Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology.

OBJECTIVE: Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE. METHODS: Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE. RESULTS: ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles. CONCLUSIONS: ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution.

Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers.

BACKGROUND: Observations with rituximab suggest B-cell independent mechanisms of cutaneous lupus erythematosus (CLE) in systemic lupus erythematosus (SLE), especially discoid lupus erythematosus (DLE). Type-I interferon receptor blockade with anifrolumab shows efficacy in SLE, but efficacy for cutaneous disease of specific morphologies has not been studied. Interferon has pleotropic immune effects and it is unknown which of these are critical to therapeutic response. OBJECTIVES: We evaluated clinical efficacy and quality-of-life impact of type-I interferon-blockade in: (i) rituximab-refractory CLE; (ii) DLE and other morphologies and (iii) transcriptomic and flow cytometric biomarkers. METHODS: We conducted a prospective single-centre study of anifrolumab in refractory mucocutaneous SLE. CLE Disease Area and Severity Index (CLASI) activity score, health-related quality of life, 96-probe TaqMan® gene expression analysis capturing key SLE blood transcriptome signatures, and eight-colour flow cytometry were undertaken at baseline, 1, 3 and 6 months. RESULTS: Seven patients [DLE (n = 5), chilblain lupus erythematosus (n = 1), subacute CLE (n = 1)] were evaluated. The median number of prior therapies was six (range 3-15), including rituximab in six of seven patients. Median CLASI-A showed rapid and sustained improvement from 17 at baseline to 6 (P = 0.016) at 1 month and 0 (P < 0.001) by 3 months. The median percentage reduction in CLASI-A at 3 months was 60%. Significant improvements were observed in Dermatology Life Quality Index scores (P < 0.001), EuroQol 5D visual analogue scale (P = 0.002) and LupusQoL fatigue, image and planning domains (P ≤ 0.05). One patient discontinued treatment owing to severe herpes zoster. Clinical responses paralleled discrete suppression of interferon-stimulated genes (ISGs) from SLE blood transcriptome module M1.2 with more varied downregulation in other interferon modules. Myeloid and inflammation-annotated genes remained upregulated throughout treatment. Intermediate monocytes (CD14++CD16+) reduced to normal levels during therapy (P = 0.014), while other flow subsets showed no substantive changes. CONCLUSIONS: These data indicate rapid efficacy of anifrolumab in DLE and rituximab-resistant CLE. Response is associated with suppression of a subset of ISGs and decline in intermediate monocytes. Suppression of all ISGs or the wider SLE blood transcriptome is not required for response.

Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index.

OBJECTIVE: BILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and potential frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument. METHODS: Frequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were developed to address known issues affecting speed and accuracy. After expert verification, accuracy and usability of the finalized Easy-BILAG was validated against standard format BILAG-2004 in a workbook exercise of 10 case vignettes. Thirty-three professionals ranging in expertise from 14 UK centres completed the validation exercise. RESULTS: Easy-BILAG incorporates all items present in ≥5% BILAG-BR records, plus full constitutional and renal domains into a rapid single page assessment. An embedded glossary and colour-coding assists domain scoring. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, P = 0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5 min) than the standard format (80.0 min, P = 0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, P = 0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice. CONCLUSION: Easy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings, which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required.

Affecting behavioural change through empowerment: conceptual insights from theory and agricultural case studies in South Asia.

Affecting behavioural change is a common underlying goal across environmental and agricultural sciences, from climate change mitigation and adaptation, biodiversity conservation, water management, to crop diversification. However, many projects fail to drive or sustain change despite sound science and good intentions. This paper draws on existing theories of behavioural change to construct a conceptual framework that explores pathways to initiate and sustain change through the lens of empowerment, self-efficacy and agency. The framework is demonstrated with case studies from a project in India and Bangladesh that examined social inclusion of marginalised and poor farmers in the context of intensifying agriculture. The framework and case studies highlight that a number of conditions are needed to affect meaningful change including that target beneficiaries are suitably motivated, believe in their own capability and power to enact change and have access to the necessary resources. We propose the framework as a tool to help project teams explore the underlying elements of the process of change when designing, implementing and assessing agricultural or environmental projects and interventions. We contend that behavioural and social change needs to be explicitly fostered in such endeavours to achieve better and longer-term outcomes for the people and environment. Supplementary Information: The online version contains supplementary material available at 10.1007/s10113-022-01939-7.

Effects of knowledge and emotion on support for novel synthetic biology applications.

There is sometimes an inherent assumption that the logical head will overrule the emotional heart in matters of science and technology. However, the literature on decision making under risk and uncertainty suggests that emotional responses may be more potent. A representative sample of Australians participated in a large, national, online survey (n = 8037), in which we measured the influence of knowledge and emotion in predicting support for possible synthetic biology (synbio) solutions to conservation, environmental, and industrial problems. A hierarchical regression model was used to examine the relative influence of affect- and emotion-related factors beyond the influence of knowledge factors in predicting support for synbio solutions. Subsequently, interaction analyses were conducted to examine the potentially moderating role of emotions in the knowledge-support relationship. There was 64% variance in overall support for synbio solutions (R2 = 0.64, p < 0.001). The most influential predictor of support in the model was positive emotion. Feeling hopeful, excited, and curious toward a synbio technology was related to greater overall support for the development of that technology. The second strongest set of predictors was affect-related measures that evaluate the technology as bad or good, harmful or beneficial, and risky or safe. Positive emotion and an assessment that the technology was good significantly moderated the effect of knowledge on support. These findings suggest that, at least initially, people are more likely to be guided by their emotions when considering support for synbio technologies, which has implications for how researchers design and implement engagement and communication strategies more broadly.

Efectos del Conocimiento y las Emociones sobre el Respaldo a las Aplicaciones Novedosas de la Biología Sintética Resumen A veces existe la suposición intrínseca de que la mente lógica anulará al corazón emocional cuando se trata de temas de ciencia y tecnología. Sin embargo, la literatura sobre la toma de decisiones durante situaciones de riesgo e incertidumbre sugiere que las respuestas emocionales pueden ser más potentes. Una muestra representativa de australianos (n = 8,037) participó en una encuesta en línea realizada a nivel nacional y a gran escala. En esta encuesta medimos la influencia del conocimiento y las emociones sobre la predicción del respaldo a posibles soluciones de biología sintética (synbio) para problemas ambientales, industriales y de conservación. Usamos un modelo de regresión jerárquica para examinar la influencia relativa de los factores relacionados con el afecto o las emociones más allá de la influencia de los factores de conocimiento sobre las predicciones del respaldo a las soluciones synbio. Después realizamos análisis de interacción para examinar el papel potencialmente moderador de las emociones en la relación conocimiento-respaldo. Hubo un 64% de varianza en el respaldo general a las soluciones synbio (R2 = 0.64, p < 0.001). El pronosticador más influyente del respaldo en el modelo fue la emoción positiva. La sensación de sentirse esperanzado, emocionado y curioso debido a la tecnología synbio estuvo relacionada con un mayor respaldo generalizado para el desarrollo de aquella tecnología. El segundo conjunto más fuerte de pronosticadores fueron las medidas relacionadas con el afecto que valoran a la tecnología como buena o mala, dañina o benéfica, y riesgosa o segura. Una emoción positiva y una valoración de que la tecnología era buena moderaron significativamente el efecto del conocimiento sobre el respaldo. Estos hallazgos sugieren que, por lo menos al inicio, las personas tienen mayor probabilidad de ser guiadas por sus emociones cuando consideran el respaldo a las tecnologías synbio, lo cual tiene consecuencias para cómo los investigadores diseñan e implementan las estrategias de participación y comunicación más extensamente.

Biological control of pests and a social model of animal welfare.

This paper considers the sociocultural implications of biological pest control that sit at the cusp of managing an invasive species for conservation or productivity (i.e. a 'natural enemy') and socially driven 'manipulating life' arguments. We consider the role of perceived humaneness or, more accurately, animal welfare as it relates to managing invasive species from a scientific and social perspective. In order to highlight and articulate particular nuances and standards across different pest control contexts, we use three case examples (feral cats, wild rabbits, and invasive cane toads) and explore where biological pest control and animal welfare interests intersect. The paper summarises key scientific welfare concerns and then extends the literature to also examine key social characteristics of each pest management scenario, including lay perceptions of animal welfare, the sociocultural context that pests exist within, and overarching psychological factors contributing to public sentiment, including perceived risks. The subsequent descriptive model presented is useful in articulating core sociocultural beliefs relative to each case and how these antecedent associations and attitudes about an animal influence subsequent beliefs about a pest management strategy and ultimately acceptance of the management approach. The model can inform invasive species management policies and highlight key sociocultural factors likely to influence public responses. The model also informs interdisciplinary science designed to develop acceptable and socially responsible biocontrol strategies that consider public perceptions of animal welfare and cultural appropriateness.

"I Believe I Know Better Even than the Psychiatrists What Caused It": Exploring the Development of Causal Beliefs in People Experiencing Psychosis.

This study aimed to describe the causal beliefs of individuals experiencing psychosis, specifically exploring how they are developed and maintained. Individuals with experience of psychosis were recruited from mental health services for in-depth interviews. A thematic analysis was used to analyse transcripts and key themes were identified. Fifteen interviews were conducted. Individuals were engaged in the process of exploring explanations for their experiences and reported sophisticated models of causation. Participants described a change in their beliefs, with the cause of their experiences not immediately clear. Individuals generated their models via external (family, professionals) and internal (evaluative, positive affect) processes and reported differing levels of conviction in relation to their beliefs. Clinicians should take the opportunity to explore the causal beliefs of their service-users, as they are able to provide intelligent and thoughtful explanatory models. In particular, clinicians should be aware of the emotional impact of different aetiological models and their personal role in the development of a client's beliefs.

The Impact of Causal Explanations on Outcome in People Experiencing Psychosis: A Systematic Review.

Findings suggest that the way an individual understands their experiences has important consequences on subsequent health behaviour. One aspect of an individual's understanding is what they believe has caused their experiences. This has been associated with treatment outcome and attitudes towards mental health problems. The aim of this systematic review was to examine the impact of causal beliefs on treatment outcome and stigma in people experiencing psychosis. Three main databases were searched and 21 articles that investigated various aspects of treatment outcome, and stigma in relation to causal beliefs was included in the review. Overall, there were a small number of replicated findings which limits the interpretation of results. There is an indication that causal explanations are associated with various treatment outcomes, including attitudes towards treatment and satisfaction with therapeutic relationships as well as internalized stigma. Spiritual beliefs appeared to be adopted as a coping mechanism and a way to reduce stigma but did not appear to be associated with treatment outcome. Individuals with psychosis do appear to develop causal beliefs that may be associated with engagement with services and treatment, as well as impacting on their attitudes towards themselves and others with mental illness. This may have important implications for clinical practice. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Individuals who have experience of psychosis develop their own subjective causal explanations, and these can be complex and contradictory. An individual's causal explanation may influence how they engage with services and treatment, as well as providing a way of coming to terms with their difficulties. Causal explanations may also contribute to the experience of stigma, which is often a significant barrier to recovery for this client group.

Ecological influences on the behaviour and fertility of malaria parasites.

BACKGROUND: Sexual reproduction in the mosquito is essential for the transmission of malaria parasites and a major target for transmission-blocking interventions. Male gametes need to locate and fertilize females in the challenging environment of the mosquito blood meal, but remarkably little is known about the ecology and behaviour of male gametes. METHODS: Here, a series of experiments explores how some aspects of the chemical and physical environment experienced during mating impacts upon the production, motility, and fertility of male gametes. RESULTS AND CONCLUSIONS: Specifically, the data confirm that: (a) rates of male gametogenesis vary when induced by the family of compounds (tryptophan metabolites) thought to trigger gamete differentiation in nature; and (b) complex relationships between gametogenesis and mating success exist across parasite species. In addition, the data reveal that (c) microparticles of the same size as red blood cells negatively affect mating success; and (d) instead of swimming in random directions, male gametes may be attracted by female gametes. Understanding the mating ecology of malaria parasites, may offer novel approaches for blocking transmission and explain adaptation to different species of mosquito vectors.

High-speed holographic microscopy of malaria parasites reveals ambidextrous flagellar waveforms.

Axonemes form the core of eukaryotic flagella and cilia, performing tasks ranging from transporting fluid in developing embryos to the propulsion of sperm. Despite their abundance across the eukaryotic domain, the mechanisms that regulate the beating action of axonemes remain unknown. The flagellar waveforms are 3D in general, but current understanding of how axoneme components interact stems from 2D data; comprehensive measurements of flagellar shape are beyond conventional microscopy. Moreover, current flagellar model systems (e.g., sea urchin, human sperm) contain accessory structures that impose mechanical constraints on movement, obscuring the "native" axoneme behavior. We address both problems by developing a high-speed holographic imaging scheme and applying it to the (male) microgametes of malaria (Plasmodium) parasites. These isolated flagella are a unique, mathematically tractable model system for the physics of microswimmers. We reveal the 3D flagellar waveforms of these microorganisms and map the differential shear between microtubules in their axonemes. Furthermore, we overturn claims that chirality in the structure of the axoneme governs the beat pattern [Hirokawa N, et al. (2009) Ann Rev Fluid Mech 41:53-72], because microgametes display a left- or right-handed character on alternate beats. This breaks the link between structural chirality in the axoneme and larger scale symmetry breaking (e.g., in developing embryos), leading us to conclude that accessory structures play a critical role in shaping the flagellar beat.

Information use and plasticity in the reproductive decisions of malaria parasites.

BACKGROUND: Investment in the production of transmissible stages (gametocytes) and their sex ratio are malaria parasite traits that underpin mosquito infectivity and are therefore central to epidemiology. Malaria parasites adjust their levels of investment into gametocytes and sex ratio in response to changes in the in-host environment (including red blood cell resource availability, host immune responses, competition from con-specific genotypes in mixed infections, and drug treatment). This plasticity appears to be adaptive (strategic) because parasites prioritize investment (in sexual versus asexual stages and male versus female stages) in manners predicted to maximize fitness. However, the information, or 'cues' that parasites use to detect environmental changes and make appropriate decisions about investment into gametocytes and their sex ratio are unknown. METHODS: Single genotype Plasmodium chabaudi infections were exposed to 'cue' treatments consisting of intact or lysed uninfected red blood cells, lysed parasitized RBCs of the same clone or an unrelated clone, and an unmanipulated control. Infection dynamics (proportion of reticulocytes, red blood cell and asexual stage parasite densities) were monitored, and changes in gametocyte investment and sex ratio in response to cue treatments, applied either pre- or post-peak of infection were examined. RESULTS AND CONCLUSIONS: A significant reduction in gametocyte density was observed in response to the presence of lysed parasite material and a borderline significant increase in sex ratio (proportion of male gametocytes) upon exposure to lysed red blood cells (both uninfected and infected) was observed. Furthermore, the changes in gametocyte density and sex ratio in response to these cues depend on the age of infection. Demonstrating that variation in gametocyte investment and sex ratio observed during infections are a result of parasite strategies (rather than the footprint of host physiology), provides a foundation to investigate the fitness consequences of plasticity and explore whether drugs could be developed to trick parasites into making suboptimal decisions.

Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus.

OBJECTIVE: To determine whether serum BAFF levels correlate with relapse or remission in patients with systemic lupus erythematosus (SLE) following B cell depletion therapy (BCDT) and to assess the relationship between serum BAFF levels, B cell numbers, and immunoglobulin and autoantibody levels during active disease, both before and after BCDT. METHODS: Thirty-five patients with active SLE underwent BCDT with rituximab and were monitored for a minimum of 18 months, using clinical and serologic measures of disease activity. Serum BAFF was measured sequentially by enzyme-linked immunosorbent assay before BCDT and during disease relapse or remission after B cell repopulation. RESULTS: Serum BAFF levels prior to BCDT correlated positively with the numbers of CD19+ B cells and with the levels of IgG and IgA. Following BCDT and subsequent B cell repopulation, BAFF levels were significantly higher during relapse, as compared with disease remission, and were significantly greater than at disease flare prior to BCDT. At the time of relapse after BCDT, serum BAFF levels were inversely correlated with B cell numbers, with flare at lower B cell numbers being associated with the highest BAFF levels. The correlations between serum BAFF levels and levels of IgG and IgA were lost following BCDT, but changes in serum BAFF levels correlated positively with changes in anti-double-stranded DNA (anti-dsDNA) antibody levels during relapse or remission after BCDT. CONCLUSION: The present findings suggest a significant role of BAFF in driving disease flare after B cell repopulation following BCDT. Sequential BCDT may promote ever-increasing levels of BAFF, accompanied by rising anti-dsDNA antibody levels and disease flare even at low B cell numbers. Therefore, our data justify the judicious use of BAFF blockade in a subgroup of lupus patients after BCDT.

Where exactly do the social and behavioural sciences fit in One Health?

At its core, One Health promotes multidisciplinary cooperation amongst researchers and practitioners to improve the effectiveness and management of complex problems raised by the interplay of human, animal and environment interactions. Contemporary One Health literature has identified reducing disciplinary barriers as key to progress in the field, along with addressing the notable absence of social sciences from One Health frameworks, among other priorities. Efforts to position social scientists as experts on behaviour change and health decision-making has helped to articulate a concrete role for progressing One Health collaborations. Yet, there are other equally valuable functions the social scientist has in understanding complex systems, like One Health. We make explicit the multiple and diverse knowledge contributions the social sciences and humanities can make to progressing the One Health agenda. Articulating these more clearly invites a broader set of interdisciplinary perspectives to One Health discussions, allowing for stronger connections between sectors, actors, disciplines, and sub-systems. This perspective piece identifies a range of entry points for researchers and practitioners to better utilize the potential contributions social sciences and humanities scholars can make to One Health goals.

The New South Wales Mouse Plague 2020-2021: A One Health description.

A mouse plague occurred in Eastern Australia from spring 2020 to winter 2021, impacting an area of around 180,000 km2. It harmed human physical and psychological health, damaged the natural and built environment, and endangered farmed, domestic and native animals. However, the mouse plague was overshadowed by the COVID-19 pandemic, especially as the end of the plague coincided with the arrival and surge of the COVID-19 delta strain in rural New South Wales (NSW). In this article, we systematically overview the multiple impacts of the plague and highlight their complex interactions. Using a One Health framework, we comprehensively review the i) human, ii) animal and iii) environmental impacts including economic dimensions. Given the damage that the mouse plague caused to infrastructure, we consider the environment from two perspectives: the natural and the built environment. This One Health description of the 2020-2021 mouse plague identifies priorities for preparedness, response and recovery at local, regional land levels to inform response and management of future mouse plague events in Australia. It also highlights the need for ongoing collaboration between researchers and practitioners in the human, animal and environmental health sectors.

Sex and death: the effects of innate immune factors on the sexual reproduction of malaria parasites.

Malaria parasites must undergo a round of sexual reproduction in the blood meal of a mosquito vector to be transmitted between hosts. Developing a transmission-blocking intervention to prevent parasites from mating is a major goal of biomedicine, but its effectiveness could be compromised if parasites can compensate by simply adjusting their sex allocation strategies. Recently, the application of evolutionary theory for sex allocation has been supported by experiments demonstrating that malaria parasites adjust their sex ratios in response to infection genetic diversity, precisely as predicted. Theory also predicts that parasites should adjust sex allocation in response to host immunity. Whilst data are supportive, the assumptions underlying this prediction - that host immune responses have differential effects on the mating ability of males and females - have not yet been tested. Here, we combine experimental work with theoretical models in order to investigate whether the development and fertility of male and female parasites is affected by innate immune factors and develop new theory to predict how parasites' sex allocation strategies should evolve in response to the observed effects. Specifically, we demonstrate that reactive nitrogen species impair gametogenesis of males only, but reduce the fertility of both male and female gametes. In contrast, tumour necrosis factor-α does not influence gametogenesis in either sex but impairs zygote development. Therefore, our experiments demonstrate that immune factors have complex effects on each sex, ranging from reducing the ability of gametocytes to develop into gametes, to affecting the viability of offspring. We incorporate these results into theory to predict how the evolutionary trajectories of parasite sex ratio strategies are shaped by sex differences in gamete production, fertility and offspring development. We show that medical interventions targeting offspring development are more likely to be 'evolution-proof' than interventions directed at killing males or females. Given the drive to develop medical interventions that interfere with parasite mating, our data and theoretical models have important implications.

Is Public Engagement in Bioengineering and Synthetic Biology Improving Research Outcomes?

Engaging diverse publics on the acceptability of large-scale biology applications such as gene drives is held in high regard by the international research community. The development of gene drives to suppress invasive and pest species and improvements to the sustainability of food systems are examples of integrative biology applications in engineering and ecology with the potential for large-scale research impact. Despite a global collective intention to ensure disruptive technologies are in broad alignment with wider social and public values, evidence of applied research organizations integrating the knowledge acquired from social research is hard to find. Concrete mechanisms to ensure public perspectives affect science decision-making are yet to emerge. We offer avenues for making inroads in what we identify as a remaining gap in public engagement research in the fields of synthetic biology and bioengineering.

Xanthogranulomatous cholecystitis: diagnostic complexity and review of the literature.

We report the case of a 39-year-old male presenting with acute onset vomiting and diarrhoea. Initially treated empirically for gastroenteritis, imaging later confirmed a complicated episode of cholecystitis with fistular formation and intra-abdominal cyst. Following cholecystectomy, histology confirmed a case of xanthogranulomatous cholecystitis (XGC). This paper presents a detailed summary of the condition alongside a literature review of all available episodes of XGC since 2017 with the aim of highlighting diagnostic conclusions regarding the nature of the disease and its clinical manifestations.

Deconvolution of whole blood transcriptomics identifies changes in immune cell composition in patients with systemic lupus erythematosus (SLE) treated with mycophenolate mofetil.

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically and biologically heterogeneous autoimmune disease. We explored whether the deconvolution of whole blood transcriptomic data could identify differences in predicted immune cell frequency between active SLE patients, and whether these differences are associated with clinical features and/or medication use. METHODS: Patients with active SLE (BILAG-2004 Index) enrolled in the BILAG-Biologics Registry (BILAG-BR), prior to change in therapy, were studied as part of the MASTERPLANS Stratified Medicine consortium. Whole blood RNA-sequencing (RNA-seq) was conducted at enrolment into the registry. Data were deconvoluted using CIBERSORTx. Predicted immune cell frequencies were compared between active and inactive disease in the nine BILAG-2004 domains and according to immunosuppressant use (current and past). RESULTS: Predicted cell frequency varied between 109 patients. Patients currently, or previously, exposed to mycophenolate mofetil (MMF) had fewer inactivated macrophages (0.435% vs 1.391%, p = 0.001), naïve CD4 T cells (0.961% vs 2.251%, p = 0.002), and regulatory T cells (1.858% vs 3.574%, p = 0.007), as well as a higher proportion of memory activated CD4 T cells (1.826% vs 1.113%, p = 0.015), compared to patients never exposed to MMF. These differences remained statistically significant after adjusting for age, gender, ethnicity, disease duration, renal disease, and corticosteroid use. There were 2607 differentially expressed genes (DEGs) in patients exposed to MMF with over-representation of pathways relating to eosinophil function and erythrocyte development and function. Within CD4 + T cells, there were fewer predicted DEGs related to MMF exposure. No significant differences were observed for the other conventional immunosuppressants nor between patients according disease activity in any of the nine organ domains. CONCLUSION: MMF has a significant and persisting effect on the whole blood transcriptomic signature in patients with SLE. This highlights the need to adequately adjust for background medication use in future studies using whole blood transcriptomics.

Gene Expression and Autoantibody Analysis Revealing Distinct Ancestry-Specific Profiles Associated With Response to Rituximab in Refractory Systemic Lupus Erythematosus.

OBJECTIVE: Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy. METHODS: We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96-probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme-linked immunosorbent assays. We determined responses to first-cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity. RESULTS: Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters were associated with U1 RNP/Sm antibodies. CONCLUSION: Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies.

Genetically engineered heat-resistant coral: An initial analysis of public opinion.

Rising seawater temperatures are contributing to coral degradation in the Great Barrier Reef. Synthetic biology technologies offer the potential to enhance coral resilience to higher water temperatures. To explore what the public think of genetically engineered coral as a future solution, qualitative responses to an open-ended question in a survey of 1,148 of the Australian public were analysed. More respondents supported the technology (59%) than did not (11%). However, a considerable proportion indicated moderate support (29%). Participants commented about the (moral) right to interfere with nature and uncertainty regarding the consequences of implementing the technology. Participants also mentioned the need to take responsibility and act to save the reef, as well as the benefits likely to result from implementing the technology. Other themes included a desire for further testing and proof, more information, and tight regulation and controls when introducing the technology.