Editorial Decision Research Articles

Interleukin-38 promotes skin tumorigenesis in an IL-1Rrp2-dependent manner.

Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL-38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12-dimethylbenzanthracene/12-O-tetradecanoyl phorbol-13-acetate-induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte-specific deletion of IL-38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL-38 is dispensable for epidermal mutagenesis, but IL-38 keratinocyte-specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL-38 activates the c-Jun N-terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer-related inflammatory cytokines and proliferation and migration of tumor cells in an IL-1 receptor-related protein 2 (IL-1Rrp2)-dependent manner. Our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2/JNK and suggest IL-38/IL-1Rrp2 as a preventive and potential therapeutic target in skin cancer.

Credit Union and Bank Subprime Lending in the Great Recession

Abstract Firm structure affects incentives and performance. We document significant differences in subprime lending between banks and credit unions prior to and during the Great Recession. In 2006, 23.6% of mortgages from commercial banks were subprime versus only 3.6% of mortgages from credit unions. Moreover, banks were more likely to fail, and had higher delinquency and net charge-off ratios immediately following the financial crisis. Our empirical models control for important differences between credit unions and banks including firm-level characteristics, borrower-level characteristics, and state-level economic conditions. We argue that the remaining difference captures the effects of credit unions’ nonprofit and cooperative structure, which encourages them to internalize the utility of their customer-owners. Our findings explain why credit unions often appear more risk averse relative to commercial banks, a result with important research and policy implications. (JEL G12, G31)

Correction.

Journal Article Correction Get access Journal of Breast Imaging, wbac029, https://doi.org/10.1093/jbi/wbac029 Published: 05 May 2022 Article history Received: 12 October 2021 Editorial decision: 20 December 2021 Published: 05 May 2022

Understanding Bank Payouts during the Crisis of 2007–2009

Abstract We study U.S. banks’ payout policy in 2007–2008. We benchmark these payouts against payouts before the crisis, measure stock price reactions to announcements of dividend changes, and analyze changes in the relation between payout growth and future performance. Further, we examine cross-sectional variation in banks’ payout policy to gauge the possible motives underlying banks’ payout decisions in 2007–2008. We do not find that banks that have a higher willingness to take risk or that have higher incentives to undertake asset substitution use their payout policy to engage in more wealth transfer compared to other banks. (JEL G21, G24, G28, G32, G35). Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.

KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7.

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and liver injury, has become a leading cause of end-stage liver diseases and liver transplantation. Krüppel-like factors 10 (KLF10) is a Cys2/His2 zinc finger transcription factor that regulates cell growth, apoptosis, and differentiation. However, whether it plays a role in the development and progression of NASH remains poorly understood. In the present study, we found that KLF10 expression was selectively upregulated in the mouse models and human patients with NASH, compared with simple steatosis (NAFL). Gain- and loss-of function studies demonstrated that hepatocyte-specific overexpression of KLF10 aggravated, whereas its depletion alleviated diet-induced NASH pathogenesis in mice. Mechanistically, transcriptomic analysis and subsequent functional experiments showed that KLF10 promotes hepatic lipid accumulation and inflammation through the palmitoylation and plasma membrane localization of fatty acid translocase CD36 via transcriptionally activation of zDHHC7. Indeed, both expression of zDHHC7 and palmitoylation of CD36 are required for the pathogenic roles of KLF10 in NASH development. Thus, our results identify an important role for KLF10 in NAFL-to-NASH progression through zDHHC7-mediated CD36 palmitoylation.

Agency Conflicts and Investment: Evidence from a Structural Estimation

Abstract We develop a dynamic capital structure model to study how agency conflicts between managers and shareholders affect the joint determination of financing and investment decisions. We show that there are two agency conflicts with opposing effects on a manager’s choice of investment: first, the consumption of private benefits channel leads managers not only to choose a lower optimal leverage, but also to underinvest, and second, compensation linked to firm size may lead managers to overinvest. We fit the model to the data and show that the average firm slightly overinvests, younger CEOs invest more than older ones, while CEOs with longer tenure overinvest more than CEOs with shorter tenure. (JEL G12, G31, G32)

Editorial Policy

Editorial Policy

Editorial Policy

Editorial Policy

Editorial Policy

Editorial Policy

Dual control of dopamine in Drosophila myeloid-like progenitor cell proliferation and regulation of lymph gland growth.

In Drosophila, definitive haematopoiesis takes place in a specialized organ termed "lymph gland". It harbours multi-potent stem-like blood progenitor cells whose development controls overall growth of this haematopoietic tissue and formation of mature blood cells. With respect to its development, neurotransmitters have emerged as potent regulators of blood-progenitor cell development and function. In this study, we extend our understanding of neurotransmitters and show that progenitors are self-sufficient with regard to synthesizing dopamine, a well-established neurotransmitter. These cells also have modules for dopamine sensing through the receptor and transporter. We found that modulating expression of these components in progenitor cells affected lymph gland growth, which suggested growth-promoting function of dopamine in blood-progenitor cells. Cell-cycle analysis of developing lymph glands revealed an unexpected requirement for intracellular dopamine in moderating the progression of early progenitor cells from S to G2 phase of the cell cycle, while activation of dopamine receptor signalling later in development regulated their progression from G2 and entry into mitosis. The dual capacity in which dopamine operated, first intracellularly to coordinate S/G2 transition and later extracellularly in G2/M transition, was critical for the growth of the lymph gland. Overall, the data presented highlight a novel non-canonical use of dopamine in the myeloid system that reveals an uncharacterized function of intracellular dopamine in cell-cycle phasing with outcomes on haematopoietic growth and immunity as well.

External light-dark cycle shapes gut microbiota through intrinsically photosensitive retinal ganglion cells.

Gut microbiota are involved in many physiological functions such as metabolism, brain development, and neurodegenerative diseases. Many microbes in the digestive tract do not maintain a constant level of their relative abundance but show daily oscillations under normal conditions. Recent evidence indicates that chronic jetlag, constant darkness, or deletion of the circadian core gene can alter the composition of gut microbiota and dampen the daily oscillation of gut microbes. However, the neuronal circuit responsible for modulating gut microbiota remained unclear. Using genetic mouse models and 16s rRNA metagenomic analysis, we find that light-dark cycle information transmitted by the intrinsically photosensitive retinal ganglion cells (ipRGCs) is essential for daily oscillations of gut microbes under temporal restricted high-fat diet conditions. Furthermore, aberrant light exposure such as dim light at night (dLAN) can alter the composition, relative abundance, and daily oscillations of gut microbiota. Together, our results indicate that external light-dark cycle information can modulate gut microbiota in the direction from the brain to the gut via the sensory system.

The DoCTRINE Guidelines: Defined Criteria To Report INnovations in Education.

Reporting guidelines assist authors in conducting and describing their research in alignment with evidence-based and expert-determined standards. However, published research-oriented guidelines do not capture all of the components that must be present in descriptions of educational innovations in health professions education. The authors aimed to create guidelines for educational innovations in curriculum development that would be easy for early-career educators to use, support reporting necessary details, and promote educational scholarship. Beginning in 2017, the authors systematically developed a reporting checklist for educational innovations in curriculum development, called Defined Criteria To Report INnovations in Education (DoCTRINE), and collected validity evidence for its use according to the 4 inferences of Kane's framework. They derived the items using a modified Delphi method, followed by pilot testing, cognitive interviewing, and interrater reliability testing. In May-November 2019, they implemented DoCTRINE for authors submitting to MedEdPORTAL, half of whom were randomized to receive the checklist (intervention group). The authors scored manuscripts using DoCTRINE while blinded to group assignment, and they collected data on final editorial decisions. The final DoCTRINE checklist consists of 19 items, categorized into 5 components: introduction, curriculum development, curriculum implementation, results, and discussion. The overall interrater agreement was 0.91. Among the 108 manuscripts submitted to MedEdPORTAL during the study period, the mean (SD) total score was higher for accepted than rejected submissions (16.9 [1.73] vs 15.7 [2.24], P = .006). There were no significant differences in DoCTRINE scores between the intervention group, who received the checklist, and the control group, who did not. The authors developed DoCTRINE, using systematic approaches, for the scholarly reporting of educational innovations in curriculum development. This checklist may be a useful tool for supporting the publishing efforts of early-career faculty.

Falling into the Gaps, Together: On Peer Review as Intellectual Accompaniment

Falling into the Gaps, Together: On Peer Review as Intellectual Accompaniment

A human coronavirus OC43-derived polypeptide causes neuropathic pain.

Human coronaviruses have been recently implicated in neurological sequelae by insufficiently understood mechanisms. We here identify an amino acid sequence within the HCoV‐OC43 p65‐like protein homologous to the evolutionarily conserved motif of myelin basic protein (MBP). Because MBP‐derived peptide exposure in the sciatic nerve produces pronociceptive activity in female rodents, we examined whether a synthetic peptide derived from the homologous region of HCoV‐OC43 (OC43p) acts by molecular mimicry to promote neuropathic pain. OC43p, but not scrambled peptides, induces mechanical hypersensitivity in rats following intrasciatic injections. Transcriptome analyses of the corresponding spinal cords reveal upregulation of genes and signaling pathways with known nociception‐, immune‐, and cellular energy‐related activities. Affinity capture shows the association of OC43p with an Na+/K+‐transporting ATPase, providing a potential direct target and mechanistic insight into virus‐induced effects on energy homeostasis and the sensory neuraxis. We propose that HCoV‐OC43 polypeptides released during infection dysregulate normal nervous system functions through molecular mimicry of MBP, leading to mechanical hypersensitivity. Our findings might provide a new paradigm for virus‐induced neuropathic pain.

Dispirited Away: The Peer Review Process

Dispirited Away: The Peer Review Process

Transforming primary human hepatocytes into hepatocellular carcinoma with genetically defined factors.

Our understanding of human hepatocellular carcinoma (HCC) development and progression has been hampered by the lack of in vivo models. We performed a genetic screen of 10 oncogenes and genetic mutations in Fah-ablated immunodeficient mice in which primary human hepatocytes (PHHs) are used to reconstitute a functional human liver. We identified that MYC, TP53R249S , and KRASG12D are highly expressed in induced HCC (iHCC) samples. The overexpression of MYC and TP53R249S transform PHHs into iHCC in situ, though the addition of KRASG12D significantly increases the tumorigenic efficiency. iHCC, which recapitulate the histological architecture and gene expression characteristics of clinical HCC samples, reconstituted HCC after serial transplantations. Transcriptomic analysis of iHCC and PHHs showed that MUC1 and FAP are expressed in iHCC but not in normal livers. Chimeric antigen receptor (CAR) T cells against these two surface markers efficiently lyse iHCC cells. The properties of iHCC model provide a biological basis for several clinical hallmarks of HCC, and iHCC may serve as a model to study HCC initiation and to identify diagnostic biomarkers and targets for cellular immunotherapy.

Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons

Aggregation of the multifunctional RNA‐binding protein TDP‐43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C‐terminal fragments of ~25 kDa ("TDP‐25") accumulate in cytoplasmic inclusions. Here, we analyze gain‐of‐function mechanisms of TDP‐25 combining cryo‐electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP‐25 inclusions are amorphous, and photobleaching experiments reveal gel‐like biophysical properties that are less dynamic than nuclear TDP‐43. Compared with full‐length TDP‐43, the TDP‐25 interactome is depleted of low‐complexity domain proteins. TDP‐25 inclusions are enriched in 26S proteasomes adopting exclusively substrate‐processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP‐25 impairs proteostasis, and this inhibitory function is enhanced by ALS‐causing TDP‐43 mutations. These findings support a patho‐physiological relevance of proteasome dysfunction in ALS/FTD.

Early career researchers have questions about peer review—we asked the ASLO editors for answers

Early career researchers have questions about peer review—we asked the <scp><i>ASLO</i></scp> editors for answers

When the New York Times Liked Ike: The Newspaper’s Controversial Presidential Endorsements of 1952 and 1956

The New York Times has only endorsed presidential candidates during party primaries—interfering in intra-party politics—twice in its history: once, in January 2016, coming out for John Kasich for the nomination that would go to Donald Trump, and the other, in January 1952, endorsing Dwight Eisenhower over his main Republican rival, Robert Taft. Understanding the exceptionalism of the 1952 election sheds light on the unusually close relationships between top members of the New York Times and the military, as well as reveals tensions within the Times over editorial decisions that the news team feared undermined its coverage. This paper uses archival collections of the New York Times—in addition to papers from several other personal and institutional archival collections—to demonstrate how important decisions were made, as well as contested, on the ground.

The impact of mandatory conflict of interest disclosures on editors' manuscript acceptance decisions: A cross-sectional observational study.

ObjectiveAlthough current ethical standards mandate conflict of interest (COI) disclosure by authors of peer‐reviewed publications, it is unknown whether disclosure affects a manuscript's fate. Our objective was to identify associations between author COI disclosure and editorial decision to publish.MethodsWe performed a cross‐sectional observational study of editorial decisions for original research and brief research report manuscripts submitted to Annals of Emergency Medicine between June 2014 and January 2018 using data from the journal's editorial decision software and data from a prior study that characterized author COI for the same manuscripts. Outcomes of interest included final editor decision to publish (primary), initial editor decision, and number of revisions. We compared outcomes for manuscripts with COI versus those without and by type of COI (commercial/government/other).ResultsOut of 1312 manuscripts in the sample, 65.1% had no COI declarations, and 34.9% had one or more. Overall likelihood of editorial decision to publish was 13.5% (115/854) for articles without COI and 26.9% (123/458) for those with COI. Overall likelihood of editorial decision to publish was 19.8% (19/96) for articles with commercial COI only versus 33.3% (35/105) for those with government COI only.ConclusionsArticles with author‐reported COI were more likely to be published than those without such a declaration. Additionally, results suggest that reports of government COI are associated with improved chance of publication. Authorities should consider relaxing COI requirements temporarily to allow investigators to perform larger scale, randomized controlled studies of the impact of mandated COI disclosure.