Non-canonical amino acids bearing thiophene and bithiophene: synthesis by an Ugi multicomponent reaction and studies on ion recognition ability

Novel thienyl and bithienyl amino acids with different substituents were obtained by a multicomponent Ugi reaction between a heterocyclic aldehyde, an amine, an acid and an isocyanide. Due to the presence of the sulphur heterocycle at the side chain, these unnatural amino acids are highly emissive and bear extra electron donating atoms so they were tested for their ability to act as fluorescent probes and chemosensors in the recognition of biomedically relevant ions in acetonitrile and acetonitrile/water solutions. The results obtained from spectrophotometric/spectrofluorimetric titrations in the presence of organic and inorganic anions, and alkaline; alkaline-earth and transition metal cations indicated that the bithienyl amino acid bearing a methoxy group is a selective colorimetric chemosensor for Cu2+, while the other (bi)thienyl amino acids act as fluorimetric chemosensors with high sensitivity towards Fe3+ and Cu2+ in a metal-ligand complex with 1:2 stoichiometry. The photophysical and ion sensing properties of these amino acids confirm their potential as fluorescent probes suitable for incorporation into peptidic frameworks with chemosensory ability.Thanks are due to Fundação para a Ciência e Tecnologia (FCT-Portugal) and FEDER-COMPETE for financial support through Centro de Química [PEst-C/QUI/UI0686/2013 (F-COMP-01-0124-FEDER-037302)] and a PhD grant to C.I.C. Esteves (SFRH/BD/68360/2010). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network and was purchased with funds from FCT and FEDER.info:eu-repo/semantics/publishedVersio

Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants

The impact of initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infecting strain on downstream immunity to heterologous variants of concern (VOC) is unknown. Studying a longitudinal healthcare worker cohort, we found that after three antigen exposures (infection+two vaccine doses), S1 antibody, memory B cells and heterologous neutralization of B.1.351, P.1 and B.1.617.2 plateaued, while B.1.1.7 neutralization and spike T cell responses increased. Serology using Wuhan Hu-1 spike receptor binding domain poorly predicted neutralizing immunity against VOCs. Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures. Neutralization potency fell differentially depending on targeted VOCs over 5-months from the second vaccine dose. Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines

Novel alanines bearing an heteroaromatic side chain: synthesis and studies on fluorescent chemosensing of metals cations with biological relevance

A family of novel thienyl-benzoxazol-5-yl-L-alanines, consisting of an alanine core bearing a benzoxazole at the side chain with a thiophene ring at position 2, substituted with different (hetero)aryl substituents, was synthesised in order to study the tuning of the photophysical and chemosensory properties of the resulting compounds. These novel heterocyclic alanines and a series of structurally related bis-thienyl-benzoxazolyl-alanines 3g-j were evaluated for the first time in the recognition of selected metal cations with environmental, medicinal and analytical interest such as Co2+, Cu2+, Zn2+ and Ni2+, in acetonitrile solution, with the heterocycles at the side chain acting simultaneously as the coordinating and reporting units, via fluorescence changes. This behaviour can be explained by the involvement of the electron donor heteroatoms in the recognition event, through complexation of the metal cations. The spectrofluorimetric titrations showed that thienyl-benzoxazolyl-alanines 3a-j and 4a,b were non-selective fluorimetric chemosensors for the above mentioned cations, with the best results being obtained for the interaction of Cu2+ with bis-alanine 3j and deprotected alanines 4a,b. The encouraging photophysical and metal ion sensing properties of these thienyl-benzoxazolyl-alanines suggest that they can be used to obtain bioinspired fluorescent reporters for metal ion such as peptides/proteins with chemosensory/probing ability.Thanks are due to Fundação para a Ciência e Tecnologia (FCT) for a PhD grant to R. C. M. Ferreira (SFRH/BD/86408/2012), and FEDER (European Fund for Regional Development)-COMPETEQREN-EU for financial support through the Chemistry Research Centre of the University of Minho (Ref. UID/QUI/00686/2013 and UID/QUI/0686/2016). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network and was purchased within the framework of the National Program for Scientific Re-equipment, contract REDE/1517/RMN/2005 with funds from POCI 2010 (FEDER) and FCT.info:eu-repo/semantics/publishedVersio

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

INTRODUCTION B.1.1.529 (Omicron) and its subvariants pose new challenges for control of the COVID-19 pandemic. Although vaccinated populations are relatively protected from severe disease and death, countries with high vaccine uptake are experiencing substantial caseloads with breakthrough infection and frequent reinfection. RATIONALE We analyzed cross-protective immunity against B.1.1.529 (Omicron) in triple-vaccinated health care workers (HCWs) with different immune-imprinted histories of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the ancestral Wuhan Hu-1, B.1.1.7 (Alpha), and B.1.617.2 (Delta) waves and after infection during the B.1.1.529 (Omicron) wave in previously infection-naïve individuals and those with hybrid immunity, to investigate whether B.1.1.529 (Omicron) infection could further boost adaptive immunity. Spike subunit 1 (S1) receptor binding domain (RBD) and whole spike binding, live virus neutralizing antibody (nAb) potency, memory B cell (MBC) frequency, and T cell responses against peptide pools and naturally processed antigen were assessed. RESULTS B and T cell recognition and nAb potency were boosted against previous variants of concern (VOCs) in triple-vaccinated HCWs, but this enhanced immunity was attenuated against B.1.1.529 (Omicron) itself. Furthermore, immune imprinting after B.1.1.7 (Alpha) infection resulted in reduced durability of antibody binding against B.1.1.529 (Omicron), and S1 RBD and whole spike VOC binding correlated poorly with live virus nAb potency. Half of triple-vaccinated HCWs showed no T cell response to B.1.1.529 (Omicron) S1 processed antigen, and all showed reduced responses to the B.1.1.529 (Omicron) peptide pool, irrespective of SARS-CoV-2 infection history. Mapping T cell immunity in class II human leukocyte antigen transgenics showed that individual spike mutations could result in loss or gain of T cell epitope recognition, with changes to T cell effector and regulatory programs. Triple-vaccinated, previously infection-naïve individuals infected during the B.1.1.529 (Omicron) wave showed boosted cross-reactive S1 RBD and whole spike binding, live virus nAb potency, and T cell immunity against previous VOCs but less so against B.1.1.529 (Omicron) itself. Immune imprinting from prior Wuhan Hu-1 infection abrogated any enhanced cross-reactive antibody binding, T cell recognition, MBC frequency, or nAb potency after B.1.1.529 (Omicron) infection. CONCLUSION Vaccine boosting results in distinct, imprinted patterns of hybrid immunity with different combinations of SARS-CoV-2 infection and vaccination. Immune protection is boosted by B.1.1.529 (Omicron) infection in the triple-vaccinated, previously infection-naïve individuals, but this boosting is lost with prior Wuhan Hu-1 imprinting. This “hybrid immune damping” indicates substantial subversion of immune recognition and differential modulation through immune imprinting and may be the reason why the B.1.1.529 (Omicron) wave has been characterized by breakthrough infection and frequent reinfection with relatively preserved protection against severe disease in triple-vaccinated individuals

Le forme della regalità nella Roma latino-sabina

The analysis of historical sources, onomastics data, and the festive calendar, shows that the most archaic Roman kingship was structured in the form of a diarchy between a lifelong king-priest and a temporary warrior-king: the latter ruled in the season of war, while in peacetime the city government was led in turn by the patres (interregnum). This diarchy could be the result of the influence, on Roman institutions, of the constitutional structures of the Greeks and of the Italic peoples, since among other Indo-European cultures, like Vedic India and the Celts, the pattern seems rather to be a triad — composed of a priest, a supreme king and a warrior king — surviving in Rome only at a theological level in the Pre-Capitoline triad Iuppiter Mars Quirinus. Given these premises, the subsequent Etruscan monarchy appears to be the result of the rising of the army commander to a tyrannical and lifelong power, and of the marginalization of the rex sacrorum, while the Republic seems a partial restoration of the oldest constitution