SO2, silicate clouds, but no CH4 detected in a warm Neptune.

WASP-107b is a warm (approximately 740 K) transiting planet with a Neptune-like mass of roughly 30.5 M⊕ and Jupiter-like radius of about 0.94 RJ (refs. 1,2), whose extended atmosphere is eroding3. Previous observations showed evidence for water vapour and a thick, high-altitude condensate layer in the atmosphere of WASP-107b (refs. 4,5). Recently, photochemically produced sulfur dioxide (SO2) was detected in the atmosphere of a hot (about 1,200 K) Saturn-mass planet from transmission spectroscopy near 4.05 µm (refs. 6,7), but for temperatures below about 1,000 K, sulfur is predicted to preferably form sulfur allotropes instead of SO2 (refs. 8-10). Here we report the 9σ detection of two fundamental vibration bands of SO2, at 7.35 µm and 8.69 µm, in the transmission spectrum of WASP-107b using the Mid-Infrared Instrument (MIRI) of JWST. This discovery establishes WASP-107b as the second irradiated exoplanet with confirmed photochemistry, extending the temperature range of exoplanets exhibiting detected photochemistry from about 1,200 K down to about 740 K. Furthermore, our spectral analysis reveals the presence of silicate clouds, which are strongly favoured (around 7σ) over simpler cloud set-ups. Furthermore, water is detected (around 12σ) but methane is not. These findings provide evidence of disequilibrium chemistry and indicate a dynamically active atmosphere with a super-solar metallicity.

15NH3 in the atmosphere of a cool brown dwarf.

Brown dwarfs serve as ideal laboratories for studying the atmospheres of giant exoplanets on wide orbits, as the governing physical and chemical processes within them are nearly identical1,2. Understanding the formation of gas-giant planets is challenging, often involving the endeavour to link atmospheric abundance ratios, such as the carbon-to-oxygen (C/O) ratio, to formation scenarios3. However, the complexity of planet formation requires further tracers, as the unambiguous interpretation of the measured C/O ratio is fraught with complexity4. Isotope ratios, such as deuterium to hydrogen and 14N/15N, offer a promising avenue to gain further insight into this formation process, mirroring their use within the Solar System5-7. For exoplanets, only a handful of constraints on 12C/13C exist, pointing to the accretion of 13C-rich ice from beyond the CO iceline of the disks8,9. Here we report on the mid-infrared detection of the 14NH3 and 15NH3 isotopologues in the atmosphere of a cool brown dwarf with an effective temperature of 380 K in a spectrum taken with the Mid-Infrared Instrument (MIRI) of JWST. As expected, our results reveal a 14N/15N value consistent with star-like formation by gravitational collapse, demonstrating that this ratio can be accurately constrained. Because young stars and their planets should be more strongly enriched in the 15N isotope10, we expect that 15NH3 will be detectable in several cold, wide-separation exoplanets.

CRP under 130 mg/L rules out the diagnosis of Legionella pneumophila serogroup 1 (URINELLA Study).

INTRODUCTION: In case of pneumonia, some biological findings are suggestive for Legionnaire's disease (LD) including C-reactive protein (CRP). A low level of CRP is predictive for negative Legionella Urinary-Antigen-Test (L-UAT). METHOD: Observational retrospective study in Nord-Franche-Comté Hospital with external validation in Besançon University Hospital, France which included all adults with L-UAT performed during January 2018 to December 2022. The objective was to determine CRP optimal threshold to predict a L-UAT negative result. RESULTS: URINELLA included 5051 patients (83 with positive L-UAT). CRP optimal threshold was 131.9 mg/L, with a negative predictive value (NPV) at 100%, sensitivity at 100% and specificity at 58.0%. The AUC of the ROC-Curve was at 88.7% (95% CI, 86.3-91.1). External validation in Besançon Hospital patients showed an AUC at 89.8% (95% CI, 85.5-94.1) and NPV, sensitivity and specificity was respectively 99.9%, 97.6% and 59.1% for a CRP threshold at 131.9 mg/L; after exclusion of immunosuppressed patients, index sensitivity and NPV reached also 100%. CONCLUSION: In case of pneumonia suspicion with a CRP level under 130 mg/L (independently of the severity) L-UAT is useless in immunocompetent patients with a NPV at 100%. We must remain cautious in patients with symptoms onset less than 48 h before CRP dosage.

Campylobacter fetus Invasive Infections and Risks for Death, France, 2000-2021.

Campylobacter fetus accounts for 1% of Campylobacter spp. infections, but prevalence of bacteremia and risk for death are high. To determine clinical features of C. fetus infections and risks for death, we conducted a retrospective observational study of all adult inpatients with a confirmed C. fetus infection in Nord Franche-Comté Hospital, Trevenans, France, during January 2000-December 2021. Among 991 patients with isolated Campylobacter spp. strains, we identified 39 (4%) with culture-positive C. fetus infections, of which 33 had complete records and underwent further analysis; 21 had documented bacteremia and 12 did not. Secondary localizations were reported for 7 (33%) patients with C. fetus bacteremia, of which 5 exhibited a predilection for vascular infections (including 3 with mycotic aneurysm). Another 7 (33%) patients with C. fetus bacteremia died within 30 days. Significant risk factors associated with death within 30 days were dyspnea, quick sequential organ failure assessment score >2 at admission, and septic shock.

High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2.

Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID-19) by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal-type carbohydrates, mainly the N-glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3-galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate-N-acetylneuraminic acid hydroxylase and α1,3-galactosyl-transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor binding domain to produce glyco-humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3-galactose epitopes. Animals rapidly developed a hyperimmune response with anti-SARS-CoV-2 end-titers binding dilutions over one to a million and end-titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV-19, neutralized spike/angiotensin converting enzyme-2 interaction at a concentration <1 µg/mL, and inhibited infection of human cells by SARS-CoV-2 in cytopathic assays. We also found that pig GH-pAb Fc domains fail to interact with human Fc receptors, thereby avoiding macrophage-dependent exacerbated inflammatory responses and a possible antibody-dependent enhancement. These data and the accumulating safety advantages of using GH-pAbs in humans warrant clinical assessment of XAV-19 against COVID-19.

Olfactory dysfunction in COVID-19, new insights from a cohort of 353 patients: The ANOSVID study.

Olfactory disorders (OD) pathogenesis, underlying conditions, and prognostic in coronavirus disease 2019 (COVID-19) remain partially described. ANOSVID is a retrospective study in Nord Franche-Comté Hospital (France) that included COVID-19 patients from March 1 2020 to May 31 2020. The aim was to compare COVID-19 patients with OD (OD group) and patients without OD (no-OD group). A second analysis compared patients with anosmia (high OD group) and patients with hyposmia or no OD (low or no-OD group). The OD group presented less cardiovascular and other respiratory diseases compared to the no-OD group (odds ratio [OR] = 0.536 [0.293-0.981], p = 0.041 and OR = 0.222 [0.056-0.874], p = 0.037 respectively). Moreover, history of malignancy was less present in the high OD group compared with the low or no-OD group (OR = 0.170 [0.064-0.455], p < 0.001). The main associated symptoms (OR > 5) with OD were loss of taste (OR = 24.059 [13.474-42.959], p = 0.000) and cacosmia (OR = 5.821 [2.246-15.085], p < 0.001). Most of all ORs decreased in the second analysis, especially for general, digestive, and ENT symptoms. Only two ORs increased: headache (OR = 2.697 [1.746-4.167], p < 0.001) and facial pain (OR = 2.901 [1.441-5.842], p = 0.002). The high OD group had a higher creatinine clearance CKD than the low or no-OD group (89.0 ± 21.1 vs. 81.0 ± 20.5, p = 0.040). No significant difference was found concerning the virological, radiological, and severity criteria. OD patients seem to have less comorbidity, especially better cardiovascular and renal function. Associated symptoms with OD were mostly neurological symptoms. We did not find a significant relationship between OD and less severity in COVID-19 possibly due to methodological bias.

Biomarker variation in patients successfully treated with tocilizumab for severe coronavirus disease 2019 (COVID-19): results of a multidisciplinary collaboration.

OBJECTIVES: Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 is likely due to a cytokine storm characterised by a major release of pro-inflammatory cytokines, including interleukin-6 (IL-6). Blocking excessive IL-6 production might be the key to the COVID-19-ARDS treatment. Beneficial effects of IL-6 blockade using a humanised anti-IL-6 receptor antibody, tocilizumab (TCZ) were previously reported in patients with COVID-19 related ARDS. The aim of the study was to study the variation over time of several biomarkers, demonstrated to be predictors of poor prognostic, in subjects successfully treated with TCZ for severe COVID-19. METHODS: Retrospective analysis of a case series of patients with COVID-19-ARDS, evidenced by RT-PCR and lung CT-scan. Patients with increasing O2 requirements, within the window of opportunity for TCZ treatment (Day 7 to Day 17 after onset of symptoms) were treated with TCZ (2 infusions of 8 mg/kg). Demographic, biological and clinical data were collected from the patients' files. Serum levels of CRP, ferritin, fibrinogen, lymphocytes, platelets, creatinine, D-dimer and liver enzymes were assayed at the time of the first TCZ administration, then every two days for 8 days. RESULTS: 40 patients were treated with TCZ. Most of them had several comorbidities, and all had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer, liver enzymes). 30 patients (75%) benefited from TCZ and 10 patients died. In the survivors, following TCZ administration CRP decreased dramatically as early as day 4 (-86.7%, p<0.0001) and returned to normal at day 6. Fibrinogen and lymphocyte count returned to normal values at day 6. Ferritin also decreased significantly. No significant change was observed for D-dimer (p=0.68) and other studied biomarkers (haemoglobin, leucocyte count, AST). CONCLUSIONS: In patients with COVID-19 acute respiratory distress syndrome, treatment with TCZ resulted in favourable evolution in 75% of the cases. Biomarkers of inflammation (CRP, ferritin, fibrinogen) decreased dramatically as early as the 4th day after TCZ injection. Lymphopenia, a predictor of poor prognostic, was reversed 6 days after TCZ injection.

Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung.

BACKGROUND: Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. OBJECTIVE: This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. METHODS: Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. RESULTS: We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. CONCLUSIONS: Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.

Nuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal App and MspA autotransporters.

Neisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6-family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46-expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross-linking and enzyme-linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose-dependent increase in DC death via caspase-dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.

Polyclonal antibodies selectively inhibit tumor growth and invasion and synergize with immune checkpoint inhibitors.

Heterologous polyclonal antibodies (pAb) were shown to possess oncolytic properties a century ago with reported clinical responses. More recent preclinical models confirmed pAb efficacy, though their ability to tackle complex target antigens reduces susceptibility to tumor escape. Owing to the recent availability of glyco-humanized pAb (GH-pAb) with acceptable clinical toxicology profile, we revisited use of pAb in oncology and highlighted their therapeutic potential against multiple cancer types. Murine antitumor pAb were generated after repeated immunization of rabbits with murine tumor cell lines from hepatocarcinoma, melanoma, and colorectal cancers. Antitumor pAb recognized and showed cytotoxicity against their targets without cross-reactivity with healthy tissues. In vivo, pAb are effective alone; moreover, these pAb synergize with immune checkpoint inhibitors like anti-PD-L1 in several cancer models. They elicited an antitumor host immune response and prevented metastases. The anticancer activity of pAb was also confirmed in xenografted NMRI nude mice using GH-pAb produced by repeated immunization of pigs with human tumor cell lines. In conclusion, the availability of bioengineered GH-pAb allows for revisiting of passive immunotherapy with oncolytic pAb to fight against solid tumor and cancer metastasis.

Anti-SARS-CoV-2 glyco-humanized polyclonal antibody XAV-19: phase II/III randomized placebo-controlled trial shows acceleration to recovery for mild to moderate patients with COVID-19.

Introduction: XAV-19 is a glyco-humanized swine polyclonal antibody targeting SARS-CoV-2 with high neutralizing activity. The safety and clinical efficacy of XAV-19 were investigated in patients with mild to moderate COVID-19. Methods: This phase II/III, multicentric, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and clinical efficacy of XAV-19 in patients with a seven-point WHO score of 2 to 4 at randomization, i.e., inpatients with COVID-19 requiring or not requiring low-flow oxygen therapy, and outpatients not requiring oxygen (EUROXAV trial, NCT04928430). Adult patients presenting in specialized or emergency units with confirmed COVID-19 and giving their consent to participate in the study were randomized to receive 150 mg of XAV-19 or placebo. The primary endpoint was the proportion of patients with aggravation within 8 days after treatment, defined as a worsening of the seven-point WHO score of at least one point between day 8 and day 1 (inclusion). The neutralization activity of XAV-19 against variants circulating during the trial was tested in parallel. Results: From March 2021 to October 2022, 279 patients received either XAV-19 (N = 140) or placebo (N = 139). A slow enrollment and a low rate of events forced the termination of the premature trial. XAV-19 was well tolerated. Underpowered statistics did not allow the detection of any difference in the primary endpoint between the two groups or in stratified groups. Interestingly, analysis of the time to improvement (secondary endpoint) showed that XAV-19 significantly accelerated the recovery for patients with a WHO score of 2 or 3 (median at 7 days vs. 14 days, p = 0.0159), and even more for patients with a WHO score of 2 (4 days vs. 14 days, p = 0.0003). The neutralizing activity against Omicron and BA.2, BA.2.12.1, BA.4/5, and BQ.1.1 subvariants was shown. Discussion: In this randomized placebo- controlled trial with premature termination, reduction of aggravation by XAV-19 at day 8 in patients with COVID-19 was not detectable. However, a significant reduction of the time to improvement for patients not requiring oxygen was observed. XAV-19 maintained a neutralizing activity against SARS-CoV-2 variants. Altogether, these data support a possible therapeutic interest for patients with mild to moderate COVID-19 requiring anti-SARS-CoV-2 neutralizing antibodies. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04928430; https://www.clinicaltrialsregister.eu/about.html (EudraCT), identifier 2020-005979-12.

First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation.

BACKGROUND: Polyclonal rabbit antithymocyte globulins (ATGs) are commonly used in organ transplantation as induction. Anti- N -glycolylneuraminic acid carbohydrate antibodies which develop in response to rabbit carbohydrate antigens might lead to unwanted systemic inflammation. LIS1, the first new generation of antilymphocyte globulins (ALGs) derived from double knockout swine, lacking carbohydrate xenoantigens was already tested in nonhuman primates and rodent models. METHODS: This open-label, single-site, dose escalation, first-in-human, phase 1 study evaluated the safety, T cell depletion, pharmacokinetics, and pharmacodynamics of LIS1. In an ascending dose cohort (n = 5), a primary kidney transplant recipient at low immunologic risk (panel reactive antibody [PRA] < 20%), received LIS1 for 5 d at either 0.6, 1, 3, 6, or 8 mg/kg. After each patient completed treatment, the data safety monitoring board approved respective dose escalation. In the therapeutic dose cohort (n = 5) in patients with PRA <50% without donor specific antibodies, 2 patients received 8 mg/kg and 3 patients 10 mg/kg. RESULTS: CD3 + T cell depletion <100/mm 3 at day 2 was observed in all patients who received 6, 8, and 10 mg/kg of LIS1. The terminal half-life of LIS1 was 33.7 d with linearity in its disposition. Lymphocyte repopulation was fast and pretransplant lymphocyte subpopulation counts recovered within 2-4 wk. LIS1 was well tolerated, neither cytokine release syndrome nor severe thrombocytopenia or leukopenia were noticed. Antibodies to LIS1 were not detected. CONCLUSIONS: In this first-in-human trial, genome-edited swine-derived polyclonal LIS1 ALG was well tolerated, did not elicit antidrug antibodies, and caused time-limited T cell depletion in low- and medium-risk kidney transplant recipients.

Retagging identifies dendritic cell-specific intercellular adhesion molecule-3 (ICAM3)-grabbing non-integrin (DC-SIGN) protein as a novel receptor for a major allergen from house dust mite.

Dendritic cells (DCs) have been shown to play a key role in the initiation and maintenance of immune responses to microbial pathogens as well as to allergens, but the exact mechanisms of their involvement in allergic responses and Th2 cell differentiation have remained elusive. Using retagging, we identified DC-SIGN as a novel receptor involved in the initial recognition and uptake of the major house dust mite and dog allergens Der p 1 and Can f 1, respectively. To confirm this, we used gene silencing to specifically inhibit DC-SIGN expression by DCs followed by allergen uptake studies. Binding and uptake of Der p 1 and Can f 1 allergens was assessed by ELISA and flow cytometry. Intriguingly, our data showed that silencing DC-SIGN on DCs promotes a Th2 phenotype in DC/T cell co-cultures. These findings should lead to better understanding of the molecular basis of allergen-induced Th2 cell polarization and in doing so paves the way for the rational design of novel intervention strategies by targeting allergen receptors on innate immune cells or their carbohydrate counterstructures on allergens.

Deciphering the contribution of human meningothelial cells to the inflammatory and antimicrobial response at the meninges.

We have investigated the response of primary human meningothelial cells to Neisseria meningitidis. Through a transcriptome analysis, we provide a comprehensive examination of the response of meningothelial cells to bacterial infection. A wide range of chemokines are elicited which act to attract and activate the main players of innate and adaptive immunity. We showed that meningothelial cells expressed a high level of Toll-like receptor 4 (TLR4), and, using a gene silencing strategy, we demonstrated the contribution of this pathogen recognition receptor in meningothelial cell activation. Secretion of interleukin-6 (IL-6), CXCL10, and CCL5 was almost exclusively TLR4 dependent and relied on MyD88 and TRIF adaptor cooperation. In contrast, IL-8 induction was independent of the presence of TLR4, MyD88, and TRIF. Transcription factors NF-κB p65, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal protein kinase (JNK1), IRF3, and IRF7 were activated after contact with bacteria. Interestingly, the protein kinase IRAK4 was found to play a minor role in the meningothelial cell response to Neisseria infection. Our work highlights the role of meningothelial cells in the development of an immune response and inflammation in the central nervous system (CNS) in response to meningococcal infection. It also sheds light on the complexity of intracellular signaling after TLR triggering.

LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation.

Anti-thymocyte or anti-lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because animal-derived, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events, possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. We investigated here the in vitro and in vivo activity of LIS1, a glyco-humanized ALG (GH-ALG) produced in pigs knocked out for the two major xeno-antigens αGal and Neu5Gc. It differs from other ATGs/ALGs by its mechanism of action excluding antibody-dependent cell-mediated cytotoxicity and being restricted to complement-mediated cytotoxicity, phagocyte-mediated cytotoxicity, apoptosis and antigen masking, resulting in profound inhibition of T-cell alloreactivity in mixed leucocyte reactions. Preclinical evaluation in non-human primates showed that GH-ALG dramatically reduced CD4+ (p=0.0005,***), CD8+ effector T cells (p=0.0002,***) or myeloid cells (p=0.0007,***) but not T-reg (p=0.65, ns) or B cells (p=0.65, ns). Compared with rabbit ATG, GH-ALG induced transient depletion (less than one week) of target T cells in the peripheral blood (<100 lymphocytes/L) but was equivalent in preventing allograft rejection in a skin allograft model. The novel therapeutic modality of GH-ALG might present advantages in induction treatment during organ transplantation by shortening the T-cell depletion period while maintaining adequate immunosuppression and reducing immunogenicity.