1-O-Octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-GS-441524 (V2043). Evaluation of Oral V2043 in a Mouse Model of SARS-CoV-2 Infection and Synthesis and Antiviral Evaluation of Additional Phospholipid Esters with Enhanced Anti-SARS-CoV-2 Activity

Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by 1.5 log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro antiviral activity by introduction of a 3-fluoro-4-methoxy-substituted benzyl or a 3- or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections

Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Análise de crescimento de açaizeiros em áreas de várzea do estuário amazônico Growth analysis of açaí palm trees (Euterpe oleracea Mart.) in floodplain of Amazon estuary

Com o objetivo de analisar o crescimento de açaizeiros (Euterpe oleracea Mart.) em áreas de várzea submetidas à exploração de palmito, visando ao manejo racional da espécie, foi realizado estudo no município de Igarapé-Miri, Pará. Foram amostrados todos os estipes e rebrotes de três plantas de cada idade após o corte (12, 24, 36 e 48 meses após a extração do palmito), e avaliada a matéria seca dos seguintes componentes: folíolos, ráquis + pecíolos, bainhas + palmitos, e estipes. As plantas selecionadas são representativas da população quanto à altura média dos estipes, número de perfilhos e número de folhas. A produção de matéria seca total foi de 2,68, 5,25, 9,23 e 42,91 kg por planta no 12º, 24º, 36º e 48º mês após a extração do palmito, respectivamente. Nos açaizais recém-explorados, os folíolos representaram cerca de 40% do peso total da parte aérea da planta, e os estipes, 10%. Após 48 meses, em açaizais recompostos, os estipes foram responsáveis por 73% do peso total da parte aérea da planta, e os folíolos, somente por 10%. Doze meses após o corte do palmito, os açaizeiros apresentavam altura média de 1 m, e atingiram mais de 3 m após 48 meses.<br>With the objective of analyzing the palm heart tree growth, in lowland areas submitted to the palm heart exploration, aiming to subsidize the rational handling of the species, a study was accomplished in the county of Igarapé-Miri, PA, Brazil. All of the stems and new budding of three plants of different ages (12, 24, 36 and 48 months after heart extraction) were sampled, and the following components were collected for dry matter evaluation: leaflets, rachis + petioles, sheath + palm hearts and trunks. Representative clumps of the population were selected based on the medium height of the trunks, and number of shoots and leaves. The total dry matter production was 2.68, 5.25, 9.23 and 42.91 kg per plant at 12, 24, 36 and 48 months after the palm heart extraction, respectively. In the recently explored palm heart areas the leaflets represented about 40% of the total weight of the aerial part of the plant and the trunks 10%. After 48 months, in recomposed areas, the trunks were responsible for 73% of the total weight of the plant, while the leaflets only for 10%. Twelve months after the cutting of palm heart, the plants presented medium height of 1 m, and reached more than 3 m after 48 months