Sensitive and specific SARS-CoV-2 antibody assays remain critical for community and hospital-based SARS-CoV-2 sero-surveillance. With the rollout of SARS-CoV-2 vaccines, such assays must be able to distinguish vaccine from natural immunity to SARS-CoV-2 and related human coronaviruses. Here, we developed and implemented multiplex microsphere-based immunoassay strategies for COVD-19 antibody studies that incorporates spike protein trimers of SARS-CoV-2 and the endemic seasonal human coronaviruses (HCoV), enabling high throughout measurement of pre-existing cross-reactive antibodies. We varied SARS-CoV-2 antigen compositions within the multiplex assay, allowing direct comparisons of the effects of spike protein, receptor-binding domain protein (RBD) and nucleocapsid protein (NP) based SARS-CoV-2 antibody detection. Multiplex immunoassay performance characteristics are antigen-dependent, and sensitivities and specificities range 92-99% and 94-100%, respectively, for human subject samples collected as early as 7-10 days from symptom onset. SARS-CoV-2 spike and RBD had a strong correlative relationship for the detection of IgG. Correlation between detectable IgG reactive with spike and NP also had strong relationship, however, several PCR-positive and spike IgG-positive serum samples were NP IgG-negative. This spike and NP multiplex immunoassay has the potential to be useful for differentiation between vaccination and natural infection induced antibody responses. We also assessed the induction of de novo SARS-CoV-2 IgG cross reactions with SARS-CoV and MERS-CoV spike proteins. Furthermore, multiplex immunoassays that incorporate spike proteins of SARS-CoV-2 and HCoVs will permit investigations into the influence of HCoV antibodies on COVID-19 clinical outcomes and SARS-CoV-2 antibody durability.
Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 (RPE) cells can acquire resistance to taxol by derepressing the ABCB1 gene, encoding for the multidrug transporter P-gP. Here we have investigated how the ABCB1 gene is derepressed. We show that activation of the ABCB1 gene is associated with reduced DNA methylation, reduced H3K9 trimethylation and increased H3K27 acetylation at the ABCB1 promoter. In addition, we find that the ABCB1 locus has moved away from the nuclear lamina in the taxol-resistant cells. This raises the question which of these alterations were causal to derepression. Directly modifying DNA methylation or H3K27 methylation had neither significant effect on ABCB1 expression, nor did it promote drug resistance. In contrast, the disruption of Lamin B Receptor (LBR), a component of the nuclear lamina involved in genome organization, did promote the acquisition of a taxol-resistant phenotype in a subset of cells. Using CRISPRa-mediated gene activation, we could further substantiate a model in which disruption of lamina association renders the ABCB1 gene permissive to derepression. Based on these data we propose a model in which nuclear lamina dissociation of a repressed gene allows for its activation, implying that deregulation of the 3D genome topology could play an important role in tumor evolution and the acquisition of drug resistance.
We show that drifting pulse solutions of a 1D complex Ginzburg-Landau equation can persist for positive growth rate e in a finite system. When e is increased, two different destabilization scenarios are observed. In sufficiently large systems, fluctuations grow out to form multiple pulses. In small systems, an increase in e eventually leads to a competition between fronts and pulses that results in a sharp transition to a state where the drifting pulse leaps forward in an incoherent fashion. Similar behavior is observed in a more realistic model. PACS numbers: 47.20.Hw, 03.40.Gc, 05.40.+j, 47.54.+r A few years ago, localized or confined traveling wave states were discovered in convection experiments in binary liquids [1 -7]. These are states of which the region where the convection occurs does not fill the total experimental cell, but instead attains a well-defined width.The discovery of these states has inspired a considerable amount of theoretical work on pulse solutions of amplitude equations [8 -12]. It is by now well established that in experiments in annular geometries a localized traveling wave state drifts slowly when the inhomogeneities of the convection cell are sufficiently small [3]. This drift velocity v~i s quite different from the group velocity vg" and this can be contributed to a slow concentration field [9,10] that "traps" the pulse in its own concentration gradient. The existence of localized states and much of their behavior can be understood in terms of pulse-shaped solutions of a complex Ginzburg-Landau amplitude equation [8,11]. The fact that the pulse velocity v~d iffers so much from vg, can, however, only be obtained from a more detailed analysis of the coupling of the convection to the slow concentration field [9,10].In the experiments in an annular geometry [2,5,6], the localized traveling wave states surprisingly persist in a regime where the conducting state (A = 0) is completely unstable (e ) 0). This persistence of pulses in an unstable background is usually explained as follows. Since an annular cell is periodic and since the pulse drifts with a velocity v~d ifferent from the velocity vg, with which the fluctuations propagate, the maximum time interval during
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