2-O-methyl-cis-adenosine 3, 5-cyclic methyl monophosphate, a new model system for cAMP. Aspects of structure and reactivity

This study is focussed on 2'-O-methyl-cis-adenosine 3',5'-cyclic methyl monophosphate (cis-4; cis describes the relationship between OMe (bound to phosphorus) and the adenine base), which is regarded a model for enzyme-bound cyclic adenosine monophosphate (cAMP). In this complex the negative phosphate charge is shielded in part via complexation with cationic sites on the enzyme surface. We report synthesis, crystal structure, solution conformation (400 MHz 1H NMR), and kinetic-mechanistic aspects of the alkaline hydrolysis of cis-4. The methanol solvate of cis-4 crystallizes in the orthorhombic space group P212121 and the cell dimensions are a = 8.170(2) Å, b = 9.249(1) Å, c = 23.699(4) Å; V = 1788.5(6) Å3; Z = 4 molecules per cell. Least-squares refinement converged at R = 0.062 for 2006 observed reflections. The adenine bases are linked via and hydrogen bonds in such a way that infinite one-dimensional chains are formed. This hydrogen bond scheme is very similar to that observed in the structure of 2'-deoxy-3',5'-di-O-acetyl adenosine. An additional hydrogen bond is formed between methanol, incorporated in the crystal structure, and the adenine base. The conformational preferences of the cis-4 dissolved in methanol have been determined with 400 MHz 1H NMR. It is found that the conformations observed in the solid and solution states are practically the same. Hydrolysis of the title compound yields two acyclic phosphate diesters (a 3'- and a 5'-phosphate diester). The intermediates formed during the hydrolysis reaction are most likely five-coordinated phosphorus (PV) compounds with a trigonal bipyramidal geometry and an equatorial-axial located 3',5'-dioxaphosphorinane ring

2-O-methyl-cis-adenosine 3, 5-cyclic methyl monophosphate, a new model system for cAMP. Aspects of structure and reactivity

This study is focussed on 2'-O-methyl-cis-adenosine 3',5'-cyclic methyl monophosphate (cis-4; cis describes the relationship between OMe (bound to phosphorus) and the adenine base), which is regarded a model for enzyme-bound cyclic adenosine monophosphate (cAMP). In this complex the negative phosphate charge is shielded in part via complexation with cationic sites on the enzyme surface. We report synthesis, crystal structure, solution conformation (400 MHz 1H NMR), and kinetic-mechanistic aspects of the alkaline hydrolysis of cis-4. The methanol solvate of cis-4 crystallizes in the orthorhombic space group P212121 and the cell dimensions are a = 8.170(2) Å, b = 9.249(1) Å, c = 23.699(4) Å; V = 1788.5(6) Å3; Z = 4 molecules per cell. Least-squares refinement converged at R = 0.062 for 2006 observed reflections. The adenine bases are linked via and hydrogen bonds in such a way that infinite one-dimensional chains are formed. This hydrogen bond scheme is very similar to that observed in the structure of 2'-deoxy-3',5'-di-O-acetyl adenosine. An additional hydrogen bond is formed between methanol, incorporated in the crystal structure, and the adenine base. The conformational preferences of the cis-4 dissolved in methanol have been determined with 400 MHz 1H NMR. It is found that the conformations observed in the solid and solution states are practically the same. Hydrolysis of the title compound yields two acyclic phosphate diesters (a 3'- and a 5'-phosphate diester). The intermediates formed during the hydrolysis reaction are most likely five-coordinated phosphorus (PV) compounds with a trigonal bipyramidal geometry and an equatorial-axial located 3',5'-dioxaphosphorinane ring

European all-cause excess and influenza-attributable mortality in the 2017/18 season: should the burden of influenza B be reconsidered?

&lt;p&gt;Objectives&lt;/p&gt; &lt;p&gt;Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe.&lt;/p&gt; &lt;p&gt;Methods&lt;/p&gt; &lt;p&gt;Based on weekly reporting of mortality from 24 European countries or sub-national regions, representing 60% of the European population excl. Russia and the Turkey part of European, we estimated age stratified all-cause excess morality using the EuroMOMO model. In addition, age stratified all-cause influenza-attributable mortality was estimated using the FluMOMO algorithm, incorporating influenza activity based on clinical and virological surveillance data, and adjusting for extreme temperatures.&lt;/p&gt; &lt;p&gt;Results&lt;/p&gt; &lt;p&gt;Excess mortality was mainly attributable to influenza activity from December 2017 to April 2018, but also due to exceptionally low temperatures in February-March 2018. The pattern and extent of mortality excess was similar to the previous A(H3N2) dominated seasons, 2014/15 and 2016/17. The 2017/18 overall all-cause influenza-attributable mortality was estimated to be 25.4 (95%CI 25.0-25.8) per 100,000 population; 118.2 (116.4-119.9) for persons aged 65. Extending to the European population this translates into over-all 152,000 deaths.&lt;/p&gt; &lt;p&gt;Conclusions&lt;/p&gt; &lt;p&gt;The high mortality among elderly was unexpected in an influenza B dominated season, which commonly are considered to cause mild illness, mainly among children. Even though A(H3N2) also circulated in the 2017/18 season and may have contributed to the excess mortality among the elderly, the common perception of influenza B only having a modest impact on excess mortality in the older population may need to be reconsidered.&lt;/p&gt;</p