Irreversibly increased nitrogen fixation in Trichodesmium experimentally adapted to elevated carbon dioxide

This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 6 (2015): 8155, doi:10.1038/ncomms9155.Nitrogen fixation rates of the globally distributed, biogeochemically important marine cyanobacterium Trichodesmium increase under high carbon dioxide (CO2) levels in short-term studies due to physiological plasticity. However, its long-term adaptive responses to ongoing anthropogenic CO2 increases are unknown. Here we show that experimental evolution under extended selection at projected future elevated CO2 levels results in irreversible, large increases in nitrogen fixation and growth rates, even after being moved back to lower present day CO2 levels for hundreds of generations. This represents an unprecedented microbial evolutionary response, as reproductive fitness increases acquired in the selection environment are maintained after returning to the ancestral environment. Constitutive rate increases are accompanied by irreversible shifts in diel nitrogen fixation patterns, and increased activity of a potentially regulatory DNA methyltransferase enzyme. High CO2-selected cell lines also exhibit increased phosphorus-limited growth rates, suggesting a potential advantage for this keystone organism in a more nutrient-limited, acidified future ocean.Grant support was provided by U.S. National Science Foundation OCE 1260490 and OCE 1143760 to D.A.H., E.A.W., and F.-X.F, and OCE 1260233, OCE OA 1220484, and G.B. Moore Foundation 3782 and 3934 to M.A.S.© The Author(s), [year]

The Influence of Tweets on the Voting Preference of Grade 12 Newly Registered Voters

Twitter has become highly ubiquitous and has been identified as the leading way to engage voters as they offer users discussion, participate in the political field, and investigate its influence on politics. The study proposed to understand the influence of tweets under the trending topic “#Halalan2022.” This study aimed to seek the influence and role of Tweets on the voting preference of the respondents. The study employed descriptive-qualitative research. A sample of 12 newly registered voters from grade 12 online-based learners of Saint Louis University Laboratory High School-Senior High, Baguio City, were chosen for this study. An open-ended survey was used for data collection and was analyzed using thematic analysis. There are six main themes: individuality, eligibility of presidential candidates, and the moral and ethical standards of newly registered voters. The influence of tweets was impactful, but there were negative responses due to firm political stands yet tweets were regarded as a deciding factor. Tweets are impactful in providing information and knowledge about the candidates’ backgrounds and platforms. However, it only becomes influential if it is factual and reliable, compatible with their political stand and chosen candidate. Tweets then serve as a deciding factor in shaping the voting preference of newly registered voters because it informs about the candidates and fortifies their political stand

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5′-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3–7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350–400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5′-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3–7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350–400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment