 mg QD or 200 mg BID. Cohort 2 pts were randomized to receive PBO or FEN 200 mg BID. Clinical efficacy was assessed based on the proportion of pts achieving ACR50 at week 12. Pts for whom samples were available were assessed for levels of rheumatoid factor (RF), total IgM and IgG, CCL4, CXCL13, CRP and IL6. Results: Primary study results are reported separately. Overall, treatment with FEN caused significant reductions in RF (by week 12) and total IgM and IgG (at weeks 4-12) relative to PBO (Table 1). Early and sustained reductions of the B cell chemokine CXCL13 and the myeloid-enriched biomarker CCL4 were observed with FEN or ADA relative to PBO by week 1. CRP levels were significantly reduced with 200 mg BID FEN by week 8, and with ADA by week 2 relative to PBO. By week 12, there was a trend toward lower IL6 levels with FEN treatment relative to PBO, whereas ADA significantly reduced IL6 levels by week 1 relative to PBO in MTX-IR pts. In TNF-IR patients, IL6 was significantly reduced by FEN treatment by week 12 relative to PBO. PK-PD relationships were observed for multiple B and myeloid cell biomarkers. No single biomarker at baseline was associated with clinical response (at 12 weeks) in MTX-IR and TNF-IR pts. However, greater baseline RF titers were associated with increased FEN clinical response in TNF-IR pts. Conclusion: FEN treatment resulted in strong pharmacodynamic effects on multiple biomarkers of B and myeloid cell biology in RA. This included reductions in total IgM and IgG that were not observed with ADA. Conversely, ADA reduced IL6 and CRP faster than FEN, highlighting key mechanistic differences between FEN and ADA. Baseline RF titer was associated with FEN clinical response in the more refractory TNF-IR pts. These data provide mechanistic insights into the efficacy of FEN in RA patients. Reference: [1] Crawford, et al., J Med Chem 2018 61(6) 2227-2245. Disclosure of Interests: Alyssa Morimoto Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Julie Rae Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Leslie Chinn Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Nandhini Ramamoorthi Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Olivia Hwang Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Alexandra Ward Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, D. James Haddon Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Caroline Looney Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Rupal Desai Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Balazs Toth Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Katie Tuckwell Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Michael J. Townsend Shareholder of: Stockholder of Genentech/Roche, Employee of: Genentech/Roche

Humans rely on the natural environment and benefit from the goods and services provided by natural ecosystems. Quantification and mapping of ecosystem services (ES) is required to better protect valued ES benefits under pressure from anthropogenic activities. The removal of excess nitrogen, a recognized catchment-derived pollutant, by biota in estuarine soft sediments is an important ES that potentially ameliorates the development of eutrophication symptoms. Here, we quantified estuarine benthic sediment characteristics and denitrification enzyme activity (DEA), a proxy of inorganic N removal, at 109 sites in four estuaries to develop a general ("global") model for predicting DEA. Our initial global model for linking DEA and environmental characteristics had good explanatory power, with sediment mud content having the strongest influence on DEA (60%), followed by sediment organic matter content (≈35%) and sediment chlorophyll a content (≈5%). Predicted and empirically evaluated DEA values in a fifth estuary (Whitford, n = 90 validation sites) were positively correlated (r = 0.77), and the fit and certainty of the model (based on two types of uncertainty measures) increased further after the validation sites were incorporated into it. The model tended to underpredict DEA at the upper end of its range (at the muddier, more organically enriched sites), and the relative roles of the three environmental predictors differed in Whitford relative to the four previously sampled estuaries (reducing the explained deviance relative to the initial global model). Our detailed quantification of DEA and methodological description for producing empirically validated maps, complete with uncertainty information, represents an important first step in the construction of nutrient pollution removal ES maps for use in coastal marine spatial management. This technique can likely be adapted to map other ecosystem functions and ES proxies worldwide.

Objectives The gene encoding glucose transporter 3 (GLUT3, SLC2A3) is present in the human population at variable copy number. An overt disease phenotype of SLC2A3 copy number variants has not been reported; however, deletion of SLC2A3 has been previously reported to protect carriers from rheumatoid arthritis, implicating GLUT3 as a therapeutic target in rheumatoid arthritis. Here we aim to perform functional analysis of GLUT3 copy number variants in immune cells, and test the reported protective association of the GLUT3 copy number variants for rheumatoid arthritis in a genetic replication study. Methods Cells from genotyped healthy controls were analyzed for SLC2A3/GLUT3 expression and glycolysis capacity. We genotyped the SLC2A3 copy number variant in four independent cohorts of rheumatoid arthritis and controls and one cohort of multiple sclerosis and controls. Results Heterozygous deletion of SLC2A3 correlates directly with expression levels of GLUT3 and influences glycolysis rates in the human immune system. The frequency of the SLC2A3 copy number variant is not different between rheumatoid arthritis, multiple sclerosis and control groups. Conclusions Despite a robust SLC2A3 gene copy number dependent phenotype, our study of large groups of rheumatoid arthritis cases and controls provides no evidence for rheumatoid arthritis disease protection in deletion carriers. These data emphasize the importance of well powered replication studies to confirm or refute genetic associations, particularly for relatively rare variants., Highlights • T cell and macrophage expression of SLC2A3/GLUT3 correlates to SLC2A3 gene copy number in a dose dependent manner. • Glycolysis rates are reduced in individuals harboring a deletion of the GLUT3 gene SLC2A3 • Deletion of SLC2A3 is not associated with protection from rheumatoid arthritis • Deletion of SLC2A3 is not associated with risk for multiple sclerosis • GLUT3 is not a viable therapeutic target for RA as previously proposed based on a protective association of SLC2A3 deletion.

Mapping ecosystem services in marine systems is difficult due to a lack of underpinning ecological data. The Ecological Principles Approach (EPA) was developed to link simple summary statements on how ecosystems function to ecosystem services and was further advanced into a mapping technique by aligning and weighting commonly available spatial datasets to generate maps of specific services. The objective of the present investigation was to validate a predicted map of biogenic habitat provision with empirical ground-truthed data. A survey was undertaken to assess the biogenic habitat structure at 56 sites in the Hauraki Gulf, New Zealand. Information on benthic biogenic structure was ranked from 1 to 5 relating to a combination of height and complexity. Rank groups were assessed for differences in predicted levels of service and the accuracy of supporting data. We found high agreement between the empirical observations and the model predictions: in areas predicted by the approach to have the highest levels of biogenic habitat complexity the habitat was typified by complex rocky reef communities and macroalgal forests. We showed that ecosystem services can be accurately mapped in marine systems at low cost and with modest data requirements, which further enhances the utility of this approach.

ObjectiveTo establish whether synovial pathobiology improves current clinical classification and prognostic algorithms in early inflammatory arthritis and identify predictors of subsequent biological therapy requirement.Methods200 treatment-naïve patients with early arthritis were classified as fulfilling RA1987 American College of Rheumatology (ACR) criteria (RA1987) or as undifferentiated arthritis (UA) and patients with UA further classified into those fulfilling RA2010 ACR/European League Against Rheumatism (EULAR) criteria. Treatment requirements at 12 months (Conventional Synthetic Disease Modifying Antirheumatic Drugs (csDMARDs) vs biologics vs no-csDMARDs treatment) were determined. Synovial tissue was retrieved by minimally invasive, ultrasound-guided biopsy and underwent processing for immunohistochemical (IHC) and molecular characterisation. Samples were analysed for macrophage, plasma-cell and B-cells and T-cells markers, pathotype classification (lympho-myeloid, diffuse-myeloid or pauci-immune) by IHC and gene expression profiling by Nanostring.Results128/200 patients were classified as RA1987, 25 as RA2010 and 47 as UA. Patients classified as RA1987 criteria had significantly higher levels of disease activity, histological synovitis, degree of immune cell infiltration and differential upregulation of genes involved in B and T cell activation/function compared with RA2010 or UA, which shared similar clinical and pathobiological features. At 12-month follow-up, a significantly higher proportion of patients classified as lympho-myeloid pathotype required biological therapy. Performance of a clinical prediction model for biological therapy requirement was improved by the integration of synovial pathobiological markers from 78.8% to 89%–90%.ConclusionThe capacity to refine early clinical classification criteria through synovial pathobiological markers offers the potential to predict disease outcome and stratify therapeutic intervention to patients most in need.

IL-17 has been implicated in the pathogenesis of multiple sclerosis (MS). Here, we show that blockade of IL-17A, but not IL-17F, attenuated experimental autoimmune encephalomyelitis (EAE). We further show that IL-17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and that they correlated with the CSF/serum albumin quotient (Qalb), a measure of blood-brain barrier (BBB) dysfunction. We then demonstrated that the combination of IL-17A and IL-6 reduced the expression of tight junction (TJ)-associated genes and disrupted monolayer integrity in the BBB cell line hCMEC/D3. However, unlike IL-17A, IL-6 in the CSF from RRMS patients did not correlate with Qalb. These data highlight the potential importance of targeting IL-17A in preserving BBB integrity in RRMS.

Seagrass meadows provide a range of important ecosystem functions that can be influenced by anthropogenic pressures. Sediment loading from coastal land use mismanagement can elevate turbidity and reduce seabed light levels, thereby impacting seagrass primary productivity and meadow health. Less understood is the impact of elevated turbidity on the nutrient removal capacity of seagrass, which is a key ecosystem function. Here, we use in situ benthic chambers to show that elevated turbidity is associated with lower nutrient (NH4+) removal within intertidal seagrass meadows. Our results suggest that reductions in sediment loading to improve water clarity may increase the nutrient removal capacity of intertidal seagrass meadows influenced by light limitation. When quantifying important ecosystem functions such as nutrient removal by seagrass it is important to consider this context dependency.

Aim: To improve on the efficiency of biomarker assay readiness, and for reliable biomarker data to support three drug programs, we implemented a fit-for-purpose approach, qualifying two biomarker assays and validating a third. Results/methodology: The qualification strategy and selection of experiments for two exploratory biomarkers (CXCL1, CCL19) was determined by the intended use of the biomarker data. The third biomarker, IL-6, was validated as the data would be used in monitoring patient safety during dose-escalation studies in a Phase I trial. All three assays passed a priori acceptance criteria. Conclusion: These assays highlight strategies and methodologies for a fit-for-purpose approach. Minimum qualification, full qualification and validation were chosen and supported programs at different stages of drug development.

New Zealand cockles ( Austrovenus stutchburyi ) are ecologically important, intertidal bivalves that have been shown to influence nutrient cycles and the productivity of microphytobenthos on sandflats. Here, we investigated the potential for cockles to impact the productivity of seagrass, Zostera muelleri , and examined interactions between these habitat-defining species where they co-occur. We sampled bivalve densities and sizes, sediment properties, and seagrass shoot densities across the boundaries of two seagrass patches on an intertidal sandflat in northern New Zealand, and measured dissolved oxygen and nutrient fluxes in light and dark benthic incubation chambers in conjunction with a 0–97% gradient in seagrass cover. Although gross primary production (GPP, μmol O 2 m −2 h −1 ) increased predictably with the cover of live seagrass, the density of cockles and sediment properties also contributed directly and indirectly. Seagrass cover was positively correlated with cockle density (ranging from 225 to 1350 individuals per m 2 ), sediment mud percentage (0.5–9.5%), and organic matter content (0.5–2.2%), all of which can affect the efflux of ammonium (readily utilisable inorganic nitrogen) from sediments. Moreover, the cover of green seagrass blades plateaued (never exceeded 70%) in the areas of highest total seagrass cover, adding complexity to cockle-seagrass interactions and contributing to a unimodal cockle-GPP relationship.

The authors thank MASTS (the Marine Alliance for Science and Technology Scotland) for funding the experimental work, the University of Waikato Distinguished Visitors fund for funding Hanley’s research visit during which the empirical work was undertaken, and Leo Xiong for programming the experiment. MC gratefully acknowledges the support of the Polish Ministry of Science and Higher Education and the Foundation for Polish Science. A substantial literature in behavioural science and psychology shows that emotions affect human choices and values. This paper investigates whether such emotional impacts are also present in stated choice experiments for environmental goods. If this were so, it would introduce an additional element of context dependence to the welfare measures derived from such methods, and would be at odds with the rational choice model underlying welfare economics. A laboratory experiment using three different emotion treatments was combined with a stated preference choice experiment concerned with changes in coastal water quality and fish populations in New Zealand. No statistically significant effects of changes in emotional state on estimated preference parameters, willingness to pay or the randomness of choices were found. The paper concludes by questioning, why such a contrast exists with empirical findings in behavioural science. Publisher PDF

Predicting and managing the potential economic, social, and ecological impacts of bioinvasions is a key goal of non-indigenous species (NIS) research worldwide. The marine fan worm, Sabella spallanzanii, is an ecosystem engineering NIS that forms dense filter-feeding canopies on hard substrata and large clumps of individuals in soft sediment habitats. In this study, we investigated the epifaunal assemblages associated with Sabella clumps of increasing size and complexity from soft-sediment benthic ecosystems in Auckland Harbour, New Zealand. The diversity and abundance of epifaunal taxa increased with clump size. Species accumulation curves suggest that with further increases in Sabella clump size, diversity will continue to increase. There were no differential effects on taxa related to feeding mode or motility despite the potential for Sabella to reduce food to suspension feeders (through competition) and increase food supply to deposit feeders (through biodeposition). Our results provide an example of local biodiversity enhancement by an NIS, though some of the species benefitting from Sabella were themselves non-indigenous or of uncertain origin (cryptogenic/indeterminate). Longer term studies of the impacts of Sabella on native biodiversity and ecosystem functioning, including on food webs, are important next steps.

Background:Fenebrutinib (GDC-0853, FEN) is an oral, non-covalent, and selective inhibitor of Bruton’s tyrosine kinase (BTK) in clinical development for autoimmune diseases.Objectives:This was a randomized, placebo-controlled, multi-center study to evaluate the efficacy, safety, and pharmacodynamic effects of FEN in patients with moderate-to-severe systemic lupus erythematosus (SLE) activity.Methods:Patients who met SLICC or revised ACR SLE criteria, had ≥1 serologic marker of SLE, SLEDAI ≥8, and were on ≥1 standard of care (SOC) therapy were included; patients with renal or CNS involvement, or exposure to B cell depleting or calcineurin inhibitor therapy were excluded. Patients were randomized to placebo (PBO), FEN 150 mg QD, or FEN 200 mg BID, for 48 weeks. A corticosteroid taper was recommended, with burst and taper permitted from Week 0 (W0) to W12 and W24 to W36. The primary endpoint was SRI-4 at W48. Post hoc subgroup analyses were conducted based on patient baseline disease characteristics.Results:This study enrolled 260 patients, with the majority recruited in Latin America, USA, and Western Europe. At W48, the SRI-4 response rates for FEN 150 mg QD and FEN 200 mg BID were 51% (95% CI: -8.5, 21.2; p value 0.37) and 52% (95% CI: -7.3, 22.4; p value 0.34), respectively, compared to 44% for PBO (Table 1). Post-hoc analysis showed larger responses in subgroups of patients with higher baseline disease activity (Table 1). Safety results were similar between FEN and PBO arms, although more serious adverse events were observed in the FEN 200 mg BID arm. Study discontinuations were balanced across the 3 arms (24-26%). FEN treatment significantly reduced levels of CD19+ B cells, anti-dsDNA autoantibodies, IgG, and a BTK-dependent RNA signature highly expressed in plasmablasts by W48 compared to PBO; C4 levels modestly improved with FEN vs. PBO (Table 2).Table 1.SRI-4 Response (%) at W48 in Primary Analysis and in Post-hoc Patient SubgroupsPBOFEN 150 mg QDFEN 200 mg BIDSRI-4 Response (%) at W4844n=8451n=8752n=88SRI-4 Response (%) in Baseline Subgroups At least 1 BILAG A48n=4254n=3959n=46 At least 1 BILAG A and SLEDAI increased DNA binding37n=1953n=1765n=26 SLEDAI arthritis with at least 4 swollen joints39n=5750n=5457n=54 SLEDAI arthritis with at least 4 tender joints39n=7153n=7059n=69 CLASI >=1021n=1436n=1131n=16Table 2.Key Biomarker ResultsPBOFEN 150 mg QDFEN 200 mg BIDMedian (%) Change from Baseline at W48 Plasmablast signature-19.7%n=52-54.3%*n=53-51.7%*n=57 CD19+B cells (cells/µl)-0.50n=38-57.0*n=49-57.5*n=48 Anti-dsDNA#(IU/ml)+6.9n=31-38.3*n=36-75.7*n=33 Total IgG (g/L)-0.20n=65-1.25*n=64-1.56*n=64 C3 (g/L)-0.02n=65+0.01n=67-0.01n=66 C4 (g/L)0.00n=65+0.02*n=67+0.01*n=66#Patients who were positive at baseline (>30 IU/mL)*Denotes significant vs. PBO; Kruskal-Wallis false-discovery rate controlled two sided (p-value ≤0.05)Conclusion:The primary endpoint of SRI-4 for FEN was not met despite evidence of strong BTK target and pathway inhibition. FEN had an acceptable safety profile. Several disease activity subgroups were suggestive of a greater treatment effect on SRI-4 compared to PBODisclosure of Interests:David Isenberg Consultant of: Study Investigator and Consultant to Genentech, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Nicholas S. Jones Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Pascal Guibord Shareholder of: Roche, Employee of: Roche, Joshua Galanter Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Chin Lee Shareholder of: Genentech/Roche and Eli Lilly, Employee of: Genentech/Roche, Anna McGregor Employee of: Genentech/Roche, Balazs Toth Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Julie Rae Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Olivia Hwang Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Armend Lokku Shareholder of: Roche, Employee of: Roche, Pedro Miranda Consultant of: Study Investigator for Genentech, Viviane de Souza Consultant of: Study investigator for Genentech, Juan Jaller-Raad Consultant of: Study investigator for Genentech, Anna Maura Fernandes Consultant of: Study investigator for Genentech, Rodrigo Garcia Salinas Consultant of: Study investigator for Genentech, Leslie Chinn Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Michael J. Townsend Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Alyssa Morimoto Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Katie Tuckwell Shareholder of: Genentech/Roche, Employee of: Genentech/Roche

Summary: Age-related macular degeneration (AMD) is a leading cause of vision loss. To better understand disease pathogenesis and identify causal genes in GWAS loci for AMD risk, we present a comprehensive database of human retina and retinal pigment epithelium (RPE). Our database comprises macular and non-macular RNA sequencing (RNA-seq) profiles from 129 donors, a genome-wide expression quantitative trait loci (eQTL) dataset that includes macula-specific retina and RPE/choroid, and single-nucleus RNA-seq (NucSeq) from human retina and RPE with subtype resolution from more than 100,000 cells. Using NucSeq, we find enriched expression of AMD candidate genes in RPE cells. We identify 15 putative causal genes for AMD on the basis of co-localization of genetic association signals for AMD risk and eye eQTL, including the genes TSPAN10 and TRPM1. These results demonstrate the value of our human eye database for elucidating genetic pathways and potential therapeutic targets for ocular diseases. : To find genes underlying risk for age-related macular degeneration, Orozco et al. analyze human ocular transcriptomes in conjunction with genotypes and build a single-nucleus atlas. They identify 15 putative causal genes, of which TSPAN10 and TRPM1 were enriched in retinal pigment epithelium, the site of early disease pathology. Keywords: eQTL, NucSeq, single cell, RNA-seq, age-related macular degeneration, AMD, retinal pigment epithelium, retina, GWAS

The concept of ecosystem services has gained traction as a means of linking societal benefits to the underlying ecology and functioning of ecosystems, and is now frequently included in decision-making and legislation. Moving the ecosystem service concept from theory into practice is now crucial. However, advancements in this area of research differ by ecosystem type, and marine systems lag significantly behind terrestrial counterparts in terms of understanding, implementation, and number of studies. In this paper we explore several reasons why ecosystem service research has been limited in marine systems and we outline the challenges that hinder progress. Marine systems suffer from a scarcity of spatial data relative to terrestrial counterparts. In terrestrial systems the spatial patterns of land-use/land-cover (LULC) are relatively straightforward to access via satellite and have been used as proxy indicators of service provisions. In contrast, remote sensing tools used to study the surface of the Earth are much less effective at capturing images of the seabed, and by extension marine habitats. Marine waters and their constituents are also frequently driven great distances by winds, tides, and currents. This creates a challenge for management as the identification and protection of areas where ecosystem services are exploited is not necessarily sufficient to ensure sustained service delivery. Further complications arise from the three-dimensional uses of marine systems, incorporating activities that use the sea surface, the water column and the benthic habitats below. Progress is being made as technological advancements are resulting in the acquisition of spatial data at faster rates and higher resolutions than previously possible. There is a growing capacity to map, model and value an increasing number of services with initiatives such as InVEST or principle-based modeling. We suggest that awareness is needed around the limited progress in marine systems as this could affect the way we value the biosphere and the relative proportion between biomes.

Background The biomarkers CXCL13 and sICAM1 have been associated with outcomes in patients with RA treated with TCZ. Objectives To determine the association of CXCL13 and sICAM1 with response to TCZ and disease activity in early RA and DMARD-IR patients. Methods Patient subsets from the FUNCTION (early RA) and LITHE (DMARD-IR) clinical trials were selected based on baseline and Week 24 sample availability; serum CXCL13 and sICAM1 levels were measured. Correlations between CXCL13 and sICAM1 levels and DAS28-ESR at baseline, and between change in CXCL13 and sICAM1 levels and change in DAS28-ESR at Week 24, were determined. Changes in CXCL13 and sICAM1 levels from baseline to Week 24 were compared between treatment arms using Welch t test. The effect of treatment, baseline DAS28-ESR and baseline CXCL13 and sICAM1 levels on the likelihood of DAS28-ESR remission and ACR50 response at Week 24 was determined via logistic regression. DAS28-ESR remission and ACR50 rates were compared against CXCL13 and sICAM1 status (high vs low based on median values) within each trial arm using a Cochran-Mantel-Haenszel test. Results Overall, 458 of 872 patients from FUNCTION (TCZ +MTX, n=60; TCZ monotherapy [TCZ-mono], n=157; placebo [PBO]+MTX, n=141) and 287 of 791 patients from LITHE (TCZ +MTX, n=137; PBO+MTX, n=150) were included. In these patient subsets, mean disease duration in FUNCTION was significantly shorter than in LITHE (0.45 vs 8.65 years). At baseline, correlation of serum CXCL13 levels with DAS28-ESR was moderate in the early RA population and weak in the DMARD-IR population (table 1). Correlation between baseline serum sICAM1 levels and DAS28-ESR was low in both populations. Serum levels of CXCL13 decreased significantly at Week 24 in all treatment arms in both populations, with greater reductions in the TCZ +MTX and TCZ-mono arms; sICAM1 levels decreased significantly at Week 24 in the TCZ-mono arm in patients with early RA and the TCZ +MTX arms in both populations but not in the PBO+MTX arms. Change in CXCL13 levels correlated moderately with change in DAS28-ESR at Week 24 in both populations (table 1). Change in sICAM1 levels correlated moderately with change in DAS28-ESR at Week 24 in the DMARD-IR population but weakly in the early RA population. Although the treatment arm had a significant effect on the likelihood of DAS28-ESR remission and achievement of ACR50, the effect of baseline levels of CXCL13 and sICAM1 were not significant. DAS28-ESR remission and ACR50 response rates at Week 24 within each treatment arm of the early RA and DMARD-IR populations were not significantly different between patients with high vs low baseline CXCL13 and sICAM1 levels. CXCL13. C-X-C motif chemokine ligand 13; DAS28-ESR, Disease Activity Score in 28 joints per erythrocyte sedimentation rate; DMARD-IR, inadequate response to disease-modifying antirheumatic drugs; RA, rheumatoid arthritis; sICAM1, soluble intercellular adhesion molecule 1. * Correlation between change in CXCL13 and sICAM1 levels from baseline to Week 24 and change in DAS28-ESR from baseline to Week 24; all patients combined. Conclusions The association of baseline CXCL13 levels with RA disease activity was stronger in the early RA population than in the DMARD-IR population. Changes in CXCL13 and sICAM1 correlated significantly with changes in DAS28-ESR at Week 24. However, baseline levels of CXCL13 and sICAM1 did not predict response to TCZ at Week 24, suggesting that although these biomarkers are associated with disease activity, they do not predict response to TCZ in all RA populations. Acknowledgements Funded by F. Hoffmann-La Roche Ltd. and Genentech, Inc. Disclosure of Interest T. Sornasse Employee of: Genentech, Inc., C. Gabay Grant/research support from: Roche, Pfizer, AB2 Bio, Consultant for: Roche, Pfizer, AbbVie, Novartis, Sanofi, M. Townsend Employee of: Genentech, Inc., R. Laubender Employee of: Roche Diagnostics, J. Wang Employee of: Roche Diagnostics, K. Tuckwell Employee of: Genentech, Inc.

Chronic inflammatory disorders are complex and characterized by significant heterogeneity in molecular, pathological, and clinical features. This heterogeneity poses challenges for the development of targeted molecular interventions for these disorders, as not all patients with a given clinical diagnosis have disease driven by a single dominant molecular pathway, hence not all patients will benefit equally from a given intervention. Biomarkers related to molecular manifestations of disease are increasingly being applied to enable stratified approaches to drug development. Biomarkers may be used to identify which patients are most likely to benefit from an intervention (predictive), identify patients at increased risk of disease progression (prognostic), and monitor biological responsiveness to an intervention (pharmacodynamic). Here we consider how biomarker-guided stratification of patients may increase benefit from targeted therapies for asthma, rheumatoid arthritis and inflammatory bowel diseases.

An Aluring new autoantibody target Autoimmunity is the immune system's ultimate act of betrayal. Cells designed to protect against invading microbes suddenly target the host instead. In the autoimmune disease systemic lupus erythematosus, antibodies target DNA and host proteins, including the RNA binding protein Ro60. Hung et al. discovered that Ro60 bound to endogenous Alu retroelements. They detected antibody-Ro60-Alu RNA immune complexes in the blood of individuals with lupus and an enrichment of Alu transcripts. Ro60 bound to Alu probably primes RNA-binding innate immune receptors within B cells, leading these cells to make antibodies that target Ro60-Alu RNA and drive disease-causing inflammation. Science , this issue p. 455