Review of Ribosome Interactions with SARS-CoV-2 and COVID-19 mRNA Vaccine

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causing pathogen of the unprecedented global Coronavirus Disease 19 (COVID-19) pandemic. Upon infection, the virus manipulates host cellular machinery and ribosomes to synthesize its own proteins for successful replication and to facilitate further infection. SARS-CoV-2 executes a multi-faceted hijacking of the host mRNA translation and cellular protein synthesis. Viral nonstructural proteins (NSPs) interact with a range of different ribosomal states and interfere with mRNA translation. Concurrent mutations on NSPs and spike proteins contribute to the epidemiological success of variants of concern (VOCs). The interactions between ribosomes and SARS-CoV-2 represent attractive targets for the development of antiviral therapeutics and vaccines. Recently approved COVID-19 mRNA vaccines also utilize the cellular machinery, to produce antigens and trigger immune responses. The design features of the mRNA vaccines are critical to efficient mRNA translation in ribosomes, and are directly related to the vaccine’s efficacy, safety, and immunogenicity. This review describes recent knowledge of how the SARS-CoV-2 virus’ genomic characteristics interfere with ribosomal function and mRNA translation. In addition, we discuss the current learning of the design features of mRNA vaccines and their impacts on translational activity in ribosomes. The understanding of ribosomal interactions with the virus and mRNA vaccines offers the foundation for antiviral therapeutic discovery and continuous mRNA vaccine optimization to lower the dose, to increase durability and/or to reduce adverse effects.

Addendum to: Murre (2021). The Godden and Baddeley (1975) experiment on context-dependent memory on land and underwater: a replication

The analysis in Murre (2021) should have been done with a repeated measures ANOVA with an order effect as a between-subjects covariate. A reanalysis reinforces the conclusion that this study was not a successful replication of Godden & Baddeley (1975).

Investigating the replicability of preclinical cancer biology

Replicability is an important feature of scientific research, but aspects of contemporary research culture, such as an emphasis on novelty, can make replicability seem less important than it should be. The Reproducibility Project: Cancer Biology was set up to provide evidence about the replicability of preclinical research in cancer biology by repeating selected experiments from high-impact papers. A total of 50 experiments from 23 papers were repeated, generating data about the replicability of a total of 158 effects. Most of the original effects were positive effects (136), with the rest being null effects (22). A majority of the original effect sizes were reported as numerical values (117), with the rest being reported as representative images (41). We employed seven methods to assess replicability, and some of these methods were not suitable for all the effects in our sample. One method compared effect sizes: for positive effects, the median effect size in the replications was 85% smaller than the median effect size in the original experiments, and 92% of replication effect sizes were smaller than the original. The other methods were binary – the replication was either a success or a failure – and five of these methods could be used to assess both positive and null effects when effect sizes were reported as numerical values. For positive effects, 40% of replications (39/97) succeeded according to three or more of these five methods, and for null effects 80% of replications (12/15) were successful on this basis; combining positive and null effects, the success rate was 46% (51/112). A successful replication does not definitively confirm an original finding or its theoretical interpretation. Equally, a failure to replicate does not disconfirm a finding, but it does suggest that additional investigation is needed to establish its reliability.

Anxiety-Related Difficulties With Complex Arithmetic

Human behavior depends on the interplay between cognition and emotion. Negative emotions like anxiety affect performance, particularly in complex tasks, by limiting cognitive resources – known as the anxiety–complexity effect. This study set out to replicate the anxiety–complexity effect in a web-based experiment. We investigated individual differences in math anxiety – a negative emotional response specific to math – and arithmetic performance ( N = 382). The mental arithmetic task consisted of a two-digit addition and subtraction, with/without carrying or borrowing, respectively. As expected and preregistered, higher math anxiety was related to poorer arithmetic performance, especially in complex tasks – indicating the anxiety–complexity effect. Consequently, the negative math anxiety-performance link is especially pronounced for complex arithmetic, which requires calculations across place-values and thus working memory resources. This successful replication of the anxiety–complexity effect suggests that math-anxious individuals have particular difficulties in complex arithmetic.

An Importin-β-like Protein from Nicotiana benthamiana Interacts with the RNA Silencing Suppressor P1b of the Cucumber Vein Yellowing Virus, Modulating Its Activity

During a plant viral infection, host–pathogen interactions are critical for successful replication and propagation of the virus through the plant. RNA silencing suppressors (RSSs) are key players of this interplay, and they often interact with different host proteins, developing multiple functions. In the Potyviridae family, viruses produce two main RSSs, HCPro and type B P1 proteins. We focused our efforts on the less known P1b of cucumber vein yellowing virus (CVYV), a type B P1 protein, to try to identify possible factors that could play a relevant role during viral infection. We used a chimeric expression system based on plum pox virus (PPV) encoding a tagged CVYV P1b in place of the canonical HCPro. We used that tag to purify P1b in Nicotiana-benthamiana-infected plants and identified by mass spectrometry an importin-β-like protein similar to importin 7 of Arabidopsis thaliana. We further confirmed the interaction by bimolecular fluorescence complementation assays and defined its nuclear localization in the cell. Further analyses showed a possible role of this N. benthamiana homolog of Importin 7 as a modulator of the RNA silencing suppression activity of P1b.

Toward the Development of Personalized Syndrome Discriminant Systems: A Discriminant System for Hypertension with Liver Yang Hyperactivity Syndrome

Traditional Chinese medicine has shown promising results in treating the symptoms of hypertension, a major global health concern not yet fully managed by modern medicine. It is, therefore, of high priority to clarify the altered pathophysiology of hypertension in individuals with liver Yang hyperactivity syndrome (HLYH) in response to effective treatments to better understand this disorder. The primary aim of this study was to construct a personalized syndrome discriminant system based on data capable of informing management strategies prior to the initiation of antihypertensive therapy or the implementation of screening strategies in at-risk HLYH. Based on the successful replication of HLYH rat models, we extracted the core discriminant factors of the disorder through the integration of physical signs, biochemical indicators, and metabolic markers. Macro and micro information was correlated to construct a syndrome discriminant system. At the macroscopic level, HLYH rat models characterized by elevated blood pressure were found to be associated with significant changes in water intake, pain threshold, retention time on a rotating platform, and body surface temperature. A total of 27 potential biomarkers and 14 metabolic pathways appeared to reflect the primary metabolic characteristics. Through the integration of these data, we successfully constructed a combined macro-micro personalized syndrome discriminant system, which provides a foundation for research regarding the risk loci of HLYH. Our findings also broaden our understanding of the biological pathways involved in HLYH.

How Did We Get Here? One District’s Approach to Device Assisted Learning Technology Implementation

The COVID-19 pandemic necessitated the importance of online and device-assisted learning. What was demonstrated at this time was how prepared districts were to make this transition. Lincoln Public Schools, in Lincoln, Nebraska, was one district that successfully planned and implemented device-assisted learning technology into their school system ahead of the pandemic. This study sought to better understand the process that district leadership enacted to inform practice on developing a technology plan and its implementation. The study's findings show that five key elements are required for successful replication: (a) shared goals, (b) right people and right-fit, (c) cross-communication, (d) implementation, and (e) growth and support. This article serves as a practitioner's guide to implementation as many districts across the country are still trying to figure out how best to serve their students and families.

HIV-1 Vif protein is stabilized by AKT-mediated phosphorylation to enhance APOBEC3G degradation

HIV-1 virus has to counter anti-viral restriction factors for its successful replication after its entry in the cell. The host-pathogen dynamics operate as soon as HIV-1 interacts with the cell. HIV-1 Vif has been known for its role in degradation of APOBEC3G; a cytosine deaminase which leads to hyper mutations in the viral DNA leading to aberrant viral replication. The cellular proteins regulating the intracellular HIV-1 Vif protein levels can have profound impact on HIV-1 pathogenesis. MDM2 is known to induce degradation of Vif with subsequent effects on APOBEC3G. Here, we have identified AKT/PKB as one of the crucial regulators of HIV-1 Vif protein. The rationale for selecting Vif as a target substrate for AKT was the presence of RMRINT motif in it, which is similar to the AKT phosphorylation motif RxRxxS/T. Immunoprecipitation assay and Kinase assay revealed that AKT and Vif interact strongly with each other and Vif is phosphorylated at T20 position by AKT. This phosphorylation stabilizes HIV-1 Vif while Vif mutant T20A degrades faster. Moreover, use of dominant negative form of AKT (KD-AKT) and AKT inhibitors were found to destabilise Vif and increase its K48-ubiquitination profile. The consequences of this AKT-Vif interplay were also validated on APOBEC3G degradation, a target of Vif. AKT inhibition was found to restore APOBEC3G levels. This process can be interpreted as a strategy used by virus to prevent MDM2 mediated Vif degradation; AKT stabilises Mdm2, which then targets Vif for degradation but at the same time AKT stabilises Vif by phosphorylating it. Thus, AKT mediated stabilization of Vif might compensate for its degradation by MDM2. This study can have significant implications as HIV-1 Tat protein and growth factors like insulin activate PI3-K/AKT Kinase pathway and can potentially affect Vif and APOBEC3G protein levels and hence HIV-1 pathogenesis.

The Relation Between Adult Weight Gain, Adipocyte Volume And The Metabolic Profile At Middle Age

Purpose Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume. Methods Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n=6 347, discovery) and Oxford Biobank (n=6 317, replication). Adult weight gain was calculated as the absolute difference between BMI at middle age and recalled BMI at age 20. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n=114) to estimate adipocyte volume. Results Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins and total intermediate-density lipoprotein. One SD weight gain was associated with 386 μm3 (95% CI 143 – 629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain. Main conclusions Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.

4-H Engineering Design Challenge Program: Engaging Youth in STEM Learning

The University of Minnesota 4-H Engineering Design Challenge program is an experiential learning opportunity in which youth work with adult volunteers to create Rube Goldberg influenced machines to address real-world issues. The program components are designed to help youth develop STEM work skills using an Engineering Design Process, increase interest in STEM content knowledge, and explore STEM career interests/aspirations. Evaluation indicates a majority of participants learn the engineering design process, principles of mechanical engineering, teamwork, public speaking, and problem solving. Programmatic outcomes and supports provide for the successful replication, adaptation, and implementation in both formal and non-formal learning environments.