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Identifying the most deprived regions of any country or city is key if policy makers are to design successful interventions. However, locating areas with the greatest need is often surprisingly challenging in developing countries. Due to the logistical challenges of traditional household surveying, official statistics can be slow to be updated; estimates that exist can be coarse, a consequence of prohibitive costs and poor infrastructures; and mass urbanisation can render manually surveyed figures rapidly out-of-date. Comparative judgement models, such as the Bradley--Terry model, offer a promising solution. Leveraging local knowledge, elicited via comparisons of different areas' affluence, such models can both simplify logistics and circumvent biases inherent to house-hold surveys. Yet widespread adoption remains limited, due to the large amount of data existing approaches still require. We address this via development of a novel Bayesian Spatial Bradley--Terry model, which substantially decreases the amount of data comparisons required for effective inference. This model integrates a network representation of the city or country, along with assumptions of spatial smoothness that allow deprivation in one area to be informed by neighbouring areas. We demonstrate the practical effectiveness of this method, through a novel comparative judgement data set collected in Dar es Salaam, Tanzania., Comment: 23 pages, 7 figures, to be published in the journal of the Royal Statistical Society: Series C

The hormone gibberellin (GA) controls plant growth and regulates growth responses to environmental stress. In monocotyledonous leaves, GA controls growth by regulating division–zone size. We used a systems approach to investigate the establishment of the GA distribution in the maize leaf growth zone to understand how drought and cold alter leaf growth. By developing and parameterizing a multiscale computational model that includes cell movement, growth-induced dilution, and metabolic activities, we revealed that the GA distribution is predominantly determined by variations in GA metabolism. Considering wild-type and UBI::GA20-OX-1 leaves, the model predicted the peak in GA concentration, which has been shown to determine division–zone size. Drought and cold modified enzyme transcript levels, although the model revealed that this did not explain the observed GA distributions. Instead, the model predicted that GA distributions are also mediated by posttranscriptional modifications increasing the activity of GA 20-oxidase in drought and of GA 2-oxidase in cold, which we confirmed by enzyme activity measurements. This work provides a mechanistic understanding of the role of GA metabolism in plant growth regulation.

Targeting the potent immunosuppressive properties of FOXP3 + regulatory T cells (T regs ) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling T reg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of T reg homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in T regs led to accumulation of effector T regs resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8–deficient lymphoid and tissue T regs , which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human T regs have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in T regs that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.

Networks arise in many applications, such as in the analysis of text documents, social interactions and brain activity. We develop a general framework for extrinsic statistical analysis of samples of networks, motivated by networks representing text documents in corpus linguistics. We identify networks with their graph Laplacian matrices, for which we define metrics, embeddings, tangent spaces, and a projection from Euclidean space to the space of graph Laplacians. This framework provides a way of computing means, performing principal component analysis and regression, and carrying out hypothesis tests, such as for testing for equality of means between two samples of networks. We apply the methodology to the set of novels by Jane Austen and Charles Dickens., Comment: 29 pages, 10 figures

During the SARS-CoV-2 pandemic, epidemic models have been central to policy-making. Public health responses have been shaped by model-based projections and inferences, especially related to the impact of various non-pharmaceutical interventions. Accompanying this has been increased scrutiny over model performance, model assumptions, and the way that uncertainty is incorporated and presented. Here we consider a population-level model, focusing on how distributions representing host infectiousness and the infection-to-death times are modelled, and particularly on the impact of inferred epidemic characteristics if these distributions are mis-specified. We introduce an SIR-type model with the infected population structured by 'infected age', i.e. the number of days since first being infected, a formulation that enables distributions to be incorporated that are consistent with clinical data. We show that inference based on simpler models without infected age, which implicitly mis-specify these distributions, leads to substantial errors in inferred quantities relevant to policy-making, such as the reproduction number and the impact of interventions. We consider uncertainty quantification via a Bayesian approach, implementing this for both synthetic and real data focusing on UK data in the period 15 Feb-14 Jul 2020, and emphasising circumstances where it is misleading to neglect uncertainty. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology.Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes.Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis.We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.

Physical perturbation of a plant canopy brought about by wind is a ubiquitous phenomenon and yet its biological importance has often been overlooked. This is partly due to the complexity of the issue at hand: wind-induced movement (or mechanical excitation) is a stochastic process which is difficult to measure and quantify; plant motion is dependent upon canopy architectural features which, until recently, were difficult to accurately represent and model in 3-dimensions; light patterning throughout a canopy is difficult to compute at high-resolutions, especially when confounded by other environmental variables. Recent studies have reinforced the expectation that canopy architecture is a strong determinant of productivity and yield; however, links between the architectural properties of the plant and its mechanical properties, particularly its response to wind, are relatively unknown. As a result, biologically relevant data relating canopy architecture, light- dynamics, and short-scale photosynthetic responses in the canopy setting are scarce. Here, we hypothesize that wind-induced movement will have large consequences for the photosynthetic productivity of our crops due to its influence on light patterning. To address this issue, in this study we combined high resolution 3D reconstructions of a plant canopy with a simple representation of canopy perturbation as a result of wind using solid body rotation in order to explore the potential effects on light patterning, interception, and photosynthetic productivity. We looked at two different scenarios: firstly a constant distortion where a rice canopy was subject to a permanent distortion throughout the whole day; and secondly, a dynamic distortion, where the canopy was distorted in incremental steps between two extremes at set time points in the day. We find that mechanical canopy excitation substantially alters light dynamics; light distribution and modeled canopy carbon gain. We then discuss methods required for accurate modeling of mechanical canopy excitation (here coined the 4-dimensional plant) and some associated biological and applied implications of such techniques. We hypothesize that biomechanical plant properties are a specific adaptation to achieve wind-induced photosynthetic enhancement and we outline how traits facilitating canopy excitation could be used as a route for improving crop yield.

Gene delivery methods are important for both therapeutic intervention and as tools in research to address specific questions. Hydrodynamic injection (HDI) is a method that facilitates the delivery and expression of genetic material in target cells, namely hepatocytes, through an intravenous injection. HDI has great utility for research involving cell death and signaling pathways essential in the processes of cancer, inflammation, and transplant therapy, as well as representing a valuable technique to establish hepatitis B virus (HBV) expression in hepatocytes. This chapter describes in detail how to generate a model of chronic HBV infection in immunocompetent mice using HDI as a delivery method.

The lack of expression of the suppressor of cytokine signalling-3 (SOCS3) or inactivation of the negative regulatory capacity of SOCS3 has been well documented in rheumatoid arthritis, viral hepatitis and cancer. The specific qualitative and quantitative consequences of SOCS3 deficiency on interleukin-6 (IL-6)-mediated pro- and anti-inflammatory responses remain controversial in vitro and unknown in vivo. Mice with a conditional deletion of SOCS3 in hematopoietic cells develop lethal inflammatory disease during adult life and develop gross histopathological changes during experimental arthritis, typified by elevated IL-6 levels. To clarify the nature of the IL-6 responses in vivo, we generated mice deficient in SOCS3 (SOCS3(-/Δvav)) or both SOCS3 and IL-6 (IL-6(-/-)/SOCS3(-/Δvav)), and examined responses in models of acute and chronic inflammation. Acute responses to IL-1β were lethal to SOCS3(-/Δvav) mice but not IL-6(-/-)/SOCS3(-/Δvav) mice, indicating that IL-6 was required for the lethal inflammation induced by IL-1β. Administration of IL-1β to SOCS3(-/Δvav) mice induced systemic apoptosis of lymphocytes in the thymus, spleen and lymph nodes that was dependent on the presence of IL-6. IL-6 deficiency prolonged survival of SOCS3(-/Δvav) mice and ameliorated spontaneous inflammatory disease developing during adult life. Infection of SOCS3(-/Δvav) mice with LCMV induced a lethal inflammatory response that was dependent on IL-6, despite SOCS3(-/Δvav) mice controlling viral replication. We conclude that SOCS3 is required for survival during inflammatory responses and is a critical regulator of IL-6 in vivo.

BH3 mimetic drugs that target BCL-2 family pro-survival proteins to induce tumour cell apoptosis represent a new era in cancer therapy. Clinical trials of navitoclax (ABT-263, which targets BCL-2, BCL-XL and BCL-W) have shown great promise, but encountered dose-limiting thrombocytopenia. Recent work has demonstrated that this is due to the inhibition of BCL-XL, which is essential for platelet survival. These findings raise new questions about the established model of platelet shedding by megakaryocytes, which is thought to be an apoptotic process. Here we generate mice with megakaryocyte-specific deletions of the essential mediators of extrinsic (Caspase-8) and intrinsic (BAK/BAX) apoptosis. We show that megakaryocytes possess a Fas ligand-inducible extrinsic apoptosis pathway. However, Fas activation does not stimulate platelet production, rather, it triggers Caspase-8-mediated killing. Combined loss of Caspase-8/BAK/BAX does not impair thrombopoiesis, but can protect megakaryocytes from death in mice infected with lymphocytic choriomeningitis virus. Thus, apoptosis is dispensable for platelet biogenesis.

SummaryUnderstanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.

Nat. Immunol. 14, 1155–1165 (2013); published online 22 September 2013; corrected after print 8 January 2014 In the version of this article initially published, the scale of the top row (Naive) for S1pr1 in Figure 5d is incorrect. With the correct scale, S1pr1 expression in naive CD8+ T cells is accurately presented as very high.

Abstract 1213 The inflammasome is an innate immune complex that recognizes a wide range of pathogen, cellular stress and damage signals. It triggers the Caspase-1-dependent production of inflammatory cytokines including IL-1β and IL-18. Sensors for the inflammasome include the nucleotide-binding oligomerisation domain, leucine-rich repeat (NLR) proteins. The best-characterised of these is NLRP3, which mediates antibacterial, viral, fungal and parasitic immune responses, and is mutated in a spectrum of autoinflammatory diseases. Activation of mammalian NLRs can also result in a Caspase-1-dependent form of cell death termed pyroptosis, the importance of which in disease states remains unclear. For example, it is known that NLRP3 activating mutations in humans can be effectively treated by neutralising IL-1β, suggesting that cell death induced by NLRP3 activation does not play a significant role in pathology. Similarly, the NLRP1b inflammasome is activated by anthrax lethal toxin to cause macrophage pyroptosis, but this does not play a role in anthrax sensitivity in vivo. Here we define a role for NLRP1 in autoinflammatory disease and the pyroptotic death of hematopoietic progenitor cells. We began by generating two mouse models, one carrying a point mutation in NLRP1a that results in constitutive activation of the protein, and another harbouring a deletion of the entire NLRP1 locus. Animals homozygous for the NRLP1a activating mutation developed a multi-organ neutrophilic inflammatory disease characterised by meningitis, hepatitis, pneumonitis, pancreatitis, pulmonary peri-arteritis, myocarditis and inflammatory bowel disease. Mean survival was approximately 3 months of age. Genetic crosses established that this inflammatory disease was driven by Caspase-1 and IL-1β, but was independent of ASC and Caspase-11, and ameliorated by IL-18. Surprisingly, in the absence of IL-1β-driven inflammation, constitutively active NLRP1a triggered the Caspase-1-dependent death of hematopoietic progenitor cells resulting in leukopenia at steady state. To evaluate the effect of activated NLRP1a during hematopoietic stress, IL-1 receptor-deficient mice homozygous for the NRLP1a activating mutation were challenged with 5-fluorouracil. Strikingly, these animals succumbed shortly after the nadir of leukopenia at 12 days post-injection. They exhibited hypoplastic bone marrow, lymphopenia, monocytopenia and a deficit of reticulocytes consistent with a functional deficiency in hematopoietic progenitor cells. Conversely, in mice lacking NLRP1, we observed improved recovery of the hematopoietic compartment following hemoablative chemotherapy, with increases in the numbers of platelets, lymphocytes and monocytes relative to littermate controls. Severe infections are commonly associated with a range of cytopenias including anemia, lymphopenia, neutropenia and thrombocytopenia, however, the etiological triggers for these conditions have not been elucidated. We therefore infected IL-1 receptor-deficient mice homozygous for the NRLP1a activating mutation with lymphocytic choriomeningitis virus (LCMV). Relative to controls, more severe cytopenia and bone marrow hypoplasia was observed. In contrast, NLRP1-deficient animals showed enhanced recovery from LCMV. Our results suggest that activation of the NLRP1 inflammasome in hematopoietic progenitors may contribute to cytopenias induced by hematopoietic stresses such as chemotherapy or infection. Disclosures: No relevant conflicts of interest to declare.