BACKGROUND. The locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans. METHODS. We used 7 Tesla functional Magnetic Resonance Imaging, sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22y; 28 women) and 19 older (~61y; 14 women) individuals. RESULTS. We found that, in older, but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC. CONCLUSION. These findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep and age-related diseases. FUNDING. This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20). Action de Recherche Concertée – Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), University of Liège, European Regional Development Fund (Radiomed & Biomed-Hub).
Ekaterina Koshmanova, Alexandre Berger, Elise Beckers, Islay Campbell, Nasrin Mortazavi, Roya Sharifpour, Ilenia Paparella, Fermin Balda, Christian Berthomier, Christian Degueldre, Eric Salmon, Laurent Lamalle, Christine Bastin, Maxime Van Egroo, Christophe Phillips, Pierre Maquet, Fabienne Collette, Vincenzo Muto, Daphne Chylinski, Heidi I.L. Jacobs, Puneet Talwar, Siya Sherif, Gilles Vandewalle
Superficial erythematous cutaneous vascular malformations are assumed to be blood vascular in origin, but cutaneous lymphatic malformations can contain blood and appear red. Management may be different and so an accurate diagnosis is important. Cutaneous malformations were investigated through 2D-histology and 3D-whole-mount-histology. Two lesions were clinically considered as port-wine birthmark, and another three lesions as erythematous telangiectasias. The aims were: i) to prove that cutaneous erythematous malformations including telangiectasia can represent a lymphatic phenotype, ii) to determine if lesions represent expanded but otherwise normal or malformed lymphatics, and iii) to determine if the presence of erythrocytes explained the red colour. Microscopy revealed all lesions as lymphatic structures. Port-wine birthmarks proved to be cystic lesions, with non-uniform lymphatic marker expression, and a disconnected lymphatic network suggesting a lymphatic malformation. Erythematous telangiectasias represented expanded but non-malformed lymphatics. Blood within lymphatics appeared to explain the colour. Blood-lymphatic-shunts could be detected in the erythematous telangiectasia. In conclusion, erythematous cutaneous capillary lesions may be lymphatic in origin but clinically indistinguishable from blood vascular malformations. Biopsy is advised for correct phenotyping and management. Erythrocytes are the likely explanation for colour accessing lymphatics through lympho-venous-shunts.
René Hägerling, Malou Van Zanten, Rose Yinghan Behncke, Sascha Ulferts, Nils R. Hansmeier, Bruno Märkl, Christian Witzel, Bernard Ho, Vaughan Keeley, Katie Riches, Sahar Mansour, Kristiana Gordon, Pia Ostergaard, Peter S. Mortimer
Maternal SARS-CoV-2 infection triggers placental inflammation and alters cord blood immune cell composition. However, most studies focus on outcomes of severe maternal infection. Therefore, we analyzed cord blood and chorionic villi from newborns of unvaccinated mothers who experienced mild/asymptomatic SARS-CoV-2 infection during pregnancy. We investigated immune cell rewiring using flow cytometry, single-cell RNA sequencing, and functional readouts using ex vivo stimulation with TLR agonists and pathogens. Maternal infection was associated with increased frequency of memory T- and B-cells, and non-classical monocytes in cord blood. Ex vivo T- and B-cell responses to stimulation were attenuated, suggesting a tolerogenic state. Maladaptive responses were also observed in cord blood monocytes, where antiviral responses were dampened but responses to bacterial TLRs were increased. Maternal infection was also associated with expansion and activation of placental Hofbauer cells, secreting elevated levels of myeloid cell recruiting chemokines. Moreover, we reported increased activation of maternal-derived monocytes/macrophages in the fetal placenta that are transcriptionally primed for antiviral responses. Our data indicate that even in the absence of vertical transmission or symptoms in the neonate, mild/asymptomatic maternal COVID-19 altered the transcriptional and functional state in fetal immune cells in circulation and in the placenta.
Brianna M. Doratt, Suhas Sureshchandra, Heather True, Monica Rincon, Nicole E. Marshall, Ilhem Messaoudi
Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity-driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesity’s procancer effects.
Kristina Camp, Michael F. Coleman, Tori McFarlane, Steven S. Doerstling, Subreen A. Khatib, Erika T. Rezeli, Alfor G. Lewis, Alexander J. Pfeil, Laura A. Smith, Laura W. Bowers, Farnaz Fouladi, Weida Gong, Elaine M. Glenny, Joel S. Parker, Ginger L. Milne, Ian M. Carroll, Anthony A. Fodor, Randy J. Seeley, Stephen D. Hursting
A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.
Gianluca T. DiGiovanni, Wei Han, Taylor P. Sherrill, Chase J. Taylor, David S. Nichols, Natalie M. Geis, Ujjal K. Singha, Carla L. Calvi, A. Scott McCall, Molly M. Dixon, Yang Liu, Ji-Hoon Jang, Sergey S. Gutor, Vasiliy V. Polosukhin, Timothy S. Blackwell, Jonathan A. Kropski, Jason J. Gokey
Pyrin, a protein encoded by the MEFV gene, plays a vital role in innate immunity by sensing modifications in Rho GTPase and assembling the pyrin inflammasome, which in turn activates downstream immune responses. We identified a novel and de novo MEFV p.E583A dominant variant in three patients from a family, distinct from the previously reported S242 and E244 sites. These patients exhibited a phenotype that diverged from those resulting from classical MEFV gene mutations, characterized by the absence of recurrent fever but the presence of recurrent chest and abdominal pain. Colchicine effectively controlled the phenotype, and the mutation was found to induce pyrin inflammasome assembly and activation in patients' peripheral blood mononuclear cells (PBMCs) and cell lines. Mechanistically, truncation experiments revealed that the E583A variant impacted the autoinhibitory structure of pyrin. Our study offers new insights into the mechanisms underlying pyrin inflammasome activation.
Qintao Wang, Taijie Jin, Shan Jian, Xu Han, Hongmei Song, Qing Zhou, Xiaomin Yu
OBJECTIVES. Sjögren's Disease (SjD) is a chronic and systemic autoimmune disease characterized by lymphocytic infiltration and the development of dry eyes and dry mouth resulting from the secretory dysfunction of the exocrine glands. SARS-CoV-2 may trigger the development or progression of autoimmune diseases, as evidenced by increased autoantibodies in patients and the presentation of cardinal symptoms of SjD. The objective of the study was to determine whether SARS-CoV-2 induces the signature clinical symptoms of SjD. METHODS. The ACE2-transgenic mice were infected with SARS-CoV-2; SjD profiling was conducted. COVID-19 patients' sera were examined to detect the presence of autoantibodies. Clinical evaluations of convalescent COVID-19 subjects, including minor salivary gland (MSG) biopsies, were collected. Lastly, monoclonal antibodies generated from single B cells of patients were interrogated for ACE2/spike inhibition and nuclear antigens. RESULTS. Mice infected with the virus showed a decreased saliva flow rate, elevated antinuclear antibodies (ANAs) with anti-SSB/La, and lymphocyte infiltration in the lacrimal and salivary glands. Sera of COVID-19 patients showed an increase in ANA, anti-SSA/Ro52, and anti-SSB/La. The male patients showed elevated levels of anti-SSA/Ro52 compared to female patients, and female patients had more diverse ANA patterns. Minor salivary gland biopsies of convalescent COVID-19 subjects showed focal lymphocytic infiltrates in four of six subjects, and 2 of 6 subjects had focus scores >2. Lastly, we found that monoclonal antibodies produced in recovered patients can block ACE2/spike interaction and recognize nuclear antigens. CONCLUSION. Overall, our study shows a direct association between SARS-CoV-2 and SjD. Hallmark features of SjD salivary glands were histologically indistinguishable from convalescent COVID-19 subjects.The results potentially implicate that SARS-CoV-2 could be an environmental trigger for SjD.
Yiran Shen, Alexandria Voigt, Laura Goranova, Mehdi A. Abed, David E. Kleiner, Jose O. Maldonado, Margaret Beach, Eileen Pelayo, John A. Chiorini, William F. Craft, David A. Ostrov, Vijay Ramiya, Sukesh Sukumaran, Ashley N. Brown, Kaley C. Hanrahan, Apichai Tuanyok, Blake M. Warner, Cuong Q. Nguyen
Hereditary spherocytosis (HS) is the most common non-immune hereditary chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS leads to perturbation of red cell metabolome, with altered glycolysis. In mice genetically lacking protein 4.2 (4.2-/-, Epb42), a murine model of HS, we show increased expression of pyruvate kinase (Pk) isoforms in whole and fractioned red cells in conjunction with abnormalities in the glycolytic pathway and in GSH system. Mitapivat, a PKs activator, metabolically re-programs 4.2-/- mouse red cells with amelioration of glycolysis and GSH cycle. This results in improved osmotic fragility, reduced phosphatidyl-serine (PS) positivity and decrease in erythroid vesicles release in vitro. Mitapivat treatment significantly decreases erythrophagocytosis and beneficially impacts iron homeostasis. In mild/moderate HS, the beneficial effect of splenectomy is still controversial. Here, we show that splenectomy improves anemia in 4.2-/- mice and that mitapivat is non-inferior to splenectomy. An additional benefit of mitapivat treatment is lower expression of markers of inflammatory vasculopathy in 4.2-/- mice with or without splenectomy, indicating a multi-systemic action of mitapivat. These findings support the notion that mitapivat treatment should be considered for symptomatic HS.
Alessandro Matte, Anand Babu Wilson, Federica Gevi, Enrica Federti, Antonio Recchiuti, Giulia Ferri, Anna Maria Brunati, Mario Angelo Pagano, Roberta Russo, Christophe Leboeuf, Anne Janin, Anna Maria Timperio, Achille Iolascon, Elisa Gremese, Lenny Dang, Narla Mohandas, Carlo Brugnara, Lucia De Franceschi
Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH). Although BCH is known to correlate with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrated that BCH is predominantly characterized by an expansion of non-proliferative suprabasal cells that are still committed to early differentiation. Furthermore, we discovered that suprabasal and superficial esophageal epithelial cells retain progenitor identity programs in EoE, which was evidenced by increased quiescent cell identity scoring and the enrichment of signaling pathways regulating stem cell pluripotency. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these alterations were not observed in GERD. These findings provide additional insights into the differentiation process in EoE and highlight the distinct characteristics of suprabasal and superficial esophageal epithelial cells in the disease.
Margarette H. Clevenger, Adam L. Karami, Dustin A. Carlson, Peter J. Kahrilas, Nirmala Gonsalves, John E. Pandolfino, Deborah R. Winter, Kelly A. Whelan, Marie-Pier Tétreault
Regulatory T cells (Tregs) expressing Chimeric Antigen Receptors (CARs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs) and donor-specific antibodies. We generated Tregs expressing HLA-A2-specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, PD1 and GITR, but not 41BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no co-stimulatory domain. These data revealed that exogenous co-stimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti-HLA-A2 alloantibodies. This study reveals a new dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.
Isaac Rosado-Sánchez, Manjurul Haque, Kevin Salim, Madeleine Speck, Vivian C.W. Fung, Dominic A. Boardman, Majid Mojibian, Giorgio Raimondi, Megan K. Levings
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