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\"This strong and timely collection provides fresh insights into how Shakespeare's plays and poems were understood to affect bodies, minds and emotions. Contemporary criticism has had surprisingly little to say about the early modern period's investment in imagining literature's impact on feeling. Shakespearean Sensations brings together scholarship from a range of well-known and new voices to address this fundamental gap. The book includes a comprehensive introduction by Katharine A. Craik and Tanya Pollard and comprises three sections focusing on sensations aroused in the plays; sensations evoked in the playhouse; and sensations found in the imaginative space of the poems. With dedicated essays on Hamlet, Macbeth, Othello and Twelfth Night, the collection explores how seriously early modern writers took their relationship with their audiences and reveals new connections between early modern literary texts and the emotional and physiological experiences of theatregoers\"-- Provided by publisher.

The mechanisms by which TCR signaling 'instructs' thymic lineages remain unclear. Bendelac and colleagues show that the TCR-induced transcription factor Egr2 specifies the early and late stages of differentiation into the natural killer T cell lineage. Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4 + CD8 + thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16 , which encodes the NKT lineage–specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb , which encodes the interleukin 2 (IL-2) receptor β-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to 'instruct' a thymic lineage.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4⁺ regulatory T cells, CD4⁺CD25⁻LAG3⁺ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4⁺CD25⁻LAG3⁺ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4⁺CD25⁻LAG3⁺ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4⁺CD25⁻LAG3⁺ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4⁺CD25⁻LAG3⁺ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.

•A network analysis combined fMRI and immunohistochemistry was performed on operant learning.•Functional connectivity in limbic areas increased at early stage of training.•Functional connectivity in sensorimotor cortex increased at late stage of training.•These connectivity changes in fMRI were validated using EGR1 immunohistochemistry. Previous studies of operant learning have addressed neuronal activities and network changes in specific brain areas, such as the striatum, sensorimotor cortex, prefrontal/orbitofrontal cortices, and hippocampus. However, how changes in the whole-brain network are caused by cellular-level changes remains unclear. We, therefore, combined resting-state functional magnetic resonance imaging (rsfMRI) and whole-brain immunohistochemical analysis of early growth response 1 (EGR1), a marker of neural plasticity, to elucidate the temporal and spatial changes in functional networks and underlying cellular processes during operant learning. We used an 11.7-Tesla MRI scanner and whole-brain immunohistochemical analysis of EGR1 in mice during the early and late stages of operant learning. In the operant training, mice received a reward when they pressed left and right buttons alternately, and were punished with a bright light when they made a mistake. A group of mice (n = 22) underwent the first rsfMRI acquisition before behavioral sessions, the second acquisition after 3 training-session-days (early stage), and the third after 21 training-session-days (late stage). Another group of mice (n = 40) was subjected to histological analysis 15 min after the early or late stages of behavioral sessions. Functional connectivity increased between the limbic areas and thalamus or auditory cortex after the early stage of training, and between the motor cortex, sensory cortex, and striatum after the late stage of training. The density of EGR1-immunopositive cells in the motor and sensory cortices increased in both the early and late stages of training, whereas the density in the amygdala increased only in the early stage of training. The subcortical networks centered around the limbic areas that emerged in the early stage have been implicated in rewards, pleasures, and fears. The connectivities between the motor cortex, somatosensory cortex, and striatum that consolidated in the late stage have been implicated in motor learning. Our multimodal longitudinal study successfully revealed temporal shifts in brain regions involved in behavioral learning together with the underlying cellular-level plasticity between these regions. Our study represents a first step towards establishing a new experimental paradigm that combines rsfMRI and immunohistochemistry to link macroscopic and microscopic mechanisms involved in learning.

Arteriovenous fistulas (AVFs) are preferred access points for hemodialysis. The present study aimed to investigate the function of early growth response-1 (Egr-1) in the proliferation and migration of smooth muscle cells (SMCs) and assess its potential as a new therapeutic target for AVF treatment. A comprehensive analysis combining public data-source mining, human tissue collection, animal studies, cell culture experiments and various molecular biology techniques was conducted. The public dataset GSE119296 was used for immunohistochemical analyses of human AVF stenosis samples. SMC-specific Egr-1 knockout mice and various in vitro assays on primary rat vascular SMCs were used to evaluate the effect of Egr-1 on the functional capacity of SMCs. RNA sequencing and chromatin immunoprecipitation sequencing was performed. Egr-1 was upregulated in human AVF stenosis samples and cultured SMCs. Knockout of Egr-1 in mice mitigated AVF outflow tract stenosis, improved flow dynamics and diminished neointima formation. In vitro, Egr-1 ablation reduced SMC proliferation and migration; Egr-1 transcriptionally activated Egr-2. Increased Egr-1 expression facilitated SMC proliferation and migration through Egr-2 regulation, contributing to AVF stenosis. Consequently, targeting Egr-1 may offer a novel therapeutic approach for managing AVF intimal hyperplasia and improving AVF patency and function in patients with end-stage renal disease.

Allergic diseases affect more than a quarter of individuals in industrialized countries, and are a major public health concern 1 , 2 . The high-affinity Fc receptor for immunoglobulin E (FcεRI), which is mainly present on mast cells and basophils, has a crucial role in allergic diseases 3 , 4 – 5 . Monomeric immunoglobulin E (IgE) binding to FcεRI regulates mast cell survival, differentiation and maturation 6 , 7 – 8 . However, the underlying molecular mechanism remains unclear. Here we demonstrate that prior to IgE binding, FcεRI exists mostly as a homodimer on human mast cell membranes. The structure of human FcεRI confirms the dimeric organization, with each promoter comprising one α subunit, one β subunit and two γ subunits. The transmembrane helices of the α subunits form a layered arrangement with those of the γ and β subunits. The dimeric interface is mediated by a four-helix bundle of the α and γ subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FcεRI dissociates into two protomers, each of which binds to an IgE molecule. This process elicits transcriptional activation of Egr1 , Egr3 and Ccl2 in rat basophils, which can be attenuated by inhibiting the FcεRI dimer-to-monomer transition. Collectively, our study reveals the mechanism of antigen-independent, IgE-mediated FcεRI activation. Biochemical and structural studies of the Fc immunoglobulin E receptor show that it exists as a homodimer on mast cell membranes, but dissociates upon IgE binding, exposing immunoreceptor tyrosine-based activation motifs that enable downstream effector activation.

Background A balance between estrogen (E2) and progesterone (P4) is vital for a successful pregnancy, and an imbalance between these two hormones yields female infertility. E2 mediates uterine receptivity and regulates endometrial growth, the immune system, and hormone signaling by rapidly inducing early growth response 1 (EGR1). However, the precise mechanism by which EGR1 regulates E2-mediated uterine growth remains unclear. This study examined the transcriptional signatures of ovariectomized (OVX) Egr1 knockout (KO) mice compared to those of wild-type (WT) mice to clarify the function of EGR1 in the E2-dependent uterine response. Results Egr1 KO uteri exhibited an impaired E2 response, with significant changes in the expression of the key genes Bgn , c-Kit , Ripor2 , and Arg2 . During early E2 response, Egr1 KO uteri showed upregulated insulin-like growth factor (IGF) signaling pathway genes and downregulated reproduction-related genes. During late E2 response, Egr1 KO uteri showed enhanced proliferative processes, such as DNA replication and mitotic cell cycle phase transition, potentially related to poly-ADP ribosylation (PARylation), along with a reduction in immune response. Notably, the transcriptional signatures in mature OVX Egr1 KO uteri resembled those in immature uteri, with similar increases in proliferation and decreases in immune response at the pathway level. Conclusions Our findings indicate that EGR1 is essential for regulating immune response and uterine proliferation via IGF signaling and PARylation, and acts as a gatekeeper transcription factor that mediates E2 actions in the mature uterus. Notably, we found that the transcriptional signatures of EGR1 in mature uteri overlapped with the primary E2 function and suggested a novel concept that these transcriptional signatures in mature Egr1 KO uteri are similar to those of immature uteri. Our findings offer novel insights into the role of EGR1 as an E2 mediator in the uterus at the molecular level.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target for the treatment of this disease. Saikosaponin A (SSA) and saikosaponin C (SSC), identified from Radix Bupleuri, exert anti-inflammatory effects. However, the topical effects of SSA and SSC on chronic inflammatory skin diseases are unclear. In this study, we investigated the effects of SSA and SSC on TSLP suppression in an AD-like inflammatory environment. We observed that SSA and SSC suppressed tumor necrosis factor-α-induced TSLP expression by downregulating the expression of the transcription factor early growth response 1 (EGR1) via inhibition of the extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and p38 mitogen-activated protein kinase pathways. We also confirmed that topical application of SSA or SSC reduced AD-like skin lesions in BALB/c mice challenged with 2,4-dinitrochlorobenzene. Our findings suggest that suppression of EGR1-regulated TSLP expression in keratinocytes might be attributable to the anti-inflammatory effects of SSA and SSC in AD-like skin lesions.

Epilepsy is mainly characterized by spontaneous seizures caused by hyperactive neural circuits. To delineate the cell-type-specific mechanisms underlying neuronal hyperexcitability, we resolve the hyperexcitability of excitatory neurons across epileptic human brain trans-foci at single-cell resolution to identify the key drivers and potential diagnostic signatures. We constructed a comprehensive atlas encompassing 240,000 cells derived from the temporal cortex and hippocampus, detecting trans-regional cellular and molecular diversity. We further delineated dynamic trajectories, gene expression patterns, and functional reorganization across cell types. Using the LASSO and random forest algorithms, we prioritized the core genes and developed a logistic regression-based diagnostic model. Despite transregional cellular landscape conservation, major cell types varied in abundance. Detailed analysis delineated various excitatory neuron subtypes’ dynamic trajectories, intricate expression, and functional reorganization, with pronounced dysfunction in the posterior hippocampal and temporal cortex networks, indicating hyperactive pro-epileptic effects. Excitatory neurons exhibit an intrinsic ability to autonomously organize themselves into distinct, highly active modules, characterized by a high activation state during epileptogenesis, as illustrated by ten epilepsy-associated functions. Transcription circuits FOSL2/FOS/EGR3/EGR1 promote neuronal hyperexcitability. Integrating epilepsy bulk RNA-seq data, we identified 24 overlapping genes between differential genes and circuit targets. The LASSO and random forest algorithms prioritized three core genes (IL1B, SOCS6, and COL4A1). A logistic regression model based on these three genes showed variable performance, with an apparent AUC of 1.000 in the discovery cohort (GSE256068) and AUCs of 0.974 and 0.722 in and two validation cohorts, indicating the need for further validation. Our study establishes the FOSL2/FOS/EGR3/EGR1 circuit as a master regulator of pathological neuronal hyperactivity across epileptic foci, linking transcriptional activation to network dysfunction. Identifying overactive factors may represent a candidate molecular pathway for future therapeutic exploration against hyperexcitability.

Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease. Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI. Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm. Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated. AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration. To further determine the function of EGR1, mice were applied. Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9. EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database. Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration. Further experiments affirmed that genetic inhibition of aggravates the severity of AKI in mouse models. Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the gene, thus promoting SOX9 cell proliferation by activating the Wnt/β-catenin pathway. Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.