Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension

AIMS: Understanding the novel signalling pathways involved in the pathogenesis of hypertension is vital for the development of effective therapeutic strategies. Recent evidence suggests a role for Toll-like receptor (TLR) 4 in the development of cardiovascular diseases. Although brain has been implicated in the pathogenesis of hypertension, the role of brain TLR4 in hypertension is largely unexplored. Therefore, we investigated the role of brain TLR4 in angiotensin (Ang) II-induced hypertension and whether central TLR4 blockade has cardioprotective effects in hypertension. METHODS AND RESULTS: Hypertension was induced in male Sprague-Dawley rats by delivering AngII for 14 days. The rats were administered either specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide, intracerebroventricularly. Blood pressure, and cardiac hypertrophy and function, was evaluated by radiotelemetry and echocardiography, respectively. Blood and paraventricular nucleus were collected for measurement of plasma norepinephrine (NE), tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and TLR4 expression, respectively. Heart was analysed for TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NFκB), and renin-angiotensin system (RAS) components. Hypertensive rats had dramatically increased TLR4 expression compared with normotensive rats. Central blockade of TLR4 delayed progression of hypertension and improved cardiac hypertrophy and function in hypertensive rats. TLR4 blockade significantly reduced myocardial TNF-α, IL-1β, iNOS levels, NFκB activity, and altered RAS components in hypertensive rats. These results were associated with reduced circulating NE levels in VIPER-treated hypertensive rats. CONCLUSION: These results provide mechanistic evidence that AngII-induced hypertensive effects are mediated, at least in part, by brain TLR4, and that brain TLR4 blockade attenuates AngII-induced hypertensive response, possibly via down-regulation of myocardial inflammatory molecules and sympathetic activity

Treatments for Dissecting Cellulitis of the Scalp: A Systematic Review and Treatment Algorithm

Abstract Background Dissecting cellulitis of the scalp (DCS) is a chronic inflammatory skin condition characterized by abscesses, nodules, fistulas, and scarring alopecia. Management of this oftentimes debilitating dermatosis can be challenging due to its recalcitrant nature. There is limited data regarding the efficacy of treatment options for DCS. Objective The aim of this study was to conduct a systematic review of the literature to explore the efficacy and safety of reported DCS treatments. Methods In October 2022, MEDLINE and EMBASE databases were searched for articles on treatments for DCS. Studies that contained outcome efficacy data for DCS treatments were included. Reviews, conference abstracts, meta-analyses, commentaries, non-relevant articles, and articles with no full-text available were excluded. Data extraction was performed by two independent reviewers. Results A total of 110 relevant articles with 417 patients were identified. A majority of studies (86.4%) were case reports or series. Treatment options included systemic antibiotics, oral retinoids, biologics, procedural treatments, combination agents, and topical treatments. Oral retinoids and photodynamic therapy were the most extensively studied medical and procedural interventions, respectively. Conclusion Overall, randomized controlled trials are needed to evaluate various treatment regimens for DCS and provide patients with a robust, evidence-based approach to therapy

Perspectives of Emergency Medicine Physicians on Hidradenitis Suppurativa Care

Introduction: Hidradenitis suppurativa (HS) is a chronic skin condition that often requires acute care during periods of flares, with many patients visiting the emergency department over 5 times before receiving a proper diagnosis. However, little is known about emergency medicine (EM) providers' experiences and knowledge of HS management. Methods: In this study, an anonymous survey was distributed to EM providers to identify knowledge and practice gaps in HS care. Results: The results showed that most respondents lacked confidence in HS diagnosis and management, especially in knowing available treatment options and managing patients with moderate to severe HS. Attendings were more confident than non-attendings in diagnosing and managing HS, and providers who saw more HS patients per month were more confident in referring patients to appropriate specialists. Over 80% of respondents referred HS patients to dermatology, which is an important initial step in HS management. Conclusion: The study highlights the importance of educating EM providers in HS recognition, timely referral to dermatology, and initial management to improve quality of life among patients and mitigate disease progression.12 month embargo; first published 01 December 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Toll-Like Receptor 4 Promotes Autonomic Dysfunction, Inflammation and Microglia Activation in the Hypothalamic Paraventricular Nucleus: Role of Endoplasmic Reticulum Stress

<div><p>Background & Purpose</p><p>Toll-like receptor 4 (TLR4) signaling induces tissue pro-inflammatory cytokine release and endoplasmic reticulum (ER) stress. We examined the role of TLR4 in autonomic dysfunction and the contribution of ER stress.</p><p>Experimental approach</p><p>Our study included animals divided in 6 experimental groups: rats treated with saline (i.v., 0.9%), LPS (i.v., 10mg/kg), VIPER (i.v., 0.1 mg/kg), or 4-PBA (i.p., 10 mg/kg). Two other groups were pretreated either with VIPER (TLR4 viral inhibitory peptide) LPS + VIPER (i.v., 0.1 mg/kg) or 4-Phenyl butyric acid (4-PBA) LPS + PBA (i.p., 10 mg/kg). Arterial pressure (AP) and heart rate (HR) were measured in conscious Sprague-Dawley rats. AP, HR variability, as well as baroreflex sensitivity (BrS), was determined after LPS or saline treatment for 2 hours. Immunofluorescence staining for NeuN, Ib1a, TLR4 and GRP78 in the hypothalamic paraventricular nucleus (PVN) was performed. TNF-α, TLR4 and GRP78 protein expression in the PVN were evaluated by western blot. Plasma norepinephrine levels were determined by ELISA.</p><p>Key Results</p><p>Acute LPS treatment increased HR and plasma norepinephrine concentration. It also decreased HR variability and high frequency (HF) components of HR variability, as well BrS. Acute LPS treatment increased TLR4 and TNF-α protein expression in the PVN. These hemodynamic and molecular effects were partially abrogated with TLR4 blocker or ER stress inhibitor pretreatment. In addition, immunofluorescence study showed that TLR4 is co-localized with GRP78in the neurons. Further inhibition of TLR4 or ER stress was able to attenuate the LPS-induced microglia activation.</p><p>Conclusions & Implications</p><p>TLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN.</p></div