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Morphea is a rare multifactorial autoimmune disorder characterized by a complex and dynamic interplay between Th1 and Th2 signaling. Active clinical trials are currently investigating the safety and efficacy of dupilumab for the treatment of primary morphea. Here, we present two cases of morphea that developed in pediatric atopic dermatitis patients treated with dupilumab. These findings may support a causal relationship between IL-4 receptor blockade and the development of the early inflammatory phase of morphea. [ABSTRACT FROM AUTHOR]

NFEI is a rare inflammatory dermatosis that requires a combination of careful clinical and histopathologic assessment to establish the diagnosis. Keywords: figurate erythema; infancy; leukocytoclastic; neutrophilic annular erythema EN figurate erythema infancy leukocytoclastic neutrophilic annular erythema 289 293 5 03/20/23 20230401 NES 230401 INTRODUCTION Neutrophilic figurate erythema of infancy (NFEI) is a rare inflammatory dermatosis and variant of annular erythema of infancy.[1] Diagnosis requires careful assessment to exclude other clinical and histopathologic mimickers.[2] Herein, we report a case of neutrophilic figurate erythema in an infant that was originally misdiagnosed histopathologically as leukocytoclastic vasculitis. Figurate erythema, infancy, leukocytoclastic, neutrophilic annular erythema. [Extracted from the article]

Abstract Background Neocortical circuits are established through the formation of synapses between cortical neurons, but the molecular mechanisms of synapse formation are only beginning to be understood. The mechanisms that control synaptic vesicle (SV) and active zone (AZ) protein assembly at developing presynaptic terminals have not yet been defined. Similarly, the role of glutamate receptor activation in control of presynaptic development remains unclear. Results Here, we use confocal imaging to demonstrate that NMDA receptor (NMDAR) activation regulates accumulation of multiple SV and AZ proteins at nascent presynaptic terminals of visual cortical neurons. NMDAR-dependent regulation of presynaptic assembly occurs even at synapses that lack postsynaptic NMDARs. We also provide evidence that this control of presynaptic terminal development is independent of glia. Conclusions Based on these data, we propose a novel NMDAR-dependent mechanism for control of presynaptic terminal development in excitatory neocortical neurons. Control of presynaptic development by NMDARs could ultimately contribute to activity-dependent development of cortical receptive fields.

T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular Ca2+ to activate the key transcription factors nuclear factor of activated T lymphocytes (NFAT) and NF-κB. The mechanism ofNFATactivation by Ca2+ has been determined. However, the role of Ca2+ in controlling NF-κB signaling is poorly understood, and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF-induced NF-κB signaling upstream of IκB kinase activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent Ca2+ release-activated Ca2+/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser-536 and that this posttranslational modification controls its nuclear localization and transcriptional activation. Notably, our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκB degradation, thereby identifying a novel Ca2+-dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKC-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR-induced NF-κB activation and define a new distal Ca2+- dependent checkpoint in TCR-induced NF-κB signaling that has broad implications for the control of immune cell development and T cell functional specificity. [ABSTRACT FROM AUTHOR]

Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like particles (VLPs) that mimic egress of infectious virus. LFV Z contains both PTAP and PPPY L-domain motifs that are known to recruit host proteins that are important for mediating efficient virus egress and spread. The viral PPPY motif is known to interact with specific host WW-domain bearing proteins. Here we identified host WW-domain bearing protein BCL2 Associated Athanogene 3 (BAG3) as a LFV Z PPPY interactor using our proline-rich reading array of WW-domain containing mammalian proteins. BAG3 is a stress-induced molecular co-chaperone that functions to regulate cellular protein homeostasis and cell survival via Chaperone-Assisted Selective Autophagy (CASA). Similar to our previously published findings for the VP40 proteins of Ebola and Marburg viruses, our results using VLP budding assays, BAG3 knockout cells, and confocal microscopy indicate that BAG3 is a WW-domain interactor that negatively regulates egress of LFV Z VLPs, rather than promoting VLP release. Our results suggest that CASA and specifically BAG3 may represent a novel host defense mechanism, whereby BAG3 may dampen egress of several hemorrhagic fever viruses by interacting and interfering with the budding function of viral PPxY-containing matrix proteins. [ABSTRACT FROM AUTHOR]

The Ebola virus (EBOV) VP40 matrix protein (eVP40) orchestrates assembly and budding of virions in part by hijacking selectWW-domain-bearing host proteins via its PPxY late (L)- domain motif. Angiomotin (Amot) is a multifunctional PPxYcontaining adaptor protein that regulates angiogenesis, actin dynamics, and cell migration/motility. Amot also regulates the Hippo signaling pathway via interactions with the WW-domain-containing Hippo effector protein Yes-associated protein (YAP). In this report, we demonstrate that endogenous Amot is crucial for positively regulating egress of eVP40 virus-like particles (VLPs) and for egress and spread of authentic EBOV. Mechanistically, we show that ectopic YAP expression inhibits eVP40 VLP egress and that Amot co-expression rescues budding of eVP40 VLPs in a dose-dependent and PPxY-dependent manner. Moreover, results obtained with confocal and total internal reflection fluorescence microscopy suggested that Amot's role in actin organization and dynamics also contributes to promoting eVP40-mediated egress. In summary, these findings reveal a functional and competitive interplay between virus and host proteins involving the multifunctional PPxY-containing adaptor Amot, which regulates both the Hippo pathway and actin dynamics. We propose that our results have wide-ranging implications for understanding the biology and pathology of EBOV infections. [ABSTRACT FROM AUTHOR]

Ebola virus (EBOV) is a member of the Filoviridae family and the cause of hemorrhagic fever outbreaks. The EBOV VP40 (eVP40) matrix protein is the main driving force for virion assembly and budding. Indeed, expression of eVP40 alone in mammalian cells results in the formation and budding of virus-like particles (VLPs) which mimic the budding process and morphology of authentic, infectious EBOV. To complete the budding process, eVP40 utilizes its PPXY L-domain motif to recruit a specific subset of host proteins containing one or more modular WW domains that then function to facilitate efficient production and release of eVP40 VLPs. In this report, we identified additional host WW-domain interactors by screening for potential interactions between mammalian proteins possessing one or more WW domains and WT or PPXY mutant peptides of eVP40. We identified the HECT family E3 ubiquitin ligase WWP1 and all four of its WW domains as strong interactors with the PPXY motif of eVP40. The eVP40-WWP1 interaction was confirmed by both peptide pulldown and coimmunoprecipitation assays, which also demonstrated that modular WW domain 1 of WWP1 was most critical for binding to eVP40. Importantly, the eVP40-WWP1 interaction was found to be biologically relevant for VLP budding since (i) small interfering RNA (siRNA) knockdown of endogenous WWP1 resulted in inhibition of eVP40 VLP egress, (ii) coexpression of WWP1 and eVP40 resulted in ubiquitination of eVP40 and a subsequent increase in eVP40 VLP egress, and (iii) an enzymatically inactive mutant of WWP1 (C890A) did not ubiquitinate eVP40 or enhance eVP40 VLP egress. Last, our data show that ubiquitination of eVP40 by WWP1 enhances egress of VLPs and concomitantly decreases cellular levels of higher-molecular-weight oligomers of eVP40. In sum, these findings contribute to our fundamental understanding of the functional interplay between host E3 ligases, ubiquitination, and regulation of EBOV VP40-mediated egress. IMPORTANCE Ebola virus (EBOV) is a high-priority, emerging human pathogen that can cause severe outbreaks of hemorrhagic fever with high mortality rates. As there are currently no approved vaccines or treatments for EBOV, a better understanding of the biology and functions of EBOV-host interactions that promote or inhibit viral budding is warranted. Here, we describe a physical and functional interaction between EBOV VP40 (eVP40) and WWP1, a host E3 ubiquitin ligase that ubiquitinates VP40 and regulates VLP egress. This viral PPXY-host WW domain-mediated interaction represents a potential new target for host-oriented inhibitors of EBOV egress. [ABSTRACT FROM AUTHOR]

The central role of calcium (Ca 2+ ) signaling in lymphocyte development and acquisition of functional immunity and tolerance is well established. Ca 2+ signals are initiated upon antigen binding to cognate receptors on lymphocytes that trigger store operated Ca 2+ entry (SOCE). The underlying mechanism of SOCE in lymphocytes involves TCR and BCR mediated activation of Stromal Interaction Molecule 1 and 2 (STIM1/2) embedded in the ER membrane. Once activated, STIM proteins oligomerize and re-localize to ER domains juxtaposed to the plasma membrane where they activate Orai channels to allow Ca 2+ to enter the cell across the plasma membrane. Importantly, STIM/Orai-dependent Ca 2+ signals guide antigen induced lymphocyte development and function principally by regulating the activity of transcription factors.The most widely studied of these transcription factors is the Nuclear Factor of Activated T cells (NFAT). NFAT is expressed ubiquitously and the mechanism by which Ca 2+ regulates NFAT activation and signaling is well known. By contrast, a mechanistic understanding of how Ca 2+ signals also shape the activation and specificity of NF-κB to control the expression of pro-inflammatory genes has lagged. Here we discuss the methodology used to investigate Ca 2+ dependent mechanisms of NF-κB activation in lymphocytes. Our approach focuses on three main areas of signal transduction and signaling: (1) antigen receptor engagement and Ca 2+ dependent initiation of NF-kB signaling, (2) Ca 2+ dependent induction of NF-κB heterodimer activation and nuclear localization, and (3) and how Ca 2+ regulates NF-κB dependent expression of target genes and proteins.

The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca 2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca 2+ -NFAT signaling., (© 2018 Lee et al.; Published by Cold Spring Harbor Laboratory Press.)

Introduction  Epidermoid cysts are a rare intracranial tumor, mostly arising from the cerebellar pontine angle but sporadically arising from the cranial diploe. Intradiploic epidermoids were first described in 1838 and have since been reported in sporadic case reports and case series. Due to the scarcity of cases, no institution has a large enough case series to fully characterize this tumor. We review numerous case series to better describe intradiploic epidermoids. Methods  Using a search for intradiploic epidermoid, several case reports and series were found. References from these articles were reviewed for further cases. Results  A total of 169 cases of intradiploic epidermoids were reviewed. The average age of patients presenting with intradiploic epidermoids was 38.1 years (standard error of the mean: 1.56). Overall, 68.9% of these patients presented with localized swelling over the scalp, 32.3% with headaches, and 42.7% with other neurologic symptoms. The most common location of the tumor was the frontal bones, with the least common the sphenoid, zygomatic, and maxillary bone. Surgical resection was curative in most cases, with a 3.2% mortality. Recurrence rate was only 5.8%, with nearly all occurring before 1999. Of the recurrent cases, malignant transformation to squamous cell carcinoma was estimated at 44% (4/9). Most of these cases are thought to have occurred as a result of incomplete resection of a primary intradiploic epidermoid. Conclusions  To date, this is the largest review of intradiploic epidermoids reported in the literature. In the reported cases, most had a benign course. However, there are occasional malignant transformations, and some patients have neurologic sequelae from mass effect or tumor infiltration. This is a surgically curative tumor in most cases., (Georg Thieme Verlag KG Stuttgart · New York.)