Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication i

Genetic and clonal heterogeneity of myelodysplastic syndromes

Les syndromes myélodysplasiques (SMD) forment un groupe de pathologies clonales de la cellule souche hématopoïétique (CSH) caractérisées par une hématopoïèse inefficace. La présence d’au moins une anomalie génétique (anomalie cytogénétique ou mutation somatique) est observée dans plus de 90% des cas. Ainsi, plusieurs clones moléculaires pouvaient coexister au moment du diagnostic de la maladie. Dans les SMD avec délétion du chromosome 5 (del(5q)), il a récemment été montré que les anomalies étaient présentes dès le stade de la CSH. Dans les SMD, la pénétrance des anomalies génétiques décrites est incomplète. De plus, peu de choses sont actuellement connues sur l’ordre d’apparition des mutations et leur impact fonctionnel sur les différents clones moléculaires dans le cas des SMD non-del(5q). Grâce au séquençage d’exome entier (WES) de patients ne présentant aucune mutation dans les gènes décrits dans les SMD, nous avons décrit l’existence de mutations dans les gènes BCOR et BCORL1, chez respectivement 4,2% et 0,8% des patients. Les mutations du gène BCOR arrivent tardivement au cours de l’évolution de la maladie et affectent le pronostic des patients. Des approches à l’échelle unicellulaire nous ont également permis d’observer que la majeure partie des mutations identifiées chez les patients sont retrouvées dès le stade CD34+CD38-. Chez les patients, plusieurs clones moléculaires coexistent à ce stade. De plus, les mutations des gènes de l’épissage et de la régulation épigénétique sont fréquemment acquises en premier dans les cellules hématopoïétiques les plus immatures des patients porteurs de SMD. Nous avons observé que certaines mutations, acquises secondairement, sont réparties inégalement dans les différents compartiments hématopoïétiques et peuvent avoir un impact sur la différenciation hématopoïétique. Enfin, nous montrons que la répartition des clones moléculaires évolue au cours du temps. En réponse au traitement par Lenalidomide, on observe également une évolution rapide de l’architecture clonale qui peut être liée au statut de réponse des patients. Ces résultats tendent à confirmer l’hétérogénéité génétique mais aussi fonctionnelle des SMD. Nous avons pu identifier de nouvelles mutations impliquées secondairement dans la physiopathologie des SMD. Il existe une dominance clonale précoce dans les SMD du fait de l’acquisition de toutes les mutations dans les cellules hématopoïétiques immatures. Cependant, les différentes populations hématopoïétiques peuvent présenter des génotypes différents. Enfin cette architecture est variable au cours de l’évolution de la maladie.Myelodysplastic syndromes (MDS) are a group of clonal disorders of the hematopoietic stem cell (HSC) characterized by ineffective hematopoiesis. At least one genetic abnormality (cytogenetic abnormality or somatic mutation) is observed in more than 90% of cases. Thus, it has been observed several molecular clones which could coexist at diagnosis of the disease. In MDS with deletion of chromosome 5 (del (5q)), it has recently been shown that defects were present in the HSC. In MDS, the penetrance of genetic abnormalities described is incomplete. In addition, little is currently known about the order of appearance of mutations and their functional impact on different molecular clones in the case of non-del (5q) MDS. Through the whole exome sequencing (WES) of patients without mutation in the genes described in MDS, we described the existence of mutations in genes BCOR and BCORL1, in respectively 4.2% and 0.8% of patients. Mutations in the gene BCOR were acquired lately during the course of the disease and affect the prognosis of patients. Approaches at the single cell level have also allowed us to observe that most of the mutations identified in patients are found at the immature differentiation stage CD34+CD38-. In patients, several molecular clones could coexist at this stage. In addition, mutations in gene splicing and epigenetic regulation are frequently first acquired in the most immature hematopoietic cells of MDS patients. We found that certain mutations, acquired in a second time, are distributed unevenly in different hematopoietic compartment and may have an impact on hematopoietic differentiation. Finally, we showed that the distribution of molecular clones evolves over time. In response to treatment with Lenalidomide, it has also been observed a rapid evolution of clonal architecture that can be linked to patient response status. These results tend to confirm the genetic but also functional heterogeneity in MDS. We have identified new mutations involved in the pathogenesis of MDS. We observed an early clonal dominance in MDS because of the acquisition of all mutations in immature hematopoietic cells. However, different hematopoietic populations can have different genotype. Finally, the architecture of mutations could be modifying during the course of the disease

Synthesis and insecticidal activities of novel solanidine derivatives

International audienceBackground Potato (Solanum tuberosum) is the fourth culture in the world and is widely used in the agri-food industries. They generate by-products in which alpha-chaconine and alpha-solanine, the two major solanidine-based glycoalkaloids of potato, are present. As secondary metabolites, they play an important role in the protection system of potato and are involved in plant protection against insects. To add value to these by-products, we described here new glycoalkaloids that could have phytosanitary properties. Results Solanidine, as a renewable source, was modified with an azido linker and coupled by copper-catalyzed alkyne azide cycloaddition to alkynyl derivatives of the monosaccharides found in the natural potato glycoalkakoids: D-glucose, D-galactose and L-rhamnose. The efficacy of our compounds was evaluated on the potato aphid Macrosiphum euphorbiae. The synthetic compounds have stronger aphicidal properties against nymphs than unmodified solanidine. They also showed strong aphicidal activities on adults and a negative impact on fecundity. Conclusion Our synthetic neoglycoalkaloids affected Macrosiphum euphorbiae survival at the nymphal stage as well as at the adult stage. Furthermore, they induced a decrease in fecundity. Our results show that chemical modifications of by-products may afford new sustainable compounds for crop and plant protection

Disruption of fungal cell wall by antifungal Echinacea extracts

In addition to widespread use in reducing the symptoms of colds and flu, Echinacea is traditionally employed to treat fungal and bacterial infections. However, to date the mechanism of antimicrobial activity of Echinacea extracts remains unclear. We utilized a set of ∼4,600 viable gene deletion mutants of Saccharomyces cerevisiae to identify mutations that increase sensitivity to Echinacea. Thus, a set of chemical-genetic profiles for 16 different Echinacea treatments was generated, from which a consensus set of 23 Echinacea-sensitive mutants was identified. Of the 23 mutants, only 16 have a reported function. Ten of these 16 are involved in cell wall integrity/struct

Identification of specific tumor markers in vulvar carcinoma through extensive human papillomavirus DNA characterization using next generation sequencing method

International audienceObjectives: A subset of vulvar carcinomas (VC) are associated with human papillomavirus (HPV) DNA. This trait can be used to identify tumor markers for patient's follow-up. A large diversity of HPV prevalence in VC has been reported, but no data are available concerning the insertional HPV status in this tumor type. Therefore, we have used an innovative next generation sequencing (NGS)-based CaptHPV method able to provide an extensive characterization of HPV DNA in tumors.Material and Methods: Tumor tissue specimens from 55 patients with VC were analyzed using p16 immunohistochemistry, in situ hybridization, polymerase chain reaction, and CaptHPV-NGS assays.Results: Our analyses showed that 8 (14.5%) of 55 cases were associated with HPV 16 DNA. No other HPV genotypes were identified. The HPV genome was in a free episomal state only in one case and both episomal and integrated into the tumor cell genome in 7. There was a single insertion in 5 cases and multiple sites, scattered at different chromosomal loci in two. ISH data suggest that some of these might reflect tumor heterogeneity. Viral integration targeted cellular genes among which were TP63, CCDC148, LOC100133091, PKP1, and POLA2. Viral integration at the PKP1 locus was associated with partial gene deletion, and no PKP1 protein was detected in tumor tissue.Conclusions: Using the NGS-based innovative capture-HPV approach, we established a cartography of HPV 16 DNA in 8 VC cases and identified novel genes targeted by integration that may be used as specific tumor markers. In addition, we established a rationale strategy for optimal characterization of HPV status in VC

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic. Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge.</p

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic. Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge