Characterization of SARS-CoV-2 replication complex elongation and proofreading activity

The replication complex (RC) of SARS-CoV-2 was recently shown to be one of the fastest RNA-dependent RNA polymerases of any known coronavirus. With this rapid elongation, the RC is more prone to incorporate mismatches during elongation, resulting in a highly variable genomic sequence. Such mutations render the design of viral protein targets difficult, as drugs optimized for a given viral protein sequence can quickly become inefficient as the genomic sequence evolves. Here, we use biochemical experiments to characterize features of RNA template recognition and elongation fidelity of the SARS-CoV-2 RdRp, and the role of the exonuclease, nsp14. Our study highlights the 2′OH group of the RNA ribose as a critical component for RdRp template recognition and elongation. We show that RdRp fidelity is reduced in the presence of the 3′ deoxy-terminator nucleotide 3′dATP, which promotes the incorporation of mismatched nucleotides (leading to U:C, U:G, U:U, C:U, and A:C base pairs). We find that the nsp10–nsp14 heterodimer is unable to degrade RNA products lacking free 2′OH or 3′OH ribose groups. Our results suggest the potential use of 3′ deoxy-terminator nucleotides in RNA-derived oligonucleotide inhibitors as antivirals against SARS-CoV-2

Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases: A Structural Perspective

A clinical casein kinase 2 inhibitor, CX-4945 (silmitasertib), shows significant affinity toward the DYRK1A and GSK3β kinases, involved in down syndrome phenotypes, Alzheimer’s disease, circadian clock regulation, and diabetes. This off-target activity offers an opportunity for studying the effect of the DYRK1A/GSK3β kinase system in disease biology and possible line extension. Motivated by the dual inhibition of these kinases, we solved and analyzed the crystal structures of DYRK1A and GSK3β with CX-4945. We built a quantum-chemistry-based model to rationalize the compound affinity for CK2α, DYRK1A, and GSK3β kinases. Our calculations identified a key element for CK2α’s subnanomolar affinity to CX-4945. The methodology is expandable to other kinase selectivity modeling. We show that the inhibitor limits DYRK1A- and GSK3β-mediated cyclin D1 phosphorylation and reduces kinase-mediated NFAT signaling in the cell. Given the CX-4945’s clinical and pharmacological profile, this inhibitory activity makes it an interesting candidate with potential for application in additional disease areas

Fly ash-derived MCM-41 as a low-cost silica support for polyethyleneimine in post-combustion CO2 capture

The mesoporous silicate molecular sieve, MCM-41, has been synthesized from pulverized coal fly ash (PFA), where the silicate filtrate used is a by-product from hydrothermal zeolite production. Rice husk ash was also used for comparison but fusion with sodium hydroxide was used to prepare the silicate filtrate, along similar lines to earlier reports of using PFA as a precursor for MCM-41 synthesis. The MCM-41 samples are chemically and mineralogically similar to a commercially available sample, but with higher pore volumes dominated by mesopores (0.92–1.13 cf. 0.88 cm3 g−1). After polyethyleneimine (PEI) impregnation for CO2 capture, the ash derived MCM-41 samples displayed higher uptakes than the commercial sample with the maximum achievable PEI loading of 60 Wt.% PEI (dry basis) before particle agglomeration occurs, approximately 13 compared to 11 Wt.%, respectively, the latter being comparable to earlier reports in the literature. The PFA sample that displays the fastest kinetics to achieve 90% of the equilibrium uptake had the largest mesopore volume of 1.13 cm3 g−1. Given the PFA-derived MCM-41 uses a waste silicate solution for hydrothermal preparation and no prior preparation is needed, production costs are estimated to be considerable lower where silicate solutions need to be prepared by base treatment, even if ash is used, as for the RHA derived MCM-41 used here

Parisian ruin over a finite-time horizon

For a risk process $R_u(t)=u+ct-X(t), t\ge 0$, where $u\ge 0$ is the initial capital, $c>0$ is the premium rate and $X(t),t\ge 0$ is an aggregate claim process, we investigate the probability of the Parisian ruin $$\mathcal{P}_S(u,T_u)=\mathbb{P}\{\inf_{t\in[0,S]} \sup_{s\in[t,t+T_u]} R_u(s)<0\},$$ with a given positive constant $S$ and a positive measurable function $T_u$. We derive asymptotic expansion of $\mathcal{P}_S(u,T_u)$, as $u\to\infty$, for the aggregate claim process $X$ modeled by Gaussian processes. As a by-product, we derive the exact tail asymptotics of the infimum of a standard Brownian motion with drift over a finite-time interval.Comment: 2

Roadside verges and cemeteries: Comparative analysis of anthropogenic orchid habitats in the Eastern Mediterranean

Several important habitats have become threatened in the last few centuries in the Mediterranean Basin due to major changes adopted in land-use practices. The consequent loss of natural and seminatural orchid habitats leads to the appreciation of small anthropogenic habitats, such as cemeteries and roadside verges. Colonization of cemeteries and roadside verges by orchids has long been known, but no study to date compared the suitability of these two anthropogenic habitats for orchids. Therefore, in this paper our aim was to survey cemeteries and roadside verges and to compare these two habitats regarding their role in conserving Mediterranean terrestrial orchids. We conducted field surveys in three Mediterranean islands, Cyprus, Crete, and Lesbos, where both cemeteries and roadside verges were sampled on a geographically representative scale. We found a total of almost 7,000 orchid individuals, belonging to 77 species in the two anthropogenic habitat types. Roadside verges hosted significantly more individuals than cemeteries in Crete and Lesbos, and significantly more species across all three islands. Our results suggest that although cemeteries have a great potential conservation value in other parts of the world, intensive maintenance practices that characterized cemeteries in these three islands renders them unable to sustain valuable plant communities. On the other hand, roadside verges play a prominent role in the conservation of Mediterranean orchids in Cyprus and Greece. The pioneer status of roadside verges facilitates their fast colonization, while roads serve as ecological corridors in fragmented landscapes

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al

Belief in a zero-sum game and subjective well-being across 35 countries

This article presents a short research report on the relationship between perceived antagonism in social relations measured using the Belief in a Zero-Sum Game (BZSG) scale, life satisfaction, and positive and negative affect. Given that individuals who believe that life is like a zero-sum game are likely to perceive their daily interactions with others as unfair, we expected that individuals with high BZSG experience more negative affect and fewer positive one, resulting in a lower satisfaction with life. In addition, we examined whether country-level BZSG may play a moderating role in these associations. Data were collected from student samples (N = 7146) in 35 countries. Multilevel modelling revealed that perceived social antagonism in social relations is negatively associated with satisfaction with life and that this relationship is mediated by both positive and negative affect at the individual level. The relation of individual BZSG and negative affect on satisfaction with life were weaker in societies with higher country-level BZSG, suggesting that the effects of BZSG may be less detrimental in these countries. These findings extend previous knowledge about predictors of life satisfaction and suggest that social beliefs might also be an important factor that influences subjective well-being. The contribution of the study is that the separate treatment of life satisfaction and positive and negative affect may be helpful in many research situations, particularly from a cross-cultural perspective.info:eu-repo/semantics/publishedVersio

Belief in a zero-sum game and subjective well-being across 35 countries

This article presents a short research report on the relationship between perceived antagonism in social relations measured using the Belief in a Zero-Sum Game (BZSG) scale, life satisfaction, and positive and negative affect. Given that individuals who believe that life is like a zero-sum game are likely to perceive their daily interactions with others as unfair, we expected that individuals with high BZSG experience more negative affect and fewer positive one, resulting in a lower satisfaction with life. In addition, we examined whether country-level BZSG may play a moderating role in these associations. Data were collected from student samples (N=7146) in 35 countries. Multilevel modelling revealed that perceived social antagonism in social relations is negatively associated with satisfaction with life and that this relationship is mediated by both positive and negative affect at the individual level. The relation of individual BZSG and negative affect on satisfaction with life were weaker in societies with higher country-level BZSG, suggesting that the effects of BZSG may be less detrimental in these countries. These findings extend previous knowledge about predictors of life satisfaction and suggest that social beliefs might also be an important factor that influences subjective well-being. The contribution of the study is that the separate treatment of life satisfaction and positive and negative affect may be helpful in many research situations, particularly from a cross-cultural perspective

The mental health continuum-short form: the structure and application for cross-cultural studies-A 38 nation study

Objective: The Mental Health Continuum-Short Form (MHC-SF) is a brief scale measuring positive human functioning. The study aimed to examine the factor structure and to explore the cross-cultural utility of the MHC-SF using bifactor models and exploratory structural equation modelling. Method: Using multigroup confirmatory analysis (MGCFA) we examined the measurement invariance of the MHC-SF in 38 countries (university students, N = 8,066; 61.73% women, mean age 21.55 years). Results: MGCFA supported the cross-cultural replicability of a bifactor structure and a metric level of invariance between student samples. The average proportion of variance explained by the general factor was high (ECV =.66), suggesting that the three aspects of mental health (emotional, social, and psychological well-being) can be treated as a single dimension of well-being. Conclusion: The metric level of invariance offers the possibility of comparing correlates and predictors of positive mental functioning across countries; however, the comparison of the levels of mental health across countries is not possible due to lack of scalar invariance. Our study has preliminary character and could serve as an initial assessment of the structure of the MHC-SF across different cultural settings. Further studies on general populations are required for extending our findings.info:eu-repo/semantics/acceptedVersio