Illinois State head men's golf coach Ray Kralis has announced the addition of Maxence Faucquez as he will join the team starting in the fall of 2024 NORMAL, Ill. – Illinois State head men's golf coach Ray Kralis has announced the addition of Maxence Faucquez "Max is strong in three big areas - driving "Those are the key ingredients for low scores as evidenced by his 71.36 scoring average over 13 events in 2023 Ranked as high as 650 in the World Amateur Golf Rankings and we are excited to welcome him to the Redbird family With the departure of this year's graduating class I am confident we have a recruiting class that is up to the challenge of moving the program forward."  finished seventh at the Belgin International Amateur Championship He had top-30 finishes at a pair of amateur championships taking 24th at the French National U18 Championships with a four-round 297 and 27th at the English Boys Amateur Championship with a 289 He also finished fifth at the Grand Prix De Chiberta with a 278 (71-69-70-68) and in the three-round Classic Du Prieure took sixth with a 218 (73-75-70) who are off to a hot start to the fall season February 19 at the Border Olympics hosted at Laredo Country Club in Laredo This season ISU finished four of the five fall tournaments under par as a team and have seven golfers with scoring averages of 73 or lower The team is ranked 65th in the opening NCAA rankings and are the top ranked team in the MVC heading into the spring season with Southern Illinois sitting second in the rankings at 148th GoRedbirds.com and the Illinois State Redbirds App: Your sources for Illinois State tickets Thanks for visiting The use of software that blocks ads hinders our ability to serve you the content you came here to enjoy We ask that you consider turning off your ad blocker so we can deliver you the best experience possible while you are here This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page either observed and verified firsthand by the reporter or reported and verified from knowledgeable sources Translations may contain inaccuracies—please refer to the original content A man who lost consciousness mid-air during a parachute jump in northern France miraculously came to his senses just meters before hitting the ground suffered only minor injuries after falling unconscious a few seconds into his jump at Marquette-lez-Lille on Monday last week deputy technical director of the Lille-Bondue parachuting school where the man made the jump told local outlet BFM TV that the skydiver first experienced a medical issue at "around 500 meters high" and that he regained consciousness just in time before landing The man had reportedly already deployed his parachute and was able to land in a nearby garden "He still had a fairly muscular landing," Motte said "He was clearly conscious with a nice little scar which earned him ten stitches." the man greatly reduced the severity of his injuries by raising his knees before hitting the ground a reflex that allowed him to somewhat cushion the fall He suffered injuries to his face and knees witnessed the fall and came to the man's rescue The jump was one of the first since the parachuting school reopened The extreme sport has seen a slew of tragic deaths in recent years In April, a Californian woman plunged to her death after her parachute failed to properly deploy The experienced parachutist performed a jump at the Skydive Lodi Parachute Center when her equipment reportedly became tangled The death came just one month after the parachute and skydiving center was ordered to pay $40 million in connection with another incident five years ago California teenager Tyler Turner fell to his death after his parachute failed to open back in 2016 The 18-year-old died along with skydiving instructor The men plummeted 13,000 feet to the ground after Kwon was unable to get their parachutes to open It was later determined that his instructor was not properly certified and Turner's family were awarded a $40 million judgment against the owner of the skydiving center Newsweek is committed to challenging conventional wisdom and finding connections in the search for common ground Newsletters in your inbox See all Chemerin is an extracellular protein with chemotactic activities and its expression is increased in various diseases such as metabolic syndrome and inflammatory conditions. Its role in lung pathology has not yet been extensively studied but both known pro- and anti-inflammatory properties have been observed. The aim of our study was to evaluate the involvement of the chemerin/ChemR23 system in the physiopathology of COVID-19 with a particular focus on its prognostic value. Blood samples from confirmed COVID-19 patients were collected at day 1, 5 and 14 from admission to Erasme Hospital (Brussels – Belgium). Chemerin concentrations and inflammatory biomarkers were analyzed in the plasma. Blood cells subtypes and their expression of ChemR23 were determined by flow cytometry. The expression of chemerin and ChemR23 was evaluated on lung tissue from autopsied COVID-19 patients by immunohistochemistry (IHC). Increased plasma chemerin levels are a marker of severity and may predict death of COVID-19 patients. However, multicentric studies are needed, before chemerin can be considered as a biomarker of severity and death used in daily clinical practice. Further studies are also necessary to identify the precise mechanisms of the chemerin/ChemR23 system in ARDS secondary to viral pneumonia. Cytokines and Soluble Mediators in Immunity Volume 13 - 2022 | https://doi.org/10.3389/fimmu.2022.941663 Background: Chemerin is an extracellular protein with chemotactic activities and its expression is increased in various diseases such as metabolic syndrome and inflammatory conditions Its role in lung pathology has not yet been extensively studied but both known pro- and anti-inflammatory properties have been observed The aim of our study was to evaluate the involvement of the chemerin/ChemR23 system in the physiopathology of COVID-19 with a particular focus on its prognostic value Methods: Blood samples from confirmed COVID-19 patients were collected at day 1 5 and 14 from admission to Erasme Hospital (Brussels – Belgium) Chemerin concentrations and inflammatory biomarkers were analyzed in the plasma Blood cells subtypes and their expression of ChemR23 were determined by flow cytometry The expression of chemerin and ChemR23 was evaluated on lung tissue from autopsied COVID-19 patients by immunohistochemistry (IHC) Results: 21 healthy controls (HC) and 88 COVID-19 patients including 40 in intensive care unit (ICU) were included Plasma chemerin concentration were significantly higher in ICU patients than in HC at all time-points analyzed (p<0.0001) they were higher in deceased patients compared to survivors (p<0.05) Logistic univariate regression and multivariate analysis demonstrated that chemerin level at day 14 of admission was an independent risk factor for death chemerin levels correlated with inflammatory biomarkers such as C-reactive protein and tumor necrosis factor α IHC analysis revealed a strong expression of ChemR23 on smooth muscle cells and chemerin on myofibroblasts in advanced acute respiratory distress syndrome (ARDS) Discussion: Increased plasma chemerin levels are a marker of severity and may predict death of COVID-19 patients before chemerin can be considered as a biomarker of severity and death used in daily clinical practice Further studies are also necessary to identify the precise mechanisms of the chemerin/ChemR23 system in ARDS secondary to viral pneumonia these experiments revealed an important role for the chemerin/ChemR23 system in lung inflammation Given that chemerin is elevated in most of the pathologies associated with a higher risk of developing severe COVID-19 and seems to be associated with lung inflammation we evaluated the chemerin/ChemR23 system in COVID-19 patients and correlated it with disease severity This prospective observational study was conducted on adult patients (from 18 to 70 years) with a confirmed COVID-19 infection (positive polymerase chain reaction (PCR) test performed on a nasopharyngeal swab) admitted to Erasme Hospital (Tertiary care center These patients were further classified into three groups: non-hospitalized (NH) hospitalized in a conventional care unit (H) and hospitalized in intensive care unit (ICU) The study was approved by the local Ethical Committee (P2020/238 for blood biobanking P2020/232 for bronchoalveolar lavage biobanking and immunohistochemistry analysis) Covid and control samples were prepared and stored identically The results of routine blood analysis were collected from the medical files including C-reactive protein (CRP) Another cohort of patients was used for bronchoalveolar lavages (BAL) collection. In this cohort, BALs were performed to confirm a SARS-CoV-2 infection or exclude opportunistic superinfections (immunocompromised patients). BAL were collected from April 2020 to November 2020. They were performed, using a disposable video-bronchoscope (Ambu® aScopeTM, Ballerup, Denmark) as described by Taton et al. (25) Samples were centrifuged (1400 rpm – 10 minutes) then supernatants were stored at -80°C and cell pellets stabilized with Cytodelics stabilizer and then stored at -80°C (Biobank ULB-COVID-19 Only confirmed COVID-19 patients from this cohort were selected for further analysis Control BAL samples were collected from patients with a pulmonary nodule or from non-infected lung transplant patients (performed as part of their routine follow up) lymphocytes and macrophages counts on BAL were obtained from the medical files Plasma and BAL chemerin levels were assessed by enzyme-linked immunosorbent assay (ELISA) (R&D systems Samples were analyzed in duplicates according to the manufacturer’s instructions Plasma levels of the Krebs Von den Lungen protein (KL-6) were detected using a sandwich ELISA assay on Lumipulse G600II and G1200 (Fujirebio monokine induced by interferon-γ (MIG macrophage inflammatory protein-1β (MIP-1β CCL4) and tumor necrosis factor α (TNFα) were measured in plasma by multiparameter-based immunoassays (Milliplex Human Cytokine/chemokine/Growth factor panel A magnetic bead panel kit-Merck Belgium) according to the manufacturer’s instructions Results were analyzed with a Bio-Plex 200® Multiplex reader Bio-Plex ManagerTM Manager 4.1 Software (BIO-RAD laboratories Formalin-fixed paraffin-embedded (FFPE) lung tissues from PCR positive COVID-19 patients stored in the Biobank ULB-COVID-19 (Department of Pathology, Erasme Hospital, BB200022) were used for immunohistochemical (IHC) staining. Autopsies were performed after 72 hours to prevent infection of the medical staff (26) areas presenting typical lesions of diffuse alveolar damage (DAD) early or late and samples with pneumonia or bronchopneumonia were selected Control tissues were obtained from autopsied patients deceased for more than 48 hours without major lung lesion and patients deceased of an ARDS from another origin IHC staining was performed using an automated immunostainer (Dako Omnis 4µm slides were incubated respectively with anti-ChemR23 (Santa Cruz Biotechnology dilution 1:300) and anti-chemerin (Santa Cruz Biotechnology dilution 1:100) antibodies and counterstained with hematoxylin Then slides were scanned with a 40x magnification (Nanozoomer Japan) before assessment by two pathologists All data were tested for normality using the Shapiro-Wilk test and according to the distribution parametric or non-parametric tests were applied Differences between the groups were assessed by one-way ANOVA or Kruskal-Wallis test Tukey or Dunn’s tests were used as post-hoc tests Data are reported as mean ± standard deviation (SD) or median with a confidence interval of 95% (CI 95%) Categorical variables are listed as numbers with percentage Chi-square test was performed to compare more than two groups and Fisher’s exact test was used for comparison between 2 groups non-parametric Spearman correlation was performed and data are reported as Spearman r and p-value To determine the association of different variables to fatal outcome a univariate logistic regression test was performed and then a multivariable regression model was chosen from a stepwise selection based on the Akaike Information Criterion (AIC) The analyses were performed on Prism 6 or SAS 9.4 software packages and all significance levels were fixed at 0.05 In this study 88 patients with a positive nasopharyngeal throat swab for COVID-19 were included: 11 non-hospitalized (NH) 37 hospitalized in a conventional care unit (H) and 40 hospitalized in intensive care unit (ICU) Blood samples were collected at the admission D1 Symptoms started on average 9 days before admission to the emergency department 21 healthy subjects (HC) (asymptomatic with negative PCR and serological tests (IgG and IgA)) were used as controls Baseline characteristics of controls and patients are reported in Table 1 and multiple comparisons between subgroups are reported in Supplemental Table 1 Sixty-seven patients were men and 42 were women Patients were older in H and ICU groups (57.6 ± 14.8 and 60.5 ± 10.9 mean ± SD) as compared to HC and NH groups (38.6 ± 7.9 and 42.2 ± 10.9 respectively; mean ± SD No significant differences were found for BMI among COVID-19 patients (average BMI for NH H and ICU groups: 28.6 kg/m² (27.2-30.45) median (95% CI)) as well as for tobacco use (18.1% of the patients) Table 1 Baseline characteristics and comorbidities Routine biological analyses of the COVID-19 patients are reported in Table 2 and multiple comparisons between subgroups are reported in Supplemental Table 2. At admission and without oxygen support, the median peripheral oxygen saturation (SpO2) decreased with severity of disease and therefore was the lowest in the ICU group (p<0.0001) (Table 2) Inflammation-related parameters such as CRP (p<0.0001) LDH (p<0.0001) and D-dimer (p<0.001) were higher and significantly different in plasma from ICU patients compared to NH and H patients Liver tests were slightly disturbed in ICU patients with a small elevation of the transaminases no alteration of the renal function or the lipids tests was observed ICU patients had higher and significantly different levels of circulating WBC (p<0.0001) with a predominance of PMN (p<0.0001) and lower levels of lymphocytes (p<0.001) Table 2 Main biological parameters at admission Figure 1 Flow cytometry analysis of the total number of plasmacytoid dendritic cells (pDC) natural killer (NK) cells CD56bright and NK cells CD56dim and their expression of ChemR23 in COVID-19 patients and healthy controls (HC) at day 1 Measurements by flow cytometry of total counts of pDCs The expression of ChemR23 was evaluated by mean fluorescence intensity (MFI) Data are presented as median with interquartile range and statistics analysis was performed using Kruskal-Wallis test followed by Dunn’s post-hoc test n=11; hospitalized non-intensive care unit (H) n=36; hospitalized in intensive care unit (ICU) **: p<0.01; ***: p<0.001; ****: p<0.0001 no significant difference in the expression of ChemR23 was observed between COVID-19 and HC in the cell types analyzed Figure 2 Chemerin assessment and its association with risk of death and inflammation (A) Time course assessment of chemerin concentration in plasma of healthy controls and subgroups of COVID-19 patients data from HC were obtained at only one time point Data are presented as median with interquartile range and statistical analysis was performed using Kruskal-Wallis test followed by Dunn’s post-hoc test (B) Comparison of plasma chemerin levels in recovered versus deceased COVID-19 patients Data are presented as median with interquartile range and statistics analysis was performed using Mann-Whitney test (C) Prediction of mortality by chemerin concentration at day 1 (black) day 5 (blue) and day 14 (red) using a ROC analysis (D) Correlation between chemerin concentrations and inflammation estimated by C-reactive protein (CRP) concentration at day 14 The r corresponds to the Spearman coefficient for non-parametric correlation n=37; hospitalized in intensive care unit (ICU) *: p<0.05; ***: p<0.001; ****: p<0.0001 Since higher chemerin levels are associated with metabolic syndrome (27) we investigated the existence of such possible associations in our population Hypertension was found in 45/109 patients (41.3%) predominantly in H and ICU groups (p<0.0001) and chemerin levels were higher in patients with hypertension (Hypertension: 164.7 ng/mL (141.3-183.5) versus non-hypertension: 118.4 ng/mL (110.8-127.0) mostly belonging to H and ICU groups but no difference in chemerin levels was observed Other comorbidities were uncommon: CKD in 8/109 (7.3%) COPD in 6/109 (5.5%) and immunosuppression in 10/109 (9.2%) and none was associated with higher chemerin levels immunosuppression in our cohort referred to patients with an immunosuppressive treatment (9/109) or having a neoplasia (1/109) none of our patients presented a hepatic disease such as viral or auto-immune hepatitis During the study period, dexamethasone treatment in patients requiring oxygen therapy was introduced to reduce mortality (28) no NH patient received dexamethasone whereas 20/37 H and 35/40 ICU patients benefited from this treatment this treatment did not modify chemerin levels (147.7 ng/mL (125.6-167.7) versus 158.0 ng/mL (127.2-189.0) in dexamethasone treated and untreated groups respectively Low correlation between chemerin levels and IFN-γ (r=0.32 no correlation was shown for IFN-α (r=0.21 Figure 3 Correlations analysis between chemerin concentration and the levels of different cytokines and chemokines measured by multiplex in plasma of COVID-19 patients at all time-points IL-8: interleukin 8; MIG: monokine induced by interferon-γ; MIP-1β: macrophage inflammatory protein-1β; TNFα: tumor necrosis factor α As expected, the duration of hospitalization was lower in the H group compared to the ICU group (6–10) days vs 21.5 (16–28) respectively An ARDS occurred in 38 out of 88 (43.2%) COVID-19 patients Chemerin levels were higher in patients with ARDS than without ARDS at D5 (181,8 (141.3-272.5) versus 115.7 (95.4-129.9) ng/ml p<0.001) and D14 (270.8 (162.3-332.2) versus 132.2 (119.8-149.4) ng/ml Table 3 Risk of death: Univariate logistic regression and multivariate model Receiver operating characteristic (ROC) curves were also generated to evaluate the predictive value of plasma chemerin on mortality. This showed that day 14 chemerin’s concentration best estimated mortality risk (AUC=0.85, p<0.01) compared to D1 (AUC=0.68, p<0.05) and D5 concentrations (AUC=0.73, p<0.05) (Figure 2D) a chemerin concentration above 291.4 ng/mL at D14 predicted the risk of death with a sensitivity of 77.78% a positive predictive value of 63.64% and a negative predictive value of 95.00% In addition to plasma chemerin analysis, BALs from 9 controls and 19 COVID-19 patients (Supplemental Table 3) were used for chemerin assessment The levels of chemerin on BAL were at least 1000x lower than observed in blood and no statistical difference was observed between chemerin concentrations in the BAL of controls and COVID-19 patients (42 (35–120) versus 44 (35–112) pg/mL respectively there was no significant difference in KL-6 levels at D1 versus D14 (p=NS) no correlation between chemerin and KL-6 levels was found (r=0.07 no expression of ChemR23 was reported on PMNs nor lymphocytes Lysis phenomena were also observed with essentially a desquamation of epithelial and endothelial cells (ECs) Given that no fibrosis was present in control lungs Figure 4 Immunohistochemistry staining of ChemR23 on lung slides from autopsied COVID-19 patients and controls (autopsied patient without major pulmonary lesion (control) and patient with ARDS from another origin (ARDS other)) Representative staining of smooth muscle cells from arteries and bronchia Representative staining of endothelial cells (black arrows) Representative image from area of acute pneumonia in COVID-19 patients Figure 5 Immunohistochemistry staining of chemerin on lung slides from autopsied COVID-19 patient patient with ARDS from another origin (ARDS other) and control (A) Representative image of alveolar lining staining (B) Representative image of endothelial cell (black arrow) staining D) Representative image of chemerin staining of spindle cell (red arrows) in organizing phase of diffuse alveolar damage In the present study we analyzed the chemerin/ChemR23 system in a cohort of confirmed COVID-19 patients that chemerin concentrations are elevated in plasma of COVID-19 patients and are associated with the severity of the disease inflammation and are an independent risk factor of mortality which correspond to our results (75.9 ng/mL (63.7-94.3)) control values for chemerin were around 373.0 ng/mL we determined chemerin concentration in plasma Chemerin can be degraded by many proteases that are possibly increased in acute inflammatory state this could explain why chemerin concentrations were lower in their COVID-19 patients compared to their controls Further studies evaluating the dosage of chemerin in plasma versus serum in patients with an acute inflammatory state are needed to address this hypothesis discrepancy among data could also results from difference in subgroup size (40 patients in our ICU group vs 9 in Kukla et al.) and the fact that possibly more severe patients could be included in our study taken into consideration that we are part of a tertiary care center chemerin levels tended to increase with the severity of the disease (e.g admission to ICU and development of an ARDS) and were higher in deceased patients as compared to subjects that recovered from the disease chemerin levels increased significantly with time but this increase was only significant for H patients and not in ICU patients even is a trend is seen between D5 and D14 Our hypothesis is that the higher mortality rate observed in ICU group (18%) compared to H group (2.7%) led to a loss of late samples that could have shown higher chemerin levels (ICU D1 n=40; ICU D5 n=35; ICU D14 n=25) The decrease in the number of samples in D14 also led to a lower statistical power The increased levels of chemerin detected in plasma of COVID-19 patients were not observed in BAL and they were much lower than the ones observed in blood This could be explained by the important dilution factor of the BAL and possible degradation of chemerin by proteases no BAL were obtained from healthy subjects and the number of BAL collected was relatively small and from heterogenous patients (some having an added bacterial infection All of these could interfere with our results and further studies are therefore necessary to determine chemerin levels in the BAL of these patients we were unable to find studies where chemerin levels were measured in BAL for comparison ChemR23 decrease on NK cells could be related to a modulating effect of pro-inflammatory cytokines or chemokines there is no available information regarding the regulation of the expression of ChemR23 on NK cells by other molecules than chemerin the role of the chemerin/ChemR23 on endothelial dysfunction observed in the COVID-19 patients deserves further studies This was confirmed by univariate logistic regression and the multivariate model We selected patients from first and second wave of SARS-CoV-2 infection and admission criteria to ICU and treatments changed during this period Although dexamethasone treatment did not modify chemerin levels other factors could be involved and bias our results flow cytometry analysis of BAL was limited due to the low number of cells in these samples and no BAL samples were obtained from healthy participants autopsies of COVID-19 patients were performed 72 hours after the patient’s death we therefore selected control tissues coming from late autopsies a desquamation of epithelial and/or endothelial cells was observed in tissues from COVID-19 patients and controls probably affecting the quality of the staining our study demonstrates that increased plasma chemerin levels are a marker of severity and death in COVID-19 patients multicentric studies and validation cohorts are needed to affirm chemerin as a biomarker of severity and death to be used in daily clinical practice Further studies are also needed to identify the precise mechanisms by which the chemerin/ChemR23 system affects ARDS secondary to viral pneumonia and its possible role in lung fibrosis The original contributions presented in the study are included in the article/Supplementary Material Further inquiries can be directed to the corresponding author The studies involving human participants were reviewed and approved by Local Ethical Committee The patients/participants provided their written informed consent to participate in this study The clinical data collection was performed by PL Technical support and material were provided by VC All authors critically reviewed the manuscript and approved its final version (Belgian National Fund for Scientific Research) and is a grant holder of Fonds Erasme NA was supported partially by a ULB grant and partially from Fonds Erasme ND is a post-doctoral clinical master specialist of the F.N.R.S received a grant from the Foundation Jaumotte-Demoulin CD is a Senior Research Associate with the F.N.R.S The CMMI is supported by the European Regional Development Fund and the Walloon Region (Wallonia-biomed The department of Pathology of Erasme hospital (PL and MR) was supported by Fonds Yvonne Boël BB and FM received grants from Foundation ULB and Fonds Erasme BB received financial support from Amgen and Boehringer Ingelheim This article was published with the financial support of the Fonds Erasme Anne Van Praet and Noémie Law-Weng-Sam (LoVMI) for blood samples handling biobanking and Multiplex analysis; Flavienne Sandras (Department of Pathology Erasme Hospital) for bronchoalveolar lavages and tissues biobanking; Justine Allard and Amandine Collin (DIAPath CMMI) for technical assistance on immunohistochemistry; Mélina Houinsou Hans (Department of Biomedical Research Erasme Hospital) for help with statistical analysis BB received a financial support from Amgen and Boehringer Ingelheim These funders were not involved in the study design the writing of this article and the decision to submit for publication The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2022.941663/full#supplementary-material Specific recruitment of antigen-presenting cells by chemerin a novel processed ligand from human inflammatory fluids a novel adipokine that regulates adipogenesis and adipocyte metabolism * J Biol Chem (2007) 282(38):28175−88 Chemerin is highly expressed in hepatocytes and is induced in non-alcoholic steatohepatitis liver Exp Mol Pathol (2013) 95(2):199−205 Mouse ChemR23 is expressed in dendritic cell subsets and macrophages and mediates an anti-inflammatory activity of chemerin in a lung disease model Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity Signaling properties of chemerin receptors CMKLR1 Identification of chemerin receptor (ChemR23) in human endothelial cells: Chemerin-induced endothelial angiogenesis Biochem Biophys Res Commun (2010) 391(4):1762−8 Chemerin connects fat to arterial contraction Arterioscler Thromb Vasc Biol (2013) 33(6):1320−8 is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains Eur J Immunol (1998) 28(5):1689−700 doi: 10.1002/(SICI)1521-4141(199805)28:05<1689::AID-IMMU1689>3.0.CO;2-I Chemerin is associated with inflammatory markers and metabolic syndrome phenotypes in hypertension patients Clin Exp Hypertens (2014) 36(5):326−32 Chemerin activates fibroblast-like synoviocytes in patients with rheumatoid arthritis Circulating levels of chemerin and adiponectin are higher in ulcerative colitis and chemerin is elevated in crohn’s disease Inflamm Bowel Diseases (2010) 16(4):630−7 Mechanisms and functions of chemerin in cancer: Potential roles in therapeutic intervention ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia The role of ChemR23 in the induction and resolution of cigarette smoke-induced inflammation Clinical characteristics of coronavirus disease 2019 in China New Engl J Med (2020) 382(18):1708−20 CrossRef Full Text | Google Scholar Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics Lancet Infect Diseases (2020) 20(9):e238−44 CrossRef Full Text | Google Scholar Clinical features of patients infected with 2019 novel coronavirus in wuhan Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in wuhan Lancet Respir Med (2020) 8(5):475−81 Imbalanced host response to SARS-CoV-2 drives development of COVID-19 21. 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Director College of the Canyons student-athletes Jaclyn Wosk (women’s tennis) and Hugo Boyer (men’s golf) have been named the COC Athletic Department’s Women’s & Men’s Student-Athletes of the Week for the period running March 4-9 Wosk and Boyer are the 11th set of honorees for the winter/spring 2024 session Wosk sported a perfect record across the Lady Cougars’ two Western State Conference (WSC) matches 6 singles player and teaming to win a pair from the No That performance helped Canyons to a 1-1 record for the week The sophomore out of Valencia High School has provided a steady presence for a Canyons (10-4 6-3) team that currently sits third in the WSC standings but leads all teams in the conference with 10 wins Following her wins against Bakersfield and L.A Wosk (8-1) is now riding a four-match unbeaten streak as a singles player She has also teamed for an 8-1 doubles record with all but one of those victories coming alongside sophomore teammate Faith Abt Boyer carded a four-under-par round of 68 at Santa Maria Country Club during the Western State Conference (WSC) tourney hosted by Allan Hancock College on March 4 That score earned the freshman from Bondues France tournament medalist honors on a day in which Canyons also finished first in the team standings Boyer’s round at Santa Maria Country Club is tied for the lowest score of the season by any Cougar tying with Ethan Posthumus’ round of 68 in the WSC opener on Feb Canyons has posted a perfect 38-0 record thus far You can be the first one to leave a comment Δdocument.getElementById( "ak_js_1" ).setAttribute( "value" Metrics details Messenger RNA (mRNA) therapies are emerging in different disease areas Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns−/− zebrafish embryos Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene encoding the lysosomal cystine-H+ symporter cystinosin and leading to cystine accumulation in all cells of the body The kidneys are the first and the most severely affected organs presenting glomerular and proximal tubular dysfunction The current therapeutic standard cysteamine but has many side effects and does not restore kidney function we show that synthetic mRNA can restore lysosomal cystinosin expression following lipofection into CTNS−/− kidney cells and injection into ctns−/− zebrafish A single CTNS mRNA administration decreases cellular cystine accumulation for up to 14 days in vitro CTNS mRNA therapy improves proximal tubular reabsorption and restores brush border expression of the multi-ligand receptor megalin this proof-of-principle study takes the first steps in establishing an mRNA-based therapy to restore cystinosin expression resulting in cystine reduction in vitro and in the ctns−/− larvae and restoration of the zebrafish pronephros function we take the first steps in exploring the potential of mRNA-based therapy to treat cystinosis We specifically focus on the kidney phenotype by studying the effect of the mRNA-treatment in 2D cultures of CTNS−/− human kidney epithelial cells proximal tubular epithelial cells cultured on a hollow fiber and in a ctns−/− zebrafish cystinosis model We opted for cystinosis as a prototypical disease to evaluate the potential of this approach as cystinosis presents with the distinct phenotype of cystine accumulation offering a clear readout to evaluate the effectiveness of the treatment and affects both podocytes and proximal tubular cells the ctns−/− zebrafish embryo was chosen as a stepping stone towards higher animal models as it enables to test the effectivity and potential toxicity of mRNA-based protein replacement after one-cell stage injection we demonstrate that a single delivery of sequence-optimized mRNA results in a reduction of cystine levels for up to 2 weeks in vitro a finding with general relevance for the future treatment of other lysosomal storage disorders Transfection of cystinosis patient (CYS) derived proximal tubular epithelial cells (PTECs) and podocytes (PODOs) with CTNS-3HA mRNA results in lysosomal expression of cystinosin-3HA reduction of cystine levels and reduced inulin leakage at 24 h post-transfection (a) Cystinosin-3HA expression (green) after transfection of CYS PTECs and PODOs with 500 ng/ml CTNS-3HA mRNA (bottom) as compared with untreated cells (top) (b) Quantification of PTECs and PODOs expressing cystinosin-3HA in randomly acquired microscopical fields (each dot is one field from 3 independent experiments) Images were obtained using a Operetta CLS High Content Screening Microscope Data were analysed with Mann–Whitney tests (c–f) Lysosomal localization was demonstrated at 24 h post-transfection by co-staining of cystinosin-3HA (green) with LAMP1 (red) in confocal images in a 2D cell model (c,d) (scale bar = 20 µm) and in PTECs on the hollow fiber membranes (HFM—e,f) (scale bar = 50 µm and 20 µm) (g,h) Reduction of lysosomal cystine accumulation in PTECs (g) and PODOs (h) at 24h post-transfection with increasing concentrations of CTNS-3HA mRNA Cellular cystine levels were analysed by LC–MS CTNS-3HA mRNA treated cells were compared with the GFP control using Kruskal Wallis test (PTECs) and Welch’s ANOVA (PODOs) (*) A second comparison between the transfected cells and wildtype control (Kruskal–Wallis—#) was performed Median and 95% CI are represented for PTECs and mean with SEM for PODOs (n = 3 independent experiments) *p < 0.05; ***,###p < 0.001; ****p < 0.0001 cells treated with CTNS-3HA mRNA show a reduced perinuclear LAMP1 signal (% of total The (peripheral) distribution in the CTNS-3HA treated PTECs was comparable to the wildtype control (Kruskal–Wallis test—#) (n = 120 cells) (i) The fold change leakage of FITC-inulin (relative to untreated PTECs) was evaluated in PTECs cultured on the hollow fiber membranes at 24 h post-transfection (n = 3 biological replicates) but with all tested mRNA concentrations leading to cystine concentrations approaching wildtype levels Transfection of cystinosis patient (CYS) derived proximal tubular epithelial cells (PTECs) and podocytes (PODOs) results in functional cystinosin-3HA expression for up to 4 and 10 days and reduces cystine levels for up to 10 and 18 days (a,b) Time course of cystinosin-3HA expression in PTECs (a) and PODOs (b) Images were obtained using the Operetta CLS High Content Screening Microscope and percentage of cells with detectable cystinosin-3HA expression quantified (each dot represents one observed field from 3 independent experiments) Data were analysed using a Kruskal Wallis test (PTECs) and Welch’s ANOVA test (PODOs) Median and 95% CI are represented for PTECs *p < 0.05; ***p < 0.001; ****p < 0.0001 (c,d) Time course of cystine reduction in CYS PTECs (c) and PODOs (d) that were transfected with CTNS-3HA mRNA 14 and 18 days post-transfection and were expressed as percentage (%) of levels measured in cells transfected with GFP mRNA Statistical significance was evaluated using individual tests for each time point one-way ANOVA (****p < 0.001) and Kruskal Wallis test ($$p < 0.01; $$$p < 0.001; $$$$p < 0.0001) Median and 95% CI are indicated for all time points To show the functional effect of the CTNS-mCherry mRNA injection, cystine levels were measured in ctns−/− zebrafish larvae at 72 h and 120 h after one-cell stage injection. Cystine accumulation decreased to 65.0% (± 5.1) at 72 h and 73.1% (± 1.7) at 120 h as compared with the sham-treated fish (Fig. 4a), demonstrating the potential of the therapeutic approach. Injection of human CTNS-mCherry mRNA in fertilized eggs of ctns−/− zebrafish decreases cystine accumulation restores tubular reabsorption and alleviates glomerular proteinuria (a) Injected ctns−/− zebrafish larvae were collected in groups of 10–12 fish Cystine levels in treated larvae were measured at 72 h and 120 h post-injection (n = 5 groups) Statistical analysis was performed using a Student’s t-test (b,c) mRNA treated ctns−/−[Tg(l-fabp:DBP:eGFP)] larvae were injected with 10 kDa dextran-AF647 for evaluation of low molecular weight proteinuria (LMWP) at 72 h post-injection and fixed for cryosection after 16 h Sections were stained with Hoechst 33342 (blue) and wheat germ agglutinin (WGA with the DBP-GFP visible in the liver (green) Tubular intensity of dextran-AF647 fluorescence (magenta) was measured and used to quantify low molecular weight protein absorption Data were analysed with a Student’s t-test and mean and SEM are indicated (n = 9 fish) (d) Glomerular proteinuria was evaluated in the ctns−/−[Tg(l-fabp:DBP:eGFP)] larvae at 120 h post-injection of CTNS-mCherry mRNA Images were generated with the Acquifer imaging machine an automatized FIJI script was used within a mask determined by segmentation of blood vessels upon traversing blood cells (e,f) Sections of injected ctns−/− fish were prepared at 72 h post-injection and stained for the megalin multi-ligand receptor on the proximal tubular brush border (green) Confocal images were obtained and Alexa-488 intensity was measured in each tubule (n = 8 fish) and showed the restauration of proximal tubular megalin expression in treated larvae Statistical significance was tested using an Student’s t-test and mean and SEM are indicated (g) Paraffin sections of embryos at 120 h post-injection were stained for cleaved caspase-3 and the proximal tubulus identified (red circle) High signal spots are accentuated by an arrow these results demonstrate that CTNS mRNA-based cystinosin expression is feasible and effective in reducing intracellular cystine the CTNS mRNA supplementation in the early stage zebrafish embryo improved the tubular reabsorption and reduced proteinuria These results illustrate that CTNS mRNA-based therapy may represent a promising approach for the treatment of cystinosis that was shown to not be toxic in the tested in vivo zebrafish embryo model in vitro transcribed mRNA is suitable for human applications and is currently being tested in clinical trials for propionic acidemia (NCT04159103 and NCT05130437) methylmalonic acidemia (NCT04899310 and NCT05295433) ornithine transcarbamylase deficiency (NCT05526066) and glycogen storage disease (NCT05095727)) In our study we could detect cystinosin-3HA protein for up to 4 days in the kidney epithelial cells The CTNS-3HA mRNA used in this study was equipped with standard translation-promoting UTRs but the identification of UTRs tailored to the specific cell types could further prolong the duration of protein expression Cystinosin-mCherry was detectable for up to 72 h post-injection using immunostaining in the live zebrafish embryo The faster decrease in detectable protein is likely caused by mRNA dilution due to the rapid cell division (from 1 to 1000 cells within 3 h) during early embryo development but will also depend on the sensitivity of the specific methods for detection which differed between the in vitro and in vivo studies we hypothesize that low levels of protein expression can still have a functional effect which also has important implications for the future investigation of a feasible dosing regimen a suitable delivery vehicle should be identified first and the immunogenicity of the packaged mRNA evaluated in a rodent model Both of these factors will greatly influence the future dosing schedule a full safety study will have to be performed in a rodent model after identification of the proper delivery vehicle it will be important to evaluate if multiple organs can be reached by a single delivery vehicle or a mix of different delivery vehicles equipped with multiple targeting molecules will be required our study is the first step to establishing mRNA-based therapy for cystinosis and paves the way for mRNA therapeutics in other genetic kidney diseases Ongoing studies will focus on the degree of correction that can be achieved with expression in the liver which is the main target organ for current mRNA delivery systems the search for kidney-targeted delivery vehicles that would allow for specific mRNA delivery to the kidney cells after systemic injection Next to the delivery vehicle in a rodent model special attention will be paid to the dosing frequency and the adaptive immune response Experiments were performed after differentiation at 37 °C for 10 (PTECs) or 12 days (PODOs) informed consent was obtained from the donors Human CTNS mRNAs (based on NM_004937.3) with C-terminal 3xHA (amino acid sequence: YPYDVPDYASYPYDVPDYAYPYDVPDYA) or mCherry-tag (KM983420.1) were synthesized by RiboPro B.V The Netherlands) and de-immunized via codon optimization and dsRNA reduction Each mRNA was equipped with translation promoting 5ʹ and 3ʹ untranslated regions (UTRs) mRNA quality was assessed by spectrophotometry and gel electrophoresis 0.15 µl of Lipofectamine MessengerMAX (LipoMM—Thermofisher) was mixed with 5 µl of Opti-MEM medium (Gibco) per sample and incubated for 10 min (min) at room temperature (RT) The solution was mixed by pipetting 5 µl of Opti-MEM per 50 ng of mRNA incubated for 5 min at room temperature (RT) before transfection and added to the cells (1/10 total volume) Cystine levels were measured, as described previously47 Cells were lysed in 100 µl 50 mM N-ethylmaleimide (NEM-Sigma) and 50 µl of 12% sulfosalicylic acid (SSA-Sigma) Cells are lysed by centrifugation at high speed (13,000 rpm 10 min) and the supernatant is isolated and stored at − 80 °C Analysis of total cystine levels was performed in the Bambino Gesù Children’s Hospital Values were normalized to total protein after a Bicinchoninic acid assay (Thermofisher) on the cell pellet the lysosomal signal was quantified in the perinuclear (< 25% of area around the nucleus) and peripheral region (> 25% of area around the nucleus) Lysosomal distribution was assessed in imageJ by calculating the % of LAMP1 intensity over the radius of the cell by means of quantification of the area under the curve after application of the ‘plot profile’ tool illustrating the mean fluorescence for each pixel detected three technical replicate samples (100 µl) were taken from the apical chamber of each biological replicate and fluorescence measured with a Tecan infinite M200PRO plate reader (Tecan Austria GmbH Austria) using a 492 nm excitation wavelength and 518 nm emission wavelength and the presence of eGFP was confirmed by PCR All experiments were reported in accordance with the ARRIVE guidelines Human mCherry-tagged CTNS mRNA solutions were prepared in RNAse free water (500 ng/µl) with 0.05% PhenolRed (Sigma) All mRNA injections were performed at the one-cell stage using a FemtoJet microinjector (Thermofisher) and borosilicate glass microcapillaries (World Precision Instruments) prepared using a micropipette puller device (Sutter Instruments) A tip opening diameter of ~ 2 µm was used and microinjections were set up with an injection volume of ~ 1.7 nl resulting in a final concentration of ~ 0.85 ng mRNA per embryo Unfertilized eggs were removed upon injection Protein expression was quantified for randomly selected embryos based on fluorescence in a predetermined 200 × 100 pixels area in the head region and confirmed on western blot Lysates were prepared from deyolked embryos by sonication with RIPA buffer (Thermofisher) and protease inhibitors (Roche) Protein content was determined with a Bicinchoninic acid assay (Thermofisher) and 50 µg was loaded onto a NuPAge 4–12% BisTris gel (Thermofisher) Proteins were transferred on a nitrocellulose membrane and incubated with anti-RFP (overnight Bands were visualized with HRP-linked secondary antibodies and ECL Plus substrate (Thermofisher) in the Syngene Chemi XRQ System Values were normalized to total protein after a Bicinchoninic acid assay (Thermofisher) slides were stained with Hoechst 33342 and 2 µg/ml CF770-conjugated wheat-germ agglutinin (biotium) for 10 min at RT Fish were fixed overnight in 4% PFA and washed with phosphate buffered saline (PBS-3x) and PBS with 0.1% Triton X-100 (Sigma) Larvae were kept overnight in 30% sucrose (Merck) followed by embedding in gelatine (Sigma) with 15% sucrose into a disposable mould (Electron microscopy sciences) Sections were made with the NX70 cryostat (4 µm USA) and blocked by overnight incubation in PBS + 0.1% Triton X-100 and 5% donkey (Abcam) or goat serum (DAKO) followed by incubation with primary antibody (overnight) and secondary Alexa-labelled antibody (2 h) Sections were stained with Hoechst 33342 and mounted with fluorescence mounting medium (DAKO) The tubulus was identified based on the inclusion of a haematoxylin and eosin staining Images were acquired on an Operetta CLS High Content Screening Microscope (Perkin-Elmer Zeiss LSM 880-Airyscan (Cell and Tissue Imaging Cluster (CIC) Zebrafish embryos were imaged with the Olympus IX71 widefield fluorescence microscope (Olympus—VIB bioimaging core Leuven Belgium) and the SMZ18 fluorescence stereomicroscope with a P2-SHR Plan Apo 1× objective Germany) and an X-Cite Xylis LED (Excelitas 10 kDa dextran images were obtained with laser scanning confocal microscopy (LC-LSM) zebrafish were imaged with the Acquifer Imaging Machine Data were analysed using GraphPad Prism version 8.0.0 for Windows (San Diego, California USA, www.graphpad.com) Normality was assessed by a QQ-plot and equality of variances with an F-test (Brown–Forsythe) When data was not normally distributed or n < 5 Average (± SEM) or median with 95% confidence interval (CI) [x,x] are presented for normal data and skewed data Outliers were removed based on a ROUT outlier test (Q = 1%) Two groups were compared with a Student’s t-test or Mann–Whitney test multiple groups with an one-way ANOVA or Kruskal Wallis test with Bonferroni or Dunn’s multiple testing Equality of variances was tested by means of a Brown–Forsythe F-test followed by Welch’s correction in the t-test or one-way ANOVA (followed by Dunnett’s multiple testing) A double-sided p-value < 0.05 was defined as being significant The data that support the findings of this study can be found in the manuscript and Supplementary Data The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request Molecular mechanisms and treatment options of nephropathic cystinosis Cystinosin deficiency causes podocyte damage and loss associated with increased cell motility Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin Cysteamine therapy: A treatment for cystinosis Hematopoietic stem cell gene therapy for cystinosis: From bench-to-bedside Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness An mRNA vaccine against SARS-CoV-2—Preliminary report Nanomedicines to deliver mRNA: State of the art and future perspectives Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia A new developing class of gene delivery: Messenger RNA-based therapeutics The potential of RNA-based therapy for kidney diseases van Asbeck, A. H., Dieker, J., Boswinkel, M., van der Vlag, J. & Brock, R. Kidney-targeted therapies: A quantitative perspective. JOCR 328, 762–775. https://doi.org/10.1016/j.jconrel.2020.09.022 (2020) Bioengineered cystinotic kidney tubules recapitulate a nephropathic phenotype Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction Inducible podocyte injury and proteinuria in transgenic zebrafish A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis Pattern recognition receptors in zebrafish provide functional and evolutionary insight into innate immune signaling pathways Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia The zebrafish embryo as a model organism for testing mRNA-based therapeutics Determinants and implications of mRNA poly(A) tail size—Does this protein make my tail look big Selective lysosomal transporter degradation by organelle membrane fusion Impact of cystinosin glycosylation on protein stability by differential dynamic stable isotope labeling by amino acids in cell culture (SILAC) Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis Systemic mRNA therapy for the treatment of Fabry disease: Preclinical studies in wild-type mice The renal Fanconi syndrome in cystinosis: Pathogenic insights and therapeutic perspectives Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney Use of human induced pluripotent stem cells and kidney organoids to develop a cysteamine/mtor inhibition combination therapy for cystinosis Combined structural and functional imaging of the kidney reveals major axial differences in proximal tubule endocytosis Distinct functions of megalin and cubilin receptors in recovery of normal and nephrotic levels of filtered albumin Megalin and cubilin in proximal tubule protein reabsorption: From experimental models to human disease purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial infarction in swine Zebrafish as an animal model for biomedical research Brief reports: Lysosomal cross-correction by hematopoietic stem cell-derived macrophages via tunneling nanotubes Williams, R. M. et al. Mesoscale nanoparticles selectively target the renal proximal tubule epithelium. Nano Lett. 15, 2358–2364. https://doi.org/10.1021/nl504610d (2015) Mrna-based nanomedicinal products to address corneal inflammation by interleukin-10 supplementation Melamed, J. R. et al. Ionizable lipid nanoparticles deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer. Sci. Adv. 9, 1444. https://doi.org/10.1126/sciadv.ade1444 (2023) Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression Cysteamine restores glutathione redox status in cultured cystinotic proximal tubular epithelial cells Urine-derived kidney progenitor cells in cystinosis Acute podocyte injury is not a stimulus for podocytes to migrate along the glomerular basement membrane in zebrafish larvae Schindler, M. et al. A novel high-content screening assay identified belinostat as protective in a focal segmental glomerulosclerosis-like zebrafish model. J. Am. Soc. Nephrol. https://doi.org/10.1681/ASN.0000000000000235 (2023) Download references The authors thank Marianne Klawitter (Department of Anatomy and Cell Biology Laleh Khodaparast and Ladan Khodaparast (Switch Laboratory Belgium and VIB Center for Brain & Disease Research Peter de Witte and Jan Maes (Department of Pharmaceutical and Pharmacological Sciences Frédéric Hendrickx and Kim van Kelst (Aquatic Facility Belgium) for their assistance and contribution in the zebrafish experiments The authors gratefully acknowledge the VIB Bio Imaging Core (VIB Leuven Belgium) for their support and assistance in this work and Pieter Vanden Berghe (Confocal Imaging Cluster (CIC) Belgium) for the usage of the confocal microscope (supported by Hercules AKUL/15/37_GOH1816N and FWO G.0929.15 to Pieter Vanden Berghe The authors express gratitude to F.W.O Vlaanderen for the support to Tjessa Bondue (11A7821N and 11A7823N) and Elena Levtchenko (1801120N) We acknowledge the KU Leuven C1 Grant to Elena Levtchenko Lambertus van den Heuvel and Rik Gijsbers (C14/17/11) and the Federal Ministry of Education and Research (BMBF) and STOP-FSGS Research Network for their support to Nicole Endlich (01GM1518B) We acknowledge Cystinosis Ireland and the Cystinosis Foundation UK co-funded Research Award 2021 The collaboration project is co-funded by the PPP Allowance made available by Health ~ Holland (Geval 2020–2022) Elena Levtchenko is a member of the European Reference Kidney Network (ERKNet) These authors contributed equally: Sante Princiero Berlingerio Lambertus van den Heuvel and Elena Levtchenko Department of Development and Regeneration Lambertus van den Heuvel & Elena Levtchenko Utrecht Institute for Pharmaceutical Sciences Elena Sendino-Garví & Manoe Jacoba Janssen Emma Children’s Hospital and Emma Center for Personalized Medicine Laboratory for Molecular Virology and Gene Therapy Department of Pharmaceutical and Pharmacological Sciences provided key reagents for the transfection Original draft preparation was carried out by T.B. All authors revised and approved the final version of the manuscript Roland Brock and Jürgen Dieker are cofounders of Mercurna B.V companies that develop mRNA therapeutics (Mercurna B.V.) and offer mRNA services (RIBOPRO B.V.) Other authors declare no competing interests Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-023-47085-w Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science When Cyril Bondue first played Triple Triad the peculiar card-collecting minigame from Final Fantasy VIII like many other fans of Squaresoft’s (now Square Enix) enduring JRPG of the late ’90s playing Triple Triad became more important than the main game itself matching elements and snatching high-ranking cards proved far more intriguing than steering the oft aloof Squall Leonhart around Balamb Dollet or Deling City—locales Bondue only cared to visit in order to seek out new NPCs with untapped and inestimable decks “I remember winning cards but being unsure of how I triggered this or that effect,” explains Bondue But I was looking at magazines and speaking more with people about the cards than the actual game itself Bondue decided to take his love for Triple Triad a step further While still attending school in his native Berlin he decided to create a fan project based on an existing franchise Triple Triad was at the forefront of his mind and thus Triple Triad Flash Online was born TTFO has over 36,000 registered users and hosts approximately 140 games per day not to mention fortnightly championships which see 150-200 players face off for coveted character cards TTFO wasn’t as well established as it is now Version 1 was simple in its makeup: as a neophyte coder Bondue struggled with sophisticated design but quickly noticed a distinct interest in his creation as the user base began to slowly multiply the speed in which any Triple Triad game plays out is variable thus Version 1’s 30-second server requests meant bouts suffered tedious amounts of lag This extended to the game’s chat function meaning messages also took half a minute to deliver and there was no way of inviting players to join games Bondue realised the burgeoning community he had helped grow needed more from TTFO and decided to upgrade Version 2 ushered in TTFO as it stands today correcting all of the previous technical handicaps and punctuating the familiar interface with the equally familiar finger-clicking jingle which guarantees to set up camp in your head after first listen Although keen at the time to overhaul its aesthetics Bondue was clear to maintain the exact same ruleset Keep up to date with the most important stories and the best deals and I’ve chosen not to add any new cards,” explains Bondue “I wanted to stick to the 110 original cards in order to keep the original balance of every original card Adding cards can break this balance.” however—the site’s main attraction—Bondue can be creative in order to generate interest in both existing and prospective users By battling through four stages of competition players can capture spoils with little experience “Championships at TTFO are the only way to earn character cards,” says Bondue “Character cards are level ten and therefore the most powerful in the game—they are very uncommon Most players won’t have them but everyone wants them and this encourages a lot of players to participate Players don’t play with regular cards You are given a set of cards [that] I choose and every new championship has its own set of rules “Whereas when you join the game at first you’ll only have level one cards you can join a championship at any time and level When you win a game you can take a card from your opponent you don’t really want to lose them—but here they’re just there for the tournament Championships make for more exciting games as you don’t have as much to lose.” long-standing MMO Final Fantasy XIV introduced a reinterpretation of the Golden Saucer—a theme park-style area which featured in Final Fantasy VII—which boasts popular minigames from previous series instalments It’d be natural for Bondue to consider the impact this may have on TTFO Yet he feels it could be good for the community by virtue of introducing a new generation to the game thus potentially raising the profile of his fan site Bear in mind Triple Triad is a game within a game from last century where schoolyard card swapping was (presumably) far more commonplace in a world predating the digital age The idea of getting younger players involved who can then migrate to a more focused arena can’t be a bad thing Although not specifically tailored to suit anyone but the TTFO community Bondue is in the process of upgrading again with plans to roll out Version 3 at some stage later this year Having worked on the particulars alongside community members since mid- 2014 a 3D Garden-esque lobby is set to offer a far more contemporary Triple Triad experience—and Bondue notes future Twitch livestreams as a possible way of further enticing new faces But the old faces are the pillars of the community has been an integral member of TTFO since 2011 “We’ve got players from all over the world,” he says as he praises the figurative closeness of the far-reaching group “The majority are Europeanbased but there’s a strong North and South American presence and there’s quite a few players from the Philippines and South East Asia who play a fair bit “Some of these players have got some really different ways of approaching the game [They] are always thinking outside the box all the rules and the way people approach it—you’re always learning I learned quickly that you can’t expect to win every game Seafire returns to the air A memorable event took place at Old Warden aerodrome Supermarine Seafire F.XVII SX336 (G-KASX) took off for its first flight in five years The shipboard fighter was damaged during a wheels up landing at Bondues (France) on 1 July 2011 It was repaired in the three years that followed making the first post restoration flight on 3 July 2014 But since then SX336 was rarely seen in the air and since 2016 the Seafire totally disappeared off stage SX336 is a Westland built Seafire (c/n FLWA/25488) the fuselage of which was salvaged from a scrapyard by ‘mr A restoration was taken up ten years later and the project was registered to Peter J In 2001 the Seafire was acquired by Tim Manna of Cranfield and registered as G-KASX in 2003 The restoration proceeded at Kennet Aviation resulting in the first flight on 3 May 2006 As a member you get access to all our premium content and benefits learn more Lymphocytic-variant hypereosinophilic syndrome (L-HES) is a form of reactive hypereosinophilia, most commonly associated with interleukin-5 over-production by clonal, most commonly CD3−CD4+CD2hiCD5hiCD45RO+ T-cells. Patients often present with predominant cutaneous and soft-tissue manifestations, while cardiovascular involvement is uncommon. We reviewed the medical files of two L-HES patients followed in our center who developed serious vascular complications and performed a literature review for similar cases. Patients with apparently clinically benign L-HES may develop arterial complications, consisting in dissection and/or aneurysm dilatation of medium-to-large vessels with serious consequences. The value of performing regular vascular imaging and monitoring during follow-up has yet to be determined. Volume 10 - 2023 | https://doi.org/10.3389/fcvm.2023.1256862 This article is part of the Research TopicCase Reports in Atherosclerosis and Vascular Medicine: 2023View all 7 articles Background: Lymphocytic-variant hypereosinophilic syndrome (L-HES) is a form of reactive hypereosinophilia most commonly associated with interleukin-5 over-production by clonal most commonly CD3−CD4+CD2hiCD5hiCD45RO+ T-cells Patients often present with predominant cutaneous and soft-tissue manifestations while cardiovascular involvement is uncommon Methods: We reviewed the medical files of two L-HES patients followed in our center who developed serious vascular complications and performed a literature review for similar cases presented with an ischemic stroke secondary to left middle cerebral artery dissection after 10 years of indolent L-HES Blood eosinophilia was controlled with oral corticosteroids (OCS) but OCS-tapering attempts with hydroxyurea and pegylated interferon failed prompting the introduction of mepolizumab with rapid normalization had been asymptomatic for 10 years without treatment when a NSTEMI occurred due to coronary artery occlusion secondary to a large cauliflower-aneurysm of the proximal aorta and aneurysmal dilatation of several coronary arteries Aortic wall staining for eosinophil major basic protein showed eosinophils in the adventitia Blood eosinophilia was controlled with OCS Conclusions: Patients with apparently clinically benign L-HES may develop arterial complications consisting in dissection and/or aneurysm dilatation of medium-to-large vessels with serious consequences The value of performing regular vascular imaging and monitoring during follow-up has yet to be determined Herein we report two patients with long-standing stable L-HES who developed serious complications due to vascular injury Medical records of patients were reviewed according to local ethics committee guidelines and a systematic literature review was conducted using the PubMed database. To formulate the search strategy, relevant keywords and Medical Subject Headings (MeSH) terms were identified to cover vascular complications among HES patients. The search equation was developed by combining these terms using Boolean operators (Supplementary Material) An initial search was performed to evaluate the relevance and specificity of the search equation Based on the outcomes of the initial search A full search was conducted using the refined search equation and the search results were screened for L-HES vascular complications Articles were selected for inclusion based on a full-text assessment of their relevance The search strategy yielded a total of 77 articles of which 3 articles met our criteria and were therefore included Patient 1: A 52-year-old woman diagnosed with L-HES in 2010 developed aphasia and right brachiofacial paresis in July 2020. Cerebral computed tomography (CT)-scan showed a cortico-subcortical left hemispheric infarction, and magnetic resonance (MR)-angiography with vessel wall imaging sequences suggested dissection of the left middle cerebral artery (Figures 1A–C) Her blood absolute eosinophil count (AEC) upon admission was 8.18 G/L (A) Cerebral CT-scan showing left middle cerebral artery irregularities with “flute-beak” appearance (B,C) Diffusion-weighted cerebral magnetic resonance showing cortico-subcortical left hemispheric infarction and intramural hypersignal on T1 sequences of the left middle cerebral artery suggesting presence of a vessel-wall hematoma Her past HES history started with the fortuitous discovery of asymptomatic blood hypereosinophilia in 1995 and Raynaud’s with toe chilblain in 2010 at which time the diagnosis of L-HES was made in presence of an AEC at 7.35 G/L and a circulating CD3−CD4+ T-cell population (1.9% of lymphocytes Oral corticosteroid (OCS) therapy was initiated with symptom improvement and normalization of AEC with persistent clinical remission at 4 mg methylprednisolone (MPDN) daily although hypereosinophilia recurred Her CD3−CD4+ T-cell counts were stable over time and cardiovascular assessments including angiography of lower extremities and repeated echocardiography and cardiac MR were normal Upon admission for stroke, HES was considered the most likely cause of vascular dissection after an extensive workup. Treatment with aspirin (80 mg/day) and atorvastatin (40 mg/day) was started in accordance with local protocols for the management of acute ischemic stroke. The daily OCS dose was increased and AEC normalized within 24 h (Figure 1D) Her neurological symptoms resolved completely within months Hypereosinophilia recurred with OCS-tapering so classical second-line agents were introduced for OCS-sparing purposes Neither hydroxyurea nor sub-cutaneous pegylated interferon-alpha (peg-IFN-α) achieved this goal She recently started mepolizumab 300 mg/4 weeks leading to a dramatic reduction of her AEC to 0.01 G/L CT-angiography of the aorta revealed giant polylobulated aneurysms occupying the non-coronary VSs; the largest aneurysm Patient 2 cardiovascular imaging and histology (A) Coronary angiography showing aneurysmal dilation of CA (→) and extrinsic compression of the left main trunk by a VS aneurysm (➤) (B) Aortic MR-angiography showing giant polylobulated aneurysms occupying the non-coronary and the left VS (C) Perioperative transesophageal echocardiography showing mural thrombus in a VS aneurysm (E) Immuno-fluorescent staining for eMBP-1 on resected aorta from patient 2 and from a control normo-eosinophilic subject with an aortic dissection showing intact eosinophils (8 per high power field) and patchy extracellular granule protein deposition in patient 2’s aortic adventitia Prominent non-specific staining was observed in the media in both patient and control with a similar pattern to control staining with rabbit immunoglobulin (not shown) Her past L-HES history was notable for pruriginous bullous skin lesions in 2010 associated with blood hypereosinophilia (4.47 G/L) and a CD3−CD4+ T-cell population (7% of total lymphocytes Because the skin lesions regressed spontaneously and both her AEC (2–3.7 G/L) and her aberrant T-cell subset remained stable over time Cardiac assessments including yearly electrocardiogram and serum Troponin were normal until January 2021 when ectasia of the aortic root and VS enlargement were noted She is currently OCS-dependent with poor tolerance Our literature review identified three other cases of severe vascular complications occurring in L-HES patients, either as unique case reports (5–6) or among complications mentioned in a L-HES patient cohort (7) (Supplementary Table S1) Development of serious vascular complications such as arterial dissection and/or aneurysmal dilatations is uncommon in patients with HES, and in L-HES only 3 cases have been reported besides ours (5–7) (Supplementary Table S1) Our observation suggests that patients with L-HES and uncontrolled eosinophilia may develop serious ischemic complications due to direct damage of the vascular wall of medium-to-large vessels many years after diagnosis even in the setting of otherwise benign disease presentations Although the causal role of eosinophils in vascular damage remains to be firmly established in the setting of HES AECs should be well controlled by treatment thereafter to prevent recurrence Our observation further underlines how unpredictable HES disease course can be and raises the question of how such rare but serious vascular complications can be detected before irreversible damage occurs. Currently, only repeated cardiac assessments (electrocardiogram, echocardiography and serum Troponin T) are recommended to detect cardiovascular complications in HES (2) Our observation underscores that attention should be paid both to the heart and adjoining vascular structures during yearly echocardiography In HES patients with persistent hypereosinophilia yearly cardiac MR may increase the likelihood of detection vascular imaging studies should be performed promptly in patients with clinical manifestations suggesting possible vasculopathy and repeated in those with a history of vascular injury to detect involvement of other vascular beds Inclusion of systematic vascular imaging among follow-up assessments in patients whose eosinophil counts are persistently elevated may be worth considering CT-angiography has a higher resolution than MR-angiography but because of significant irradiation MR-angiography is more appropriate for screening dissection and (pseudo)aneurysmal formation of medium to large-caliber vessels are uncommon but serious complications of HES Screening for these complications could be of clinical interest further inquiries can be directed to the corresponding author Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article The author(s) declare financial support was received for the research FNRS (National Fund for Scientific Research) grants n° F 5/4/150/5 (FR) AB is co-holder of an Actelion chair for Research in Pulmonary Hypertension We are grateful to the technicians in the Immunodermatology Laboratory as well as Professors Kristin Leiferman and Gerald Gleich for eMBP1 and EDN immuno-staining of the resected aorta specimens is a member of the EuroBloodNet European Reference Network FR has received consultancy fees from AstraZeneca AB has received consultancy fees from Amicus FV has received consultancy fees from Livanova The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2023.1256862/full#supplementary-material Proposed refined diagnostic criteria and classification of eosinophil disorders and related syndromes Hypereosinophilic syndrome: considerations for the cardiologist Recurrent cardiac arrest due to eosinophilia-related coronary vasospasm successfully treated by benralizumab Eosinophilia associated with CD3(−)CD4(+) T cells: characterization and outcome of a single-center cohort of 26 patients PubMed Abstract | Crossref Full Text | Google Scholar Dissection of the posterior inferior cerebellar artery in the hypereosinophilic syndrome The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3−CD4+ aberrant T-cell phenotype Coexistence of giant aneurysm of sinus of valsalva and coronary artery aneurysm associated with idiopathic hypereosinophilic syndrome Spontaneous coronary artery dissection and eosinophilic inflammation: a cause and effect relationship Contributions of eosinophils to human health and disease doi: 10.1146/annurev-pathmechdis-012419-032756 Crossref Full Text | Google Scholar Molecular profiling of CD3−CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways Peripheral T cell lymphoma presenting as hypereosinophilia with vasculitis lymphocytic variant hypereosinophilic syndrome Vanden Eynden F and Roufosse F (2023) Case report: Serious unexpected vascular events in two patients with lymphocytic variant hypereosinophilic syndrome Received: 11 July 2023; Accepted: 4 September 2023;Published: 27 September 2023 © 2023 Torcida, Casalino, Bondue, Jodaitis, Vanden Eynden and Roufosse. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Florence Roufosse ZmxvcmVuY2Uucm91Zm9zc2VAaHVicnV4ZWxsZXMuYmU= †These authors contributed equally to this work and share first authorship Mégane Lourenco On fait quoi à Lille ce week-end Diffusion en avant-première des films du festival de Cannes à Lille Une publication partagée par UGC Cinemas (@ugccinemas) "Le Bazaar et CampinkCosmos vous présentent le TEA POT & DONUT QUEER FESTIVAL. Une programmation inédite avec les DRAGS OLYMPICS pour la première fois en France la diffusion du Rocky Horreur Picture Show & bien plus encore….!" La braderie de wazemmes aura lieu cette année le 25 mai Périmètre :- rue de wazemmes de la place de la solidarité à la rue d’Artois- rue de la justice- rue d’Artois du bd Victor Hugo à la rue Barthélémy Delespaul le festival des jardins de Lille-Sud pose ses bagages pots et bancs au Grand Sud.Organisé par la Mairie de quartier les acteurs associatifs du territoire et le Grand Sud cette journée sera l'occasion de découvrir et fêter la nature les habitantes et habitants sont invités à être ensemble.Le Grand Sud ouvrira grandes ses portes pour ce véritable temps convivial ouvert à toutes et tous et proposera plusieurs interventions artistiques : Concert d'Esprit Freestyle DJ set et quizz musical de DJ DO ou encore initiation roller mené par le Roller Derby Lille !Samedi 25 maiDe 14h à 19hGratuit" Une publication partagée par Restaurant Le Souk Lille (@lesouklille) Village Italien Place du Théâtre Une publication partagée par Le Bonbon Lille (@le_bonbon_lille) Grand Opening de la Guinguette de la Ferme à Bondues  La Guinguette de la Ferme est de retour ce week-end  Les festivités dureront le samedi ainsi que le dimanche  Une publication partagée par La Guinguette de la Ferme (@guinguette.bondues) MARCHÉ FERMIER par le CIVAM Hauts-de-France "10h-18h, en continu. Les producteurs du CIVAM (Centres d’Initiatives pour Valoriser l’Agriculture et le Milieu rural) vous proposent leurs bons produits locaux et de saison. Marché de producteurs : La ferme Carré (produits laitiers au lait de vache) HORTUS & Sauvageonnes(Plantes Aromatiques à Parfum et Médicinales) Le rucher de Leaya (Miel et produits de la ruche) Le potager de la Grande Ourse (légumes) Les Chtites Biquettes (yahourts et fromages au lait de chèvre) La Cantine des évidences (restauration)À noter : une petite restauration sera proposée pour les usagers souhaitant pique-niquer sur site." Des courts de tennis de Roland-Garros ouverts gratuitement au public cet été la Grand-Place de Roubaix va se transformer en paradis des fleurs Un pop-up 100% maillots de foot vintage débarque à Lille ce weekend Sign In Subscribe Now There will be no 41st Oscar Hickes Memorial Hockey Tournament in Port Alice this year one of the organizers for the longest running hockey tournament on Vancouver Island broke the sad news on social media on Tuesday RELATED: 40th anniversary Oscar Hickes Murray stated the organizers asked the Village of Port Alice if the tournament could be held at the shuttered Doug Bondue Arena like it always has been (other than the one year it was held in Port Hardy in the 90s) loading and then evacuating the system after the ice is removed and the financial burden on the taxpayers of the village Port Alice Mayor Kevin Cameron confirmed Murray’s statement noting it was “very accurate with what today’s situation is without the financial backing of Neucel (Port Alice’s dormant pulp mill) the village has had to make numerous cuts to their operating budget which included closing the arena for the 2018-2019 season (the rink did open for the 40th annual Oscar Hickes weekend in 2019 Neucel still owes the village approximately two years worth of taxes (totalling around two million dollars) and Cameron stated there has been “nothing to this point” regarding any kind of payment from Neucel “When the mill was running it brought in 28 million to the coffers for the island in general with the majority of that being spent in Tri-Port,” Cameron added noting that if things do change financially for the better in Port Alice the annual Oscar Hickes weekend will definitely return once again ‘Oscar Hickes’ was born Oscar Tootoo in 1952 in Churchill He grew up playing hockey with his brothers and absolutely loved the sport Tootoo went to Vancouver to see a specialist to correct a knee injury so he could play hockey that winter The doctor informed him his playing days were over and he passed away minutes later in his car from a heart attack The Oscar Hickes Memorial Hockey Tournament officially started that same year in Port Alice @NIGazetteeditor@northislandgazette.comLike us on Facebook and follow us on Twitter Dialogue and debate are integral to a free society and we welcome and encourage you to share your views on the issues of the day. 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To learn about our commenting policies and how our community-based moderation works, please read our Community Guidelines With a winning percentage that Tiger Woods in his prime would be proud to own Greg Koster once again showed he is the class of the field at the 60th anniversary of Sunnydale's Men's Tillicum The long weekend got off to a close start with golfers bunched up near the lead Koster and Tyler Van Anrooy led the field with solid one-under par 70s Koster separated himself from the field by shooting a 66 Day three left the rest of the field shaking their collective heads They watched as Koster shot a sizzling seven-under par 64 – leaving them wondering when he was planning on retiring from the game Koster finished with a three-day total of 200 The rest of the weekend proved to be just as exciting with two hole in ones On Saturday Rory Bondue aced #10 with a one hopper and Earl Costello did the same Sunday on #15 Costello also sank a 20-foot putt to win Friday night's horse race with partner Shane Robinson Saturday KP winners were Tyler Van Anrooy #3 Sunday KP winners were Mitch Carr-Hilton #3 Monday KP winners were Taylor Thibeault #3 Dave Pye and the Sunnydale Men's Club for their hard work; clubhouse manager Ben Gill and his staff for great food and service Congratulations go to Sunnydale's new superintendent Aaron Sorenson and his staff for the best condition players have seen in the tournament's long history Thank you to both men's and ladies' club volunteers Clara Morgane présente son cabaret sensuel au Sébasto' La très célèbre Clara Morgane présentera son spectacle "Clara Oulala" le 10 février 2023 au Sébasto de Lille Une jolie mise en bouche pour la Saint-Valentin  Le symbole du chic et de l'érotisme fera une halte par chez nous dans le cadre de sa tournée actuelle Son cabaret d'une durée d'1h40 invitera les spectateurs à une parenthèse de sensualité En savoir plus L’exposition est pensée comme un beau spectacle invitant au voyage au rêve ou à l’aventure à travers des dioramas pouvant atteindre des dizaines de mètres carrés Les célèbres petites figurines en plastique attendent les enfants d’hier et d’aujourd’hui pour vivre une fantastique aventure ! Château d’Harry Potter Retrouvez les univers variés de l’artiste à La Fileuse de Loos  Du 11 février au 17 février 2023Gratuit de 10h à 12h30 et de13h30 à 17hFermé le lundi Doudoune Club du Forest à Bondues c'est dans le club hippique de Bondues (20 min de Lille) qu'il faudra se rendre  chaussez vos plus belles moonboots et go "sur les pistes" pour le Doudoune Club du Forest  Inspirée des discothèques à ciel ouvert des plus grosses stations de ski et des débuts de soirée en after-ski aux pieds des pistes cette folle soirée se passera indoor et outdoor avec la tenue vestimentaires adéquate !  Une publication partagée par ⚜ LA LILLOISE ⚜ (@la.lilloise) En savoir plus Prolongation de l'expo "Prière de toucher l'art et la matière" L’ART ET LA MATIÈRE est une invitation à contempler l’oeuvre d’art par le toucher. En renversant les codes et les consignes de la visite traditionnelle du musée cette exposition raconte une histoire de la sculpture occidentale de l’Antiquité à l’Art moderne Elle a pour thème la figuration humaine dont la découverte est proposée grâce à des reproductions d’œuvres tactiles l’oeuvre d’art se révèle autrement et met en éveil nos sens." En savoir plus BonnuitLes grands inventeurs ne cessent de rivaliser d'originalité pour faire de vos nuits un vrai moment de sérénité Entre les oreillers qui empêchent son conjoint de ronfler ou les lits qui bougent tout seul pour ne pas que ce fameux conjoint prenne toute la place on ne sait plus où donner de la tête quand il s'agit de bichonner son sommeil la solution est toute simple et en plus 100% Lilloise On vous emmène à la découverte des matelas Bonnuit vous révolutionnez votre manière de consommer de la même façon que la marque a pour ambition de révolutionner la literie.  Autre avantage de Bonnuit  on priorise le juste prix en valorisant les fabrications à la demande et en supprimant les intermédiaires sans valeur ajoutée dans l'ensemble de sa chaine de valeur afin de proposer le prix le plus justifié possible C'est la suppression d'intermédiaires qui va permettre de réduire le coût global de chaque produit favorisant ainsi un circuit nettement plus court entre l'usine de fabrication de Bonnuit et le consommateur Un effort de proximité qui permet notamment à ce même consommateur de connaître les coûts réels intégrés au prix du produit tout en assurant une relation directe avec la marque" Pourquoi on vous en parle ? Car ces petits bijoux sont fabriqués aux portes de Lille ! 100% française et ultra locale, la marque Bonnuit possède 2 magasins (l'un à Cysoing l'autre à Bondues) et il est possible de visiter leurs showrooms pour mieux vous rendre compte de la qualité de la literie notez d'une croix rouge les dates du 2 et du 3 juin car le magasin à Cysoing organise ses portes ouvertes  Il est même d'ailleurs possible de visiter les ateliers en toute transparence afin que vous puissiez voir le travail derrière ces fameux matelas bien consommer et valoriser un travail de qualité et local : c'est tout ça le pari de Bonnuit Et vos nuits vous diront merci !  BonnuitSite web Le CBD pourrait augmenter les effets indésirables des médicaments l’Europe a 100% de chances d’être touchée par un tsunami d’ici 30 ans année la plus chaude enregistrée et la première à franchir le plafond de +1,5°C