Could Inelastic Interactions Induce Quantum Probabilistic Transitions?

What are quantum entities? Is the quantum domain deterministic or probabilistic? Orthodox quantum theory (OQT) fails to answer these two fundamental questions. As a result of failing to answer the first question, OQT is very seriously defective: it is imprecise, ambiguous, ad hoc, non-explanatory, inapplicable to the early universe, inapplicable to the cosmos as a whole, and such that it is inherently incapable of being unified with general relativity. It is argued that probabilism provides a very natural solution to the quantum wave/particle dilemma and promises to lead to a fully micro-realistic, testable version of quantum theory that is free of the defects of OQT. It is suggested that inelastic interactions may induce quantum probabilistic transitions

The roles of XJ13 and XJ44-specific mutations within the Candid #1 GPC in Junin virus attenuation

Junin virus (JUNV) is a member of the Arenaviridae family of viruses and is the pathogen responsible for causing Argentine hemorrhagic fever, a potentially lethal disease endemic to Argentina. A live attenuated vaccine for human use, called Candid#1, is approved only in Argentina. Candid#1 vaccine strain of Junin virus was obtained through serial passage in mouse brain tissues followed by passage in Fetal Rhesus macaque lung fibroblast (FRhL) cells. Previously, the mutations responsible for attenuation of this virus in Guinea pigs were mapped in the gene encoding for glycoprotein precursor (GPC) protein. The resulting Candid#1 glycoprotein complex has been shown to cause endoplasmic reticulum (ER) stress in vitro resulting in the degradation of the GPC. To evaluate the attenuating properties of specific mutations within GPC, we created recombinant viruses expressing GPC mutations specific to key Candid#1 passages and evaluated their pathogenicity in our outbred Hartley guinea pig model of Argentine hemorrhagic fever. Here, we provide evidence that early mutations in GPC obtained through serial passaging attenuate the visceral disease and increase immunogenicity in guinea pigs. Specific mutations acquired prior to the 13th mouse brain passage (XJ13) are responsible for attenuation of the visceral disease while having no impact on the neurovirulence of Junin virus. Additionally, our findings demonstrate that the mutation within an N-linked glycosylation motif, acquired prior to the 44th mouse brain passage (XJ44), is unstable but necessary for complete attenuation and enhanced immunogenicity of Candid#1 vaccine strain. The highly conserved N-linked glycosylation profiles of arenavirus glycoproteins could therefore be viable targets for designing attenuating viruses for vaccine development against other arenavirus-associated illnesses

Heartland Virus: An Evolving Story of an Emerging Zoonotic and Vector-Borne Disease

Heartland virus (HRTV) is an emerging tick-borne bandavirus that is capable of causing severe disease characterized by acute thrombocytopenia and lymphopenia. The virus is endemic to the eastern United States and is carried by the Lone Star tick (Amblyomma americanum). Since its discovery in 2009, at least 60 human infections have been recorded across this area, with an overall 5–10% estimated mortality rate. All infections reported thus far have occurred following a known tick bite or exposure to tick-infested areas, but the possibility of nosocomial transmission has not been ruled out. Despite relatively high rates of seroprevalence among certain wildlife species such as white-tailed deer, the reservoir species for HRTV remains unknown, as the virus has never been isolated from any mammalian wildlife species. Furthermore, how the virus is transmitted to its vector species in nature remains unknown, though laboratory studies have confirmed both horizontal and vertical transmission of HRTV in A. americanum. In addition, the recent 2017 introduction of the Asian longhorned tick (Haemaphysalis longicornis) to the US has raised concerns about possible spillover of HRTV into a new tick species that has been confirmed to be a competent vector for HRTV in the laboratory. Thus, an increased awareness of its clinical presentation is needed, and further research is urgently required to establish the natural transmission cycle and develop new countermeasures for this novel zoonotic pathogen

In vitro anti-influenza activity of in silico repurposed candidate drug Cycrimine

Background: Due to the limitations of current antiviral therapies because of drug resistance and the emergence of new circulating viral strains, novel effective antivirals are urgently needed. Results of the previous drug repurposing by virtual screening of DrugBank revealed the anticholinergic drug cycrimine as a possible inhibitor of the influenza virus infection. Methods: In this study we examined the potential antiviral activity of cycrimine in vitro. Results: The experimental results showed the anti-influenza activity of cycrimine against two different influenza A subtypes in cell culture. Conclusions: The findings of this study suggest cycrimine as a potential therapeutic agent for influenza. ©2019 International Medical Press

Depletion of CD4 and CD8 T Cells Reduces Acute Disease and Is Not Associated with Hearing Loss in ML29-Infected STAT1-/- Mice

Lassa virus (LASV) is a zoonotic virus endemic to western Africa that can cause a potentially lethal and hemorrhagic disease, Lassa fever (LF). Survivors suffer a myriad of sequelae, most notably sudden onset sensorineural hearing loss (SNHL), the mechanism of which remains unclear. Unfortunately, studies aiming to identify the mechanism of these sequelae are limited due to the biosafety level 4 (BSL4) requirements of LASV itself. ML29, a reassortant virus proposed as an experimental vaccine candidate against LASV, is potentially an ideal surrogate model of LF in STAT1-/- mice due to similar phenotype in these animals. We intended to better characterize ML29 pathogenesis and potential sequelae in this animal model. Our results indicate that while both CD4 and CD8 T cells are responsible for acute disease in ML29 infection, ML29 induces significant hearing loss in a mechanism independent of either CD4 or CD8 T cells. We believe that this model could provide valuable information for viral-associated hearing loss in general

Vaccination has minimal impact on the intrahost diversity of H3N2 influenza viruses

<div><p>While influenza virus diversity and antigenic drift have been well characterized on a global scale, the factors that influence the virus’ rapid evolution within and between human hosts are less clear. Given the modest effectiveness of seasonal vaccination, vaccine-induced antibody responses could serve as a potent selective pressure for novel influenza variants at the individual or community level. We used next generation sequencing of patient-derived viruses from a randomized, placebo-controlled trial of vaccine efficacy to characterize the diversity of influenza A virus and to define the impact of vaccine-induced immunity on within-host populations. Importantly, this study design allowed us to isolate the impact of vaccination while still studying natural infection. We used pre-season hemagglutination inhibition and neuraminidase inhibition titers to quantify vaccine-induced immunity directly and to assess its impact on intrahost populations. We identified 166 cases of H3N2 influenza over 3 seasons and 5119 person-years. We obtained whole genome sequence data for 119 samples and used a stringent and empirically validated analysis pipeline to identify intrahost single nucleotide variants at ≥1% frequency. Phylogenetic analysis of consensus hemagglutinin and neuraminidase sequences showed no stratification by pre-season HAI and NAI titer, respectively. In our study population, we found that the vast majority of intrahost single nucleotide variants were rare and that very few were found in more than one individual. Most samples had fewer than 15 single nucleotide variants across the entire genome, and the level of diversity did not significantly vary with day of sampling, vaccination status, or pre-season antibody titer. Contrary to what has been suggested in experimental systems, our data indicate that seasonal influenza vaccination has little impact on intrahost diversity in natural infection and that vaccine-induced immunity may be only a minor contributor to antigenic drift at local scales.</p></div

Phylogenetic trees of HA and NA consensus sequences from the 2007–2008 season.

<p>Maximum likelihood trees of HA (left) and NA (right) with tips coded by vaccine status and pre-season HAI (left; blue >40, magenta <40) or NAI (right; blue ≥40, magenta <40) titer. HAI (left) and NAI (right) titers are shown on tips as well. Outgroups are HA (EU103823.1) and NA (CY114383.1) for the vaccine strain A/Wisconsin/67/2005. Bootstrap values (n = 1000 bootstraps) are shown and nodes with bootstrap values <50 are collapsed for easier visualization.</p

Intrahost diversity in samples from the 2007–2008 season.

<p>(A) Histogram of the number of iSNV at a given frequency. Bin width = 0.01. (B) Histogram of the number of samples in which each iSNV is found. Arrows indicate bars with one SNV, which are hard to discern in the histogram. These polymorphic SNV, at PB2 position 900 and PA position 515 respectively, were found at 4–6% frequency within hosts and in similar numbers of individuals across vaccination groups. (C) Number of HA iSNV per sample stratified by pre-season HAI titer. >40 = serologically immune, <40 = not serologically immune. (D) Number of NA iSNV per sample stratified by pre-season NAI titer. ≥40 = serologically immune, <40 = not serologically immune.</p

Number of iSNV (mean ± interquartile range) by segment and treatment group for samples from the 2007–2008 season.

<p>Number of iSNV (mean ± interquartile range) by segment and treatment group for samples from the 2007–2008 season.</p

Structural mapping of HA variants.

<p>A homology model of the A/Brisbane/10/2007 (H3N2) HA trimer is shown, with each monomer represented by a different color (purple, grey, and teal) and HA1 and HA2 designated by lighter and darker shades of the same color, respectively. (A) A side view of HA. All identified non-synonymous mutations and known antigenic amino acid positions are shown as balls on the grey monomer. Those variants colored red are within known antigenic sites, while light orange mutations are not. (B) A side and top view of HA. All amino acid positions within known antigenic sites are displayed as balls, with the antigenic mutations identified here shown in red on all three monomers.</p