Controlling long-term SARS-CoV-2 infections is important for slowing viral evolution

The rapid emergence and expansion of novel SARS-CoV-2 variants is an unpleasant surprise that threatens our ability to achieve herd immunity for COVID-19. These fitter SARS-CoV-2 variants often harbor multiple point mutations, conferring one or more traits that provide an evolutionary advantage, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we explore the mechanism by which fitter variants of SARS-CoV-2 arise during long-term infections using a mathematical model of viral evolution and identify means by which this evolution can be slowed. While viral load and infection duration play a strong role in favoring the emergence of such variants, the overall probability of emergence and subsequent transmission from any given infection is low, suggesting that viral variant emergence and establishment is a product of random chance. To the extent that luck plays a role in favoring the emergence of novel viral variants with an evolutionary advantage, targeting these low-probability random events might allow us to tip the balance of fortune away from these advantageous variants and prevent them from being established in the population.https://www.nature.com/articles/s41598-021-02148-8First author draf

TGF-β Signaling Initiated in Dendritic Cells Instructs Suppressive Effects on Th17 Differentiation at the Site of Neuroinflammation

While the role of Transforming Growth Factor β (TGF-β) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-β signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-β extrinsic pathway via DCs. First, we provide evidence that TGF-β limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-β controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-β controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-β intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-β can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-β in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets

Genomic analysis of early murine mammary gland development using novel probe-level algorithms

We describe a novel algorithm (ChipStat) for detecting gene-expression changes utilizing probe-level comparisons of replicate Affymetrix oligonucleotide microarray data. A combined detection approach is shown to yield greater sensitivity than a number of widely used methodologies including SAM, dChip and logit-T. Using this approach, we identify alterations in functional pathways during murine neonatal-pubertal mammary development that include the coordinate upregulation of major urinary proteins and the downregulation of loci exhibiting reciprocal imprinting

Controlling long-term SARS-CoV-2 infections can slow viral evolution and reduce the risk of treatment failure.

The rapid emergence and expansion of novel SARS-CoV-2 variants threatens our ability to achieve herd immunity for COVID-19. These novel SARS-CoV-2 variants often harbor multiple point mutations, conferring one or more evolutionarily advantageous traits, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we used a stochastic evolutionary modeling framework to explore the emergence of fitter variants of SARS-CoV-2 during long-term infections. We found that increased viral load and infection duration favor emergence of such variants. While the overall probability of emergence and subsequent transmission from any given infection is low, on a population level these events occur fairly frequently. Targeting these low-probability stochastic events that lead to the establishment of novel advantageous viral variants might allow us to slow the rate at which they emerge in the patient population, and prevent them from spreading deterministically due to natural selection. Our work thus suggests practical ways to achieve control of long-term SARS-CoV-2 infections, which will be critical for slowing the rate of viral evolution.DGE-1762114 - National Science FoundationPublished versio

Optimization rules for SARS-CoV-2 M\u3csup\u3epro\u3c/sup\u3e antivirals: Ensemble docking and exploration of the coronavirus protease active site

© 2020 by the authors. Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 Mpro), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 Mpro active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 Mpro crystal structures. Several key preferences for strong binding to the four subsites (S1, S1\u27, S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 -log10(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 Mpro inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 -log10(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 Mpro [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals

Rapid relaxation of pandemic restrictions after vaccine rollout favors growth of SARS-CoV-2 variants: a model-based analysis

The development and deployment of several SARS-CoV-2 vaccines in a little over a year is an unprecedented achievement of modern medicine. The high levels of efficacy against transmission for some of these vaccines makes it feasible to use them to suppress SARS-CoV-2 altogether in regions with high vaccine acceptance. However, viral variants with reduced susceptibility to vaccinal and natural immunity threaten the utility of vaccines, particularly in scenarios where a return to pre-pandemic conditions occurs before the suppression of SARS-CoV-2 transmission. In this work we model the situation in the United States in May-June 2021, to demonstrate how pre-existing variants of SARS-CoV-2 may cause a rebound wave of COVID-19 in a matter of months under a certain set of conditions. A high burden of morbidity (and likely mortality) remains possible, even if the vaccines are partially effective against new variants and widely accepted. Our modeling suggests that variants that are already present within the population may be capable of quickly defeating the vaccines as a public health intervention, a serious potential limitation for strategies that emphasize rapid reopening before achieving control of SARS-CoV-2.Published versio

Endemicity is not a victory: the unmitigated downside risks of widespread SARS-CoV-2 transmission

The strategy of relying solely on current SARS-CoV-2 vaccines to halt SARS-CoV-2 transmission has proven infeasible. In response, many public-health authorities have advocated for using vaccines to limit mortality while permitting unchecked SARS-CoV-2 spread (“learning to live with the disease”). The feasibility of this strategy critically depends on the infection fatality rate (IFR) of SARS-CoV-2. An expectation exists that the IFR will decrease due to selection against virulence. In this work, we perform a viral fitness estimation to examine the basis for this expectation. Our findings suggest large increases in virulence for SARS-CoV-2 would result in minimal loss of transmissibility, implying that the IFR may vary freely under neutral evolutionary drift. We use an SEIRS model framework to examine the effect of hypothetical changes in the IFR on steady-state death tolls under COVID-19 endemicity. Our modeling suggests that endemic SARS-CoV-2 implies vast transmission resulting in yearly US COVID-19 death tolls numbering in the hundreds of thousands under many plausible scenarios, with even modest increases in the IFR leading to unsustainable mortality burdens. Our findings highlight the importance of enacting a concerted strategy and continued development of biomedical interventions to suppress SARS-CoV-2 transmission and slow its evolution.https://www.mdpi.com/2673-8112/2/12/121Published versio

Approaching Charlotte Brontë in the Twenty-First Century

This is the peer reviewed version of the following article: Wynne, D. (2017). Approaching Charlotte Brontë in the Twenty-First Century. Literature Compass, 14(12), e12355. DOI: 10.1111/lic3.12355, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/lic3.12355/abstract. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingThis essay offers an overview of recent criticism in Charlotte Brontë studies. In the year of Brontë's bicentenary, it takes stock of some of the latest approaches and topics covered, including material culture, disability, screen and stage adaptations, sexuality, regional identity, education, trading networks, the periodical press, and the law. Although much of this new criticism contributes to a fresh understanding of Charlotte Brontë's work and legacy, Jane Eyre continues to dominate most critical discussions, and this essay calls for more attention to be paid to The Professor, Shirley, and Villette. It welcomes those historicist readings that continue the important work of contextualizing Brontë's oeuvre, a project that has transformed her from the reticent provincial writer of semi‐autobiographical fiction presented by early critics into a political and socially engage