Chiral 1,5-disubstituted 1,2,3-triazoles-versatile tools for foldamers and peptidomimetic applications

1,4- A nd 1,5-Disubstituted triazole amino acid monomers have gained increasing interest among peptidic foldamers, as they are easily prepared via Cu- A nd Ru-catalyzed click reactions, with the potential for side chain variation. While the latter is key to their applicability, the synthesis and structural properties of the chiral mono-or disubstituted triazole amino acids have only been partially addressed. We here present the synthesis of all eight possible chiral derivatives of a triazole monomer prepared via a ruthenium-catalyzed azide alkyne cycloaddition (RuAAC). To evaluate the conformational properties of the individual building units, a systematic quantum chemical study was performed on all monomers, indicating their capacity to form several low energy conformers. This feature may be used to effect structural diversity when the monomers are inserted into various peptide sequences. We envisage that these results will facilitate new applications for these artificial oligomeric compounds in diverse areas, ranging from pharmaceutics to biotechnology

Separation in Biorefineries by Liquid Phase Adsorption: Itaconic Acid as Case Study

In biorefinery processes often the downstream processing is the technological bottleneck for an overall high efficiency. On the basis of recent developments, the selective liquid phase adsorption applying highly hydrophobic porous materials opened up new opportunities for process development. In this contribution, the efficiency of selective liquid phase adsorption is demonstrated for the separation and purification of itaconic acid from aqueous solutions for the first time. A wide range of different adsorbents was screened, revealing the surface polarity as well as textural properties as critical parameters for their performance. Adsorption from mixed solutions of itaconic acid and glucose exhibited extraordinary high selectivities for adsorbents with highly hydrophobic surfaces, especially certain activated carbons and hyper-cross-linked polymers. Evaluation of the pH dependence showed that the respective molecular species of itaconic acid/itaconate has a major impact on the adsorption performance. Additionally, experiments on a continuously operated fixed-bed adsorber were carried out, and the desorption behavior was evaluated. Overall, the technical feasibility of the selective adsorptive removal of itaconic acid from aqueous solutions with hydrophobic adsorbents is demonstrated as a model system for an alternative technology to conventional separation strategies in biorefinery concepts

Grignard synthesis of fluorinated nanoporous element organic frameworks based on the heteroatoms P, B, Si, Sn and Ge

We present the synthesis and characterization of fluorinated polymers based on P, B, Si, Sn and Ge as heteroatoms via Grignard activation. The polymers are microporous with hydrophobic surfaces. The borate-based polymer was successfully applied as solid acid catalyst in the esterification of acetic acid with ethanol. Grignard synthesis of fluorinated nanoporous element organic frameworks based on the heteroatoms P, B, Si, Sn and Ge Recently, porous polymers have attracted considerable attention as highly versatile materials for adsorption, separation and storage of gases, in catalysis, for optoelectronic applications and energy storage. Especially, metal–organic frameworks (MOFs) and covalent organic frameworks (COFs) are of interest due to their high surface areas and pore volumes. In order to tune the surface polarity, porous ionic organic networks were reported. Depending on the desired properties such as porosity, polarity and functionality, these materials can be tailored for their application by varying the organic linker and connector element. The utilization of fluorinated linkers was reported for different MOFs and a COF, showing enhanced properties in terms of stability, hydrophobicity, gas affinity and selectivity in comparison to their non-fluorinated materials. In continuation of our work on element organic frameworks (EOFs) with P, Si and Sn as connector elements, here we present the synthesis and characterization of respective fluorinated porous polymers with P, B, Si, Sn and Ge as heteroatoms. The catalytic application of the borate based polymer as solid acid catalyst was demonstrated in the esterification of acetic acid with ethanol as test reaction. As the activation of the fluorinated biphenyl linker was not successful neither via lithiation as reported for the non-fluorinated linker nor via classical Grignard reaction, a magnesium-halogen exchange was applied. The linker 4,4′-dibromooctafluorbiphenyl was activated twofold with isopropylmagnesium chloride lithium chloride (turbo Grignard) and subsequent reaction with the respective element chlorides in a one-pot procedure (Scheme 1) resulted in the fluorinated polymers EF-EOF (E = P, B, Si, Sn, Ge). (Perfluorophenyl)-magnesium bromide was used for end-capping, converting remaining E–Cl bonds into E–Ar bonds to form fully substituted trivalent or tetravalent centers, respectively. In all cases, the resulting polymers were obtained as fluffy white powders

Adverse clinical sequelae after skin branding: a case series

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Ruthenium-catalyzed azide alkyne cycloaddition reaction: scope, mechanism and applications

The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years

GRB 221009A, The BOAT

GRB 221009A has been referred to as the Brightest Of All Time (the BOAT). We investigate the veracity of this statement by comparing it with a half century of prompt gamma-ray burst observations. This burst is the brightest ever detected by the measures of peak flux and fluence. Unexpectedly, GRB 221009A has the highest isotropic-equivalent total energy ever identified, while the peak luminosity is at the $\sim99$th percentile of the known distribution. We explore how such a burst can be powered and discuss potential implications for ultra-long and high-redshift gamma-ray bursts. By geometric extrapolation of the total fluence and peak flux distributions GRB 221009A appears to be a once in 10,000 year event. Thus, while it almost certainly not the BOAT over all of cosmic history, it may be the brightest gamma-ray burst since human civilization began.Comment: Resubmitted to ApJ

Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.publishedVersio

Structural and Functional Roles of Coevolved Sites in Proteins

Understanding the residue covariations between multiple positions in protein families is very crucial and can be helpful for designing protein engineering experiments. These simultaneous changes or residue coevolution allow protein to maintain its overall structural-functional integrity while enabling it to acquire specific functional modifications. Despite the significant efforts in the field there is still controversy in terms of the preferable locations of coevolved residues on different regions of protein molecules, the strength of coevolutionary signal and role of coevolution in functional diversification.In this paper we study the scale and nature of residue coevolution in maintaining the overall functionality and structural integrity of proteins. We employed a large scale study to investigate the structural and functional aspects of coevolved residues. We found that the networks representing the coevolutionary residue connections within our dataset are in general of 'small-world' type as they have clustering coefficient values higher than random networks and also show smaller mean shortest path lengths similar and/or lower than random and regular networks. We also found that altogether 11% of functionally important sites are coevolved with any other sites. Active sites are found more frequently to coevolve with any other sites (15%) compared to protein (11%) and ligand (9%) binding sites. Metal binding and active sites are also found to be more frequently coevolved with other metal binding and active sites, respectively. Analysis of the coupling between coevolutionary processes and the spatial distribution of coevolved sites reveals that a high fraction of coevolved sites are located close to each other. Moreover, approximately 80% of charge compensatory substitutions within coevolved sites are found at very close spatial proximity (<or= 5A), pointing to the possible preservation of salt bridges in evolution.Our findings show that a noticeable fraction of functionally important sites undergo coevolution and also point towards compensatory substitutions as a probable coevolutionary mechanism within spatially proximal coevolved functional sites