Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells

The aryl hydrocarbon receptor (AHR)controls interleukin 22 production by T helper 17 cells (Th17). IL-22contributes to intestinalhomeostasis but has also been implicated inchronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes that in turn play an important feedback role that curtails the duration of AHR signaling by metabolizingAHRligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signalingby disruptingmetabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-)we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cellsis profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s)

Dirty Entrepreneurship : The Intersectionality of Entrepreneurs’ Dirty Recycling Businesses

Although much has been made about heroic entrepreneurs, there is recent interest in less glamorous forms of entrepreneurship. The least glamorous is dirty entrepreneurship. In this study, we used an inductive approach and a sample of entrepreneurs engaged in dirty plastic recycling businesses to develop an intersectionality model of entrepreneurs’ dirty recycling businesses. This inductive study offers new insights into how individuals’ intersectionality pushes them into dirty entrepreneurship, how they approach their businesses, and who they stigmatize. Interestingly, individuals’ dirty place and caste push them into dirty entrepreneurship that collectively cleans the environment despite not intending to do so.©2024 Authors. Under Sage's Green Open Access policy, the Accepted Version of the article may be posted in the author's institutional repository and reuse is restricted to non-commercial and no derivative uses.fi=vertaisarvioitu|en=peerReviewed

Entrepreneurial Responses to Chronic Adversity

This open acess book extends recent work on entrepreneurship in response to adverse events to explore entrepreneurial responses by people who face chronic adversity more deeply. Instead of focusing on the sort of responses intended to destroy the institutions that create and sustain chronic adversity, the authors are interested in how individuals use entrepreneurial action to find a way within these adverse constraints to improve their lives. They explore the positive outcomes arising from these entrepreneurial actions for the entrepreneurial actor and their family members as well as the negative consequences of these entrepreneurial responses to chronic adversity—outcomes that diminish others’ well-being. The book relies on the lived experiences of those facing chronic adversity to provide insights into the bright—and dark—sides of entrepreneurship and the complexity of these relationships. It will serve as a valuable resource to scholars seeking to understand how entrepreneurial action is conceived and implemented by those facing challenging resource-poor environments

Intersectionality in intractable dirty work: how Mumbai ragpickers make meaning of their work and lives

Recent dirty work research has begun to explore intersectionality, attending to how meaning is made at the intersection of multiple sources of taint. This research has shown that individuals often construct both positive and negative meanings, which can be challenging to manage because the meanings people construct require a certain coherence to provide a foundation for action. This challenge is intensified when dirty work is intractable—when it is difficult, if not impossible, for a person to avoid doing this work. Our study of meaning making in the face of intractable dirty work examines ragpickers in Mumbai, India, who handle and dispose of garbage, and are further tainted by belonging to the lowest caste in Indian society, and living in slums. These ragpickers constructed both an overarching sense of helplessness rooted in the intractability of their situation, and a set of positive meanings—survival, destiny, and hope—rooted in specific facets of their lives and enacted through distinct temporal frames. By holding and combining these disparate meanings, they achieved “functional ambivalence”—the simultaneous experience of opposing orientations toward their work and lives that facilitated both acceptance and a sense of agency, and enabled them to carry on in their lives

An attractiveness bias? How women entrepreneurs’ physical appearance affects men investors

Women founders frequently appear to encounter varied and often negatively biased decisions from investors. Our study builds on the theoretical and practical interest in understanding whether and how biases against women entrepreneurs are attributed to men investors’ cognitive and physiological (i.e., hormonal) responses to the women’s physical appearance. Using a cross-sectional research design, we recruited 106 experienced investors and randomly assigned them to one of two versions of a prerecorded pitch to test the effect of a woman entrepreneur’s physical attractiveness. The versions were identical in content and form but were delivered by different actresses, one of whom was considered highly attractive. We asked participants to observe the pitch and answer questions on related topics, including how likely they believed the business described would successfully progress through the screening stage of the investment process. In contrast to our hypothesis, we find that a woman entrepreneur’s attractiveness positively influences men investors’ assessments of her competence. These competence assessments lead to evaluations that the entrepreneur’s proposal would progress through the investment screening stage. We also theorize and find that men investors have a marked increase in cortisol levels when presented with an attractive woman entrepreneur. This increased cortisol leads to evaluations that the entrepreneur’s proposal would progress through the screening stage. Identifying the role physiological mechanisms play in investment evaluations underscores the importance of adopting proactive measures to ensure equitable and fair investment practices alongside fostering introspection within the investment community

Open-system orchestration as a relational source of sensing capabilities: Evidence from a venture association

Research on innovation networks has highlighted the pivotal role that actors with more prominence and power, such as hub firms, may play in orchestrating the activities of other network members along a collective innovation effort. Our study examined the undertheorized, but no less important, type of orchestration that characterizes other organizations, such as business incubators and venture associations, who seek to support the dispersed entrepreneurial efforts of network members. We refer to this type as ‘open-system’ orchestration, as opposed to the commonly studied ‘closed-system’ type performed by hub firms. Our findings reveal how the processes of open-system orchestration differ markedly from those of closed-system orchestration, and detail how these processes influence the micro-foundations of network members’ sensing capabilities. By doing so, we also offer empirical substantiation and theoretical elaboration to the idea that dynamic capabilities might not reside exclusively inside firms, but could be co-created relationally with other parties in the business ecosystem

Leveraging the T2T Assembly to Resolve Rare and Pathogenic Inversions in Reference Genome Gaps

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the inversion breakpoint region was missing from at least one of the human reference genomes (GRCh37, GRCh38, T2T-CHM13) and a reference agnostic analysis was needed. One of these cases, an INV9 mappable only in de novo assembled lrGS data using T2T-CHM13 disrupts EHMT1 consistent with a Mendelian diagnosis (Kleefstra syndrome 1; MIM#610253). Next, by pairwise comparison between T2T-CHM13, GRCh37, and GRCh38, as well as the chimpanzee and bonobo, we show that hundreds of megabases of sequence are missing from at least one human reference, highlighting that primate genomes contribute to genomic diversity. Aligning population genomic data to these regions indicated that these regions are variable between individuals. Our analysis emphasizes that T2T-CHM13 is necessary to maximize the value of lrGS for optimal inversion detection in clinical diagnostics. These results highlight the importance of leveraging diverse and comprehensive reference genomes to resolve unsolved molecular cases in rare diseases

Cytochrome P450 1 genes in birds : evolutionary relationships and transcription profiles in chicken and Japanese quail embryos

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 6 (2011): e28257, doi:10.1371/journal.pone.0028257.Cytochrome P450 1 (CYP1) genes are biomarkers for aryl hydrocarbon receptor (AHR) agonists and may be involved in some of their toxic effects. CYP1s other than the CYP1As are poorly studied in birds. Here we characterize avian CYP1B and CYP1C genes and the expression of the identified CYP1 genes and AHR1, comparing basal and induced levels in chicken and quail embryos. We cloned cDNAs of chicken CYP1C1 and quail CYP1B1 and AHR1. CYP1Cs occur in several bird genomes, but we found no CYP1C gene in quail. The CYP1C genomic region is highly conserved among vertebrates. This region also shares some synteny with the CYP1B region, consistent with CYP1B and CYP1C genes deriving from duplication of a common ancestor gene. Real-time RT-PCR analyses revealed similar tissue distribution patterns for CYP1A4, CYP1A5, CYP1B1, and AHR1 mRNA in chicken and quail embryos, with the highest basal expression of the CYP1As in liver, and of CYP1B1 in eye, brain, and heart. Chicken CYP1C1 mRNA levels were appreciable in eye and heart but relatively low in other organs. Basal transcript levels of the CYP1As were higher in quail than in chicken, while CYP1B1 levels were similar in the two species. 3,3′,4,5,5′-Pentachlorobiphenyl induced all CYP1s in chicken; in quail a 1000-fold higher dose induced the CYP1As, but not CYP1B1. The apparent absence of CYP1C1 in quail, and weak expression and induction of CYP1C1 in chicken suggest that CYP1Cs have diminishing roles in tetrapods; similar tissue expression suggests that such roles may be met by CYP1B1. Tissue distribution of CYP1B and CYP1C transcripts in birds resembles that previously found in zebrafish, suggesting that these genes serve similar functions in diverse vertebrates. Determining CYP1 catalytic functions in different species should indicate the evolving roles of these duplicated genes in physiological and toxicological processes.Funding to MEJ and BB was from the Carl Tryggers Stiftelse and The Swedish Research Council Formas. Funding for BRW and JJS was from the United States National Institutes of Health (National Institute of Environmental Health Sciences), grants R01ES015912 and P42ES007381 to JJS