Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis

Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log10 CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log10 CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log10 CFU/g, while the burdens were 4.64, 7.16, and 1.44 log10 CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was -0.66 log10 CFU/mL/day, decreasing from an average of 4.75 log10 CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of -0.4 log10 CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (-0.33 log10 CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC0-24) of 25 to 50 mg · h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM. IMPORTANCE Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Here, we demonstrated the efficacy of APX2039, the second member of the gepix class, in rabbit and mouse models of cryptococcal meningitis. We also analyzed the drug levels in the blood and cerebrospinal fluid in the highly predictive rabbit model and built a mathematical model to describe the behavior of the drug with respect to the elimination of the fungal pathogen. We demonstrated that the oral administration of APX2039 resulted in a rapid decrease in the CSF fungal burden, with an effective fungicidal activity of -0.66 log10 CFU/mL/day, comparing favorably with good clinical outcomes in humans associated with reductions of -0.4 log10 CFU/mL/day. The drug APX2039 had good penetration of the central nervous system and is an excellent candidate for future clinical testing in humans for the treatment of CM

A second update on mapping the human genetic architecture of COVID-19

Matters Arising From: COVID-19 Host Genetics Initiative. Nature https://doi.org/10.1038/s41586-021-03767-x (2021)Data availability: Summary statistics generated by the COVID-19 HGI are available online, including per-ancestry summary statistics for African, admixed American, East Asian, European and South Asian ancestries (https://www.covid19hg.org/results/r7/). The analyses described here used the data release 7. If available, individual-level data can be requested directly from contributing studies, listed in Supplementary Table 1. We used publicly available data from GTEx (https://gtexportal.org/home/), the Neale laboratory (http://www.nealelab.is/uk-biobank/), the Finucane laboratory (https://www.finucanelab.org), the FinnGen Freeze 4 cohort (https://www.finngen.fi/en/access_results) and the eQTL catalogue release 3 (http://www.ebi.ac.uk/eqtl/).Code availability: The code for summary statistics lift-over, the projection PCA pipeline including precomputed loadings and meta-analyses (https://github.com/covid19-hg/); for heritability estimation (https://github.com/AndrewsLabUCSF/COVID19_heritability); for Mendelian randomization and genetic correlation (https://github.com/marcoralab/MRcovid); and subtype analyses (https://github.com/mjpirinen/covid19-hgi_subtypes) are available at GitHub.Reporting summary: Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article online at: https://www.nature.com/articles/s41586-023-06355-3#MOESM2 .Supplementary information is available online at: https://www.nature.com/articles/s41586-023-06355-3#Sec4 .Copyright © The Author(s) 2023. Investigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development1,2. Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release2. The increased number of candidate genes at the identified loci helped to map three major biological pathways that are involved in susceptibility and severity: viral entry, airway defence in mucus and type I interferon

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.Radiolog

Cryptography based on the Matrices

In this work we introduce a new method of cryptography based on the matrices over a finite field $\mathbb{F}_{q}$, were $q$ is a power of a prime number $p$. The first time we construct the matrix $M=\left( \begin{array}{cc} A_{1} & A_{2} \\ 0 & A_{3} \\ \end{array} \right)$ were \ $A_{i}$ \ with $i \in \{1, 2, 3 \}$ is the matrix of order $n$ \ in \ $\mathcal{M}(\mathbb{F}_{q})$ - the set of matrices with coefficients in $\mathbb{F}_{q}$ - and $0$ is the zero matrix of order $n$. We prove that $M^{l}=\left( \begin{array}{cc} A_{1}^{l} & (A_{2})_{l} \\ 0 & A_{3}^{l} \\ \end{array} \right)$ were $(A_{2})_{l}=\sum\limits_{k=0}^{l-1} A_{1}^{l-1-k}A_{2}A_{3}^{k}$ for all $l\in \mathbb{N}^{\ast}$. After we will make a cryptographic scheme between the two traditional entities Alice and Bob

Diversité Génétique des Premières Variétés de Canne à Sucre d’Origine Réunionno-Ivoirienne Présélectionnées à Ferké en Côte d’Ivoire

Objectifs: L’étude visait à contribuer à l’amélioration de la productivité en culture cannière en Côte d’Ivoire. Plus spécifiquement, elle visait à caractériser la diversité génétique du tout premier lot de 148 variétés de canne à sucre d’origine réunionno-ivoiriennes présélectionnées au stade « une ligne » en vue d’essais classiques de sélection de 1ère et 2ème étapes à conduire par la suite dans les conditions d’exploitation des complexes sucriers de Ferké.Méthodes et résultats: Elle a été conduite en station expérimentale, sous irrigation par aspersion en couverture intégrale, au complexe sucrier de Ferké 2, au Nord Côte d’Ivoire. Ces variétés ont été présélectionnées en 1ère repousse parmi 985 clones plantés par famille, à raison d’un individu par ligne de 3 m de long sans répétition et comparés à une variété témoin (SP70-1006). Celle-ci a été plantée régulièrement toutes les 5 lignes afin de faciliter la notation des clones pour différents caractères agromorphologiques et phytosanitaires par comparaison avec le témoin. Les variables quantitatives et qualitatives relatives aux variétés présélectionnées, observées à la récolte en 1ère repousse à l’âge de 10 mois, ont fait l’objet d’une série d’analyses multivariées. L’étude a montré que les variables quantitatives permettant de mieux expliquer la diversité des variétés présélectionnées comprenaient, dans l’ordre décroissant, le taux de floraison, le nombre de tiges/3m, le diamètre des tiges et la longueur des tiges. Ces variables ont fortement contribué à la discrimination de 8 groupes qui suggéraient une assez bonne diversité génétique parmi les 148 clones présélectionnés. Les 4 groupes les mieux représentés (63,5 % de l’effectif total) comprenaient chacun 20 à 30 individus, tandis que les moins représentés (36.5 %) 11 à 15 individus chacun.Conclusion et application des résultats: Les variables qualitatives les plus pertinentes dans la discrimination des groupes portent sur très bon tallage, tallage moyen, port plus ou moins droit, d’une part, et port droit, d’autre part, qui sont associés, respectivement, aux groupes G1, G7 et G2. Quant aux variables port penché et port en bataille qui sont également pertinentes, elles semblaient être associées à 6 groupes à la fois (G2, G3, G4, G5, G6, G8). La variabilité génétique ainsi révélée est nécessaire aux prochains essais de sélection prévus en plantations commerciales.Mots clés: Sélection massale, vigueur végétative, stade ligne, variable quantitative, variable qualitative, analyse multivariée, groupe dissemblable, adaptation, contexte agro-écologiqueEnglish Title: Genetic Diversity of First Sugarcane Varieties of Reunion-Ivorian Origin Preselected in Ferké, Ivory CoastEnglish AbstractObjectives: The overall study objective was to contribute to sugarcane yield improvement in Ivory Coast. It aimed to characterize the genetic diversity of the first batch of 148 sugar cane varieties of Reunion-Ivorian origin preselected at the "one-row" stage for standard selection trials of 1st and 2nd stages to be carried out under Ferké commercial field conditions.Methodology and results: It was conducted on Ferké 2 experimental station under full sprinkler irrigation in northern Ivory Coast. These varieties were pre-selected in 1st regrowth among 985 clones planted per family, one individual per row 3 m long without repetition and compared to a control variety (SP70-1006).That one was replicated several times every 5 rows to ease agronomics observations of clones in comparison with the control. Quantitative as well as qualitative traits observed at the age of 10 months were subjected to a series of multivariate analyses. The study showed that quantitative traits, which better explained diversity of varieties, were the following in decreasing order: flowering rate, number of millable stalks/3m, stalk diameter, and stalk height. Those phenotypic traits highly contributed to discrimination of varieties into 8 clusters, which suggested a good genetic diversity among all 148 preselected clones. Four best-represented clusters (63.5 % of total) comprised 20-30 individuals each, whereas less represented clusters (36.5 %) involved 11-15 individuals each.Conclusion and application of results: Quantitative traits most relevant in variety clustering were high tillering, moderate tillering, erect traits, which were associated respectively with clusters G1, G7 and G2. As for lodging traits, they were associated with 6 clusters all together, namely G2, G3, G4, G5, G6 and G8. The genetic variability so shown is a prerequisite for further selections trials under commercial field conditions.Keywords: visual selection, vegetative vigor, one-row stage, phenotypic trait, multivariate analysis, clustering, adaptation, agro-ecologic conditio