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Human genetic studies have linked rare coding variants in microglial genes, such as TREM2, and more recently PLCG2 to Alzheimer’s disease (AD) pathology. The P522R variant in PLCG2 has been shown to confer protection for AD and to result in a subtle increase in enzymatic activity. PLCγ2 is a key component of intracellular signal transduction networks and induces Ca2+ signals downstream of many myeloid cell surface receptors, including TREM2. To explore the relationship between PLCγ2 and TREM2 and the role of PLCγ2 in regulating immune cell function, we generated human induced pluripotent stem cell (iPSC)- derived macrophages from isogenic lines with homozygous PLCG2 knockout (Ko). Stimulating TREM2 signalling using a polyclonal antibody revealed a complete lack of calcium flux and IP1 accumulation in PLCγ2 Ko cells, demonstrating a non-redundant role of PLCγ2 in calcium release downstream of TREM2. Loss of PLCγ2 led to broad changes in expression of several macrophage surface markers and phenotype, including reduced phagocytic activity and survival, while LPS-induced secretion of the inflammatory cytokines TNFα and IL-6 was unaffected. We identified additional deficits in PLCγ2- deficient cells that compromised cellular adhesion and migration. Thus, PLCγ2 is key in enabling divergent cellular functions and might be a promising target to increase beneficial microglial functions.

In the article, we propose a general theoretical framework to distinguish a set of possible options for integration between social sciences. Adopting the so-called ‘nation’ metaphor in order to investigate relationships between disciplines, the framework uses an analogy with Dani Rodrik’s ‘world political trilemma’ (whereby democracy—here self-determination of science—national sovereignty—here disciplines—and global economic integration—here disciplinary integration—are mutually incompatible) to distinguish three different roads to the realisation of the unity of social science (‘reductionism’, ‘integration’ and ‘complexity’). The framework is then applied to recent proposals for unifying the social sciences that have originated within the economics profession at a time of pervasive specialisation and increasing fragmentation. While discussing the origins, the feasibility and the desirability of disciplinary integration projects, we concentrate on the issue of pluralism in both social sciences and within economics and on the ‘structural’ conditions that would permit economics to participate in the development of a transdisciplinary behavioural science.

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This paper provides my reflections on the state of economic methodology and philosophy of economics as of the beginning of 2020 following the end of a fifteen year co-editorship of the Journal of Economic Methodology with Wade Hands. It looks at how economic methodology and philosophy of economics, as a meta-field type of research, has changed since it emerged as a distinct subfield in economics in the 1980s. Using an evolution of technology analysis, it distinguishes two different possible scenarios for the field’s future according to environmental factors operating upon it and how specialization in research may affect both it and economics, and then makes a crossdisciplinarity argument for its further development as a diverse, pluralistic domain of research.JEL Codes : B41, B20.

This paper discusses how counterfactual thinking can be incorporated into behavioral economics by relating it to a type of attribution substitution involved in choices people make in conditions of Knightian uncertainty. It draws on Byrne’s ‘rational imagination’ account of counterfactual thinking, evidence from cognitive science regarding the forms it takes, and identifies types of attribution substitution specific to economic behavior. This approach, which elucidates the reflective stage of causal reasoning, is relevant for the explanation of hypothetical causal rules suitable for diverse tasks such as planning, expectations and mental simulations and for behavioural change interventions, which take into account people’s social and institutional embeddedness. The paper closes with a discussion of how this implies a specifically social Homo sapiens individual conception.

Background TREM2 is a microglial cell surface receptor, with risk mutations linked to Alzheimer’s disease (AD), including R47H. TREM2 signalling via SYK aids phagocytosis, chemotaxis, survival, and changes to microglial activation state. In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid and prevents microglial activation. The R47H mutation is proposed to reduce TREM2 ligand binding. We investigated cell phenotypes of the R47H mutant and TREM2 KO in a model of human microglia, and compared their transcriptional signatures, to determine the mechanism by which R47H TREM2 disrupts function. Methods We generated human microglia-like iPSC-macrophages (pMac) from isogenic induced pluripotent stem cell (iPSC) lines, with homozygous R47H mutation or TREM2 knockout (KO). We firstly validated the effect of the R47H mutant on TREM2 surface and subcellular localization in pMac. To assess microglial phenotypic function, we measured phagocytosis of dead neurons, cell morphology, directed migration, survival, and LPS-induced inflammation. We performed bulk RNA-seq, comparing significant differentially expressed genes (DEGs; p Results R47H modified surface expression and shedding of TREM2, but did not impair TREM2-mediated signalling, or gross phenotypes that were dysregulated in the TREM2 KO (phagocytosis, motility, survival). However, altered gene expression in the R47H TREM2 pMac overlapped by 90% with the TREM2 KO and was characterised by dysregulation of genes involved with immunity, proliferation, activation, chemotaxis, and adhesion. Downregulated mediators of ECM adhesion included the vitronectin receptor αVβ3, and consequently, R47H TREM2 pMac adhered weakly to vitronectin compared with WT pMac. To counteract these transcriptional defects, we investigated TGFβ1, as a candidate upstream regulator. TGFβ1 failed to rescue vitronectin adhesion of pMac, although it improved αVβ3 expression. Conclusions The R47H mutation is not sufficient to cause gross phenotypic defects of human pMac under standard culture conditions. However, overlapping transcriptional defects with TREM2 KO supports the hypothesised partial loss-of-function effects of the R47H mutation. Furthermore, transcriptomics can guide us to more subtle phenotypic defects in the R47H cells, such as reduced cell adhesion, and can be used to predict targets for therapeutic intervention.

Summary Excessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro‐inflammatory cytokine interleukin(IL)‐1β. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti‐inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo. A specific inhibitor of the β HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL‐1β and IL‐6 in vivo when administered orally, and was brain‐penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation., HSP90 inhibitors inhibit priming and activation of the NLRP3 inflammasome.

Emerging evidence suggests the role of environmental chemicals, in particular endocrine-disrupting chemicals (EDCs), in progression of breast cancer and treatment resistance, which can impact survival outcomes. However, most research tends to focus on tumor etiology and the effect of single chemicals, offering little insight into the effects of realistic complex mixture exposures on tumor progression. Herein, we investigated the effect of a polycyclic aromatic hydrocarbon (PAH)-enriched EDC mixture in a panel of normal and breast cancer cells and in a tumor organoid model. Cells or organoids in culture were treated with EDC mixture at doses estimated from US adult intake of the top four PAH compounds within the mixture from the National Health and Nutrition Examination Survey database. We demonstrate that low-dose PAH mixture (6, 30 and 300 nM) increased aryl hydrocarbon receptor (AhR) expression and CYP activity in estrogen receptor (ER) positive but not normal mammary or ER-negative breast cancer cells, and that upregulated AhR signaling corresponded with increased cell proliferation and expression of antiapoptotic and antioxidant proteins XIAP and SOD1. We employed a mathematical model to validate PAH-mediated increases in AhR and XIAP expression in the MCF-7 ER-positive cell line. Furthermore, the PAH mixture caused significant growth increases in ER-negative breast cancer cell derived 3D tumor organoids, providing further evidence for the role of a natural-derived PAH mixture in enhancing a tumor proliferative phenotype. Together, our integrated cell signaling, computational and phenotype analysis reveals the underlying mechanisms of EDC mixtures in breast cancer progression and survival.

This paper estimates the effects of potential post-Brexit UK trade and domestic agricultural policy scenarios on the economic welfare (real income) of farm households, at both regional (devolved ad...

This paper aims to contribute to the analysis of expectations and belief reversals in a evolutionary and complexity economics framework. It formulates its analysis in terms of the concept of reflexivity, drawing on the ideas regarding reflexivity in financial markets of George Soros, and lays out a model of how a financial cycle expresses a systematic pattern of interacting feedback effects. The paper develops this analysis as a complex interaction between sets of heterogeneous expectations derived from the behavior of reflexive economic agents. Positive and negative feedback phases in a cycle are distinguished and associated with boom and bust stages of that cycle. A central role is played by agents’ beliefs and judgments underlying their expectations, and how those beliefs and judgments in uncertain circumstances are changeable and subject to abrupt reversals which can manifest themselves in “Minsky moments.” The paper argues that agents’ belief reversals result from their misconceptions about causal processes in booms and upswings, a misconception that reflects their tendency to think causally in terms of negative feedback patterns rather than positive ones.

The subject of this special issue of the Forum for Social Economics is ‘Identity, Institutions, and Power.’ As an introduction and as background for how the papers in the issue address this complex...

Care is central to the human experience and part of the social provisioning process. Adam Smith recognised this, associating care with sympathy. Later contributions in the political economy traditi...

The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease. Fenamate non-steroidal anti-inflammatory drugs (NSAIDs) were recently described as NLRP3 inflammasome inhibitors via chloride channel inhibition. Fenamate NSAIDs inhibit cyclooxygenase (COX) enzymes, limiting their potential as therapeutics for NLRP3-associated diseases due to established side effects. The aim here was to develop properties of the fenamates that inhibit NLRP3, and at the same time to reduce COX inhibition. We synthesised a library of analogues, with feedback from in silico COX docking potential, and IL-1β release inhibitory activity. Through iterative screening and rational chemical design, we established a collection of chloride channel inhibiting active lead molecules with potent activity at the canonical NLRP3 inflammasome and no activity at COX enzymes, but only in response to stimuli that activated NLRP3 by a K+ efflux-dependent mechanism. This study identifies a model for the isolation and removal of unwanted off-target effects, with the enhancement of desired activity, and establishes a new chemical motif for the further development of NLRP3 inflammasome inhibitors., The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Intestinal metaplasia (IM) in the esophagus is a potentially premalignant mucosal change. The aim of this study was to compare the frequency of IM detection during upper endoscopy by forceps biopsy sampling (FB) versus wide-area transepithelial sampling (WATS) brush.Patients presenting for upper endoscopy for foregut symptoms or surveillance of Barrett's esophagus (BE) at 9 centers in the United States were randomized to either FB or WATS.Of 1002 patients, FB was done in 505 and WATS in 497. The overall frequency of finding IM was 21% and was similar with FB (19.6%) and WATS (22.7%, P = .2). Low-grade dysplasia was found in 8 patients. No patient had high-grade dysplasia. There was no difference in detection of dysplasia between FB and WATS. In patients with no history of IM, WATS found significantly more IM compared with FB when a columnar-lined esophagus (CLE) was present (32.4% with WATS vs 15.2% with FB, P = .004). In 184 patients with known BE, FB and WATS found IM with similar frequency (38.5% FB vs 41.9% WATS, P = .6) with no difference in short- or long-segment BE.Overall, FB and WATS detected a similar frequency of IM and dysplasia. WATS was twice as likely as FB to find IM in patients without a history of BE who had CLE on endoscopy. In patients with known BE, WATS and FB showed IM and dysplasia with similar frequency. These findings suggest that WATS can be used instead of FB with similar or improved efficacy at detecting IM and dysplasia. (Clinical trial registration number: NCT03859557.).

Stratification economics (SE) is an emergent subfield in economics, but its JEL classification misrepresents its content and its relationship to the whole of economics. This paper first develops a more accurate characterization of SE by identifying its differences with mainstream economics (ME), its commonalities with economics in a broad sense, and how the combination of these differences and commonalities define it as a distinct research program. It then applies this definition to an economic goods taxonomy that makes a distinction between local public goods and common pool goods to interpret SE’S distinct research program as an economics of exclusion. The paper closes with a discussion of how SE might explain socioeconomic change in social group identity terms.

This paper investigates whether specialisation in research is causing economics to become an increasingly fragmented and diverse discipline with a continually rising number of niche-based research programmes and a declining role for dominant cross-science research programmes. It opens by framing the issue in terms of centrifugal and centripetal forces operating on research in economics, and then distinguishes descriptive from normative pluralism. It reviews recent research regarding the JEL code and economics’ J. B. Clark Award that points towards rising specialisation and fragmentation of research in economics. It then reviews five related arguments that might explain increasing specialisation and fragmentation in economics: (i) Smith’s early division of labour view, (ii) Kuhn’s later thinking about the importance of specialisation, (iii) Heiner’s behavioral burden of knowledge argument, (iv) Ross’s innovation-diffusion analysis and Arthur’s theory of technological change as determinants of speci...

Microglia orchestrate neuroimmune responses in several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Microglia clear up dead and dying neurons through the process of efferocytosis, a specialized form of phagocytosis. The phagocytosis function can be disrupted by environmental or genetic risk factors that affect microglia. This paper presents a rapid and simple in vitro microscopy protocol for studying microglial efferocytosis in an induced pluripotent stem cell (iPSC) model of microglia, using a human neuroblastoma cell line (SH-SY5Y) labeled with a pH-sensitive dye for the phagocytic cargo. The procedure results in a high yield of dead neuroblastoma cells, which display surface phosphatidylserine, recognized as an "eat-me" signal by phagocytes. The 96-well plate assay is suitable for live-cell time-lapse imaging, or the plate can be successfully fixed prior to further processing and quantified by high-content microscopy. Fixed-cell high-content microscopy enables the assay to be scaled up for screening of small molecule inhibitors or assessing the phagocytic function of genetic variant iPSC lines. While this assay was developed to study phagocytosis of whole dead neuroblastoma cells by iPSC-macrophages, the assay can be easily adapted for other cargoes relevant to neurodegenerative diseases, such as synaptosomes and myelin, and other phagocytic cell types.

Piero Sraffa’s Production of Commodities by Means of Commodities (1960) was path-breaking as a contribution to political economy and penetrating as a critique of the orthodox economics of the twentieth century. As Ajit Sinha recently put it, the book produced a ‘revolution in economic theory’ (Sinha, A Revolution in Economic Theory: The Economics of Piero Sraffa, London: Palgrave Macmillan, 2016; cf. Martins, “The Sraffian Methodenstreit and the Revolution in Economic Theory,” Cambridge Journal of Economics 43 (2): 507–525, 2019), the impact and significance of which continues to be investigated. At the same time, despite the depth and far-reaching implications of Sraffa’s critique of orthodox economics it was ignored by the great majority of economists, and this not only complicates our understanding of its impact on economic theory, but also creates a paradox regarding our interpretation of ‘the’ history of economics. For Sraffa, ‘the’ history of economics dates back at least to Adam Smith and David Ricardo as founders of a subject specifically understood as political economy. Yet economics today is no longer identified as political economy by most people in the field, but is conventionally said to be a science independent of history, politics, and social values, and thus makes little reference to how the social organization of the economy was a distinctive characteristic of the thinking of Smith, Ricardo, Marx, and others in the history of political economy.

This chapter examines John Tomer’s contributions to our understanding of the concept of human capital. Tomer criticized the standard mainstream view of the concept as narrowly focused on education and training and as seeing investments in human capital as having “an individual, cognitive, and machine-like nature.” A broader concept included attention to the people’s noncognitive development, and employed both social capital and personal capital concepts. This produces a more expansive view of human development, allows for a humanistic psychological perspective, and supports a multi-dimensional, Maslovian understanding of the hierarchy of human needs. Tomer framed his policy thinking regarding investments in human capital in terms of the goal of helping people become ‘smart’ persons. He recognized that a barrier to accomplishing this is high levels of economic inequality. The chapter thus goes on to discuss how socially stratified societies generate economic inequality in regard to human capital investments, and how thinking in terms of people’s capabilities can help us advance progressive economic and social policies agendas.

This paper examines how attribute substitution (AS), central to the psychology of choice and behavioral economic reasoning, can be understood when combined with counterfactual thinking (CFT), often called ‘what if’ or ‘if only’ thinking, and how their combination creates important opportunities for the seeing heterodox economics as a single research program alternative to mainstream economics. The first section of the paper discusses AS, CFT, and what a AS-CFT behavioral framework involves, and then emphasizes how this framework departs from fundamental assumptions mainstream rational choice theory employs. The second section reviews the foundations of behavioral thinking regarding AS, describes what it involves when it includes attention to CFT, distinguishes between more automatic and more reflective types of behavioral adjustment. It notes that heterodox economics has generally emphasized ecological rationality and bounded rationality in its use of AS. The third section then discusses how six prominent heterodox approaches can each be understood to draw on this combination of AS and CFT, and how this represents common ground for a shared critique of the mainstream economic approach. What distinguishes them is how they differ regarding the weight and emphasis placed on more automatic versus more reflective types of behavioral adjustment. The fourth section argues that within this shared framework these different heterodox approaches practice a division of labor in how they address different aspects of economic life understood in behavioral and counterfactual terms.

This chapter develops a conception of reflexive economic agents as an alternative to the standard utility conception and explains individual identity in terms of how agents adjust to change in a self-organizing way, an idea developed from Herbert Simon. It seeks to model the behavior of economic agents in a manner that builds on the important contributions of Stefano Zambelli to the understanding of computation and dynamical economic systems. This chapter distinguishes closed equilibrium and open process conceptions of the economy and argues the former fails to explain time in a before-and-after sense in connection with Aristotle’s sea battle problem. A causal model is developed to represent the process conception, and a structure-agency understanding of the adjustment behavior of reflexive economic agents is illustrated using Merton’s self-fulfilling prophecy analysis. Simon’s account of how adjustment behavior has stopping points is then shown to underlie how agents’ identities are disrupted and then self-organized, and the identity analysis this involves is applied to the different identity models of Merton, Ross, Arthur, and Kirman. Finally, the self-organization idea is linked to the recent ‘preference purification’ debate in bounded rationality theory regarding the ‘inner rational agent trapped in an outer psychological shell,’ and it is argued that the behavior of self-organizing agents involves them taking positions toward their own individual identities.