The extreme genetic diversity of the HIV-1 remains as a daunting challenge for the development of an effective AIDS vaccine. One strategy for creating a single vaccine that protects against the HIV-1 expanding population is to reconstruct centralized immunogenic sequences that minimize the genetic distance to circulating strains that the vaccine is targeting. Such centralized genes can be estimated with inferred consensus, ancestral and center-of-tree sequences. Although the increased breadth of antibody and T-cell responses induced by the centralized vaccines to date are encouraging, they are modest and may only be partly effective in combating HIV-1. One of the reasons of this limited success might be that several features of HIV-1 molecular evolution have not been yet taken into account in the design of these centralized vaccines, the most important likely being its high recombination rate and complex nucleotide substitution process. Here we describe evolutionary methodologies for the inference of centralized HIV-1 genes, with particular focus on the sources of error introduced by recombination and the model of evolution, in order to foster the development of more effective immunogens before synthesis and assessment in the lab, and final testing in AIDS vaccine trials.
Methods of analysis for four additives (two antioxidants, IRGANOX 245 and 1035; an ultraviolet absorber, CHIMMASORB 81; and an optical brightening agent, UVITEX OB) in olive oil are reported. These additives have the potential to migrate from food-contact materials into the European Union fatty food simulant olive oil, which is the most difficult matrix for analysis. The additives were chosen because they differed in their chemically active groups, had different functions within the polymer, have low proposed specific migration limits and are commonly used in food-contact materials such as polystyrenes and polyolefins. The proposed analytical methods for the additives are simple, rapid, inexpensive and also broadly applicable to the aqueous food simulants. All methods were evaluated by constructing calibration curves, measurement of recovery and precision, and determining the limits of detection. Most of the methods involve direct injection of an olive oil solution for high-performance liquid chromatography analysis with ultraviolet-visible or fluorescence detection. The methods allowed establishment of additive stability and measurement of migration of the selected additives into olive oil at different time-temperature conditions used in migration studies into food simulants.
Abstract Objectives COVID‐19 can lead to a hyperinflammatory state. CD6 is a glycoprotein expressed on mature T lymphocytes which is a crucial regulator of the T‐cell activation. Itolizumab is a humanised antibody targeting CD6. Nonclinical and clinical data in autoimmune diseases indicate that it lowers multiple cytokines primarily involving the Th1/Th17 pathway. The primary objective of this study was to assess the impact of itolizumab in arresting the lung function deterioration of COVID‐19 patients. Secondary objectives included safety, duration of ventilation, 14‐day mortality and evaluation of interleukin 6 concentration. Methods Patients with confirmed SARS‐CoV‐2 received itolizumab in combination with other therapies included in the national protocol for COVID‐19. Results Seventy critical, severe or moderate patients were treated with itolizumab in 10 Cuban hospitals. Median age was 68, and 94% had comorbidities. After 72 h, most patients improved the PO 2 /FiO 2 ratio and reduced FiO2 requirements. Ventilation time was 8 days for critical and 1 day for severe cases. Ten patients had related adverse events while 3 subjects developed related serious events. In 30 patients, interleukin 6 decreased in individuals with high level and did not change in those with lower concentration. Fourteen‐day lethality rate was 4% and 18% for moderate and severe patients, respectively. The proportion of moderate or severe patients with ventilation or death at day 14 was 9.8%. Time to treatment, neurological manifestations and biomarkers such as NLR were significantly associated with higher lethality. Conclusions The opportune administration of itolizumab might interrupt the hyperinflammatory cascade and prevent COVID‐19 morbidity and mortality.
The different types and measures of genetic diversity and the different tools to analyze it in a subdivided population are reviewed. Emphasis is put on the classical genetic analysis coming from population genetics and on the more recent Weitzman’s approach. The latter is questioned because it ignores within population genetic diversity. We discuss different reasons to emphasize either within or between breed variation and the methodology to establish some compromise. Finally, some directions of future research are presented.
SERS permits identifying the nature of molecules in extremely low concentrations, but it is hindered by poor enhancement or low reproducibility. We demonstrate controllable approximately 10(10) signal amplification reaching the zeptomol detection limit for a nonresonant molecule by sandwiching the analyte between the tips of star-shaped gold nanoparticles and a planar gold surface using a simple synthetic procedure. This unprecedented control over light-intensity amplification opens a new avenue toward high-yield, fully reproducible, SERS-based, zeptomol detection and holds promise for nonlinear optics applications at the single-particle level.
Inbreeding depression is a widespread phenomenon that reflects the burden of deleterious effects hidden in heterozygosis in non-inbred populations but exposed in homozygosis in inbred individuals, known as inbreeding load ( B ). This load can be due to partially or fully recessive deleterious mutations (dominance model) or to heterozygote advantage (overdominance model, where both homozygotes are deleterious relative to the heterozygote). There are many studies addressing the changes in inbreeding load in finite populations assuming the dominance model. However, the contribution of overdominance to inbreeding depression has been focused on infinite-size populations. We carried out computer simulations to investigate the joint impact of dominant and pure overdominant mutations on inbreeding load, both for self-fertilizing populations and for panmictic populations suffering from a drastic bottleneck. We found that the overdominant inbreeding load can be substantially reduced by drift even for symmetrical overdominance, at least when considering mutations of small effect. For panmictic bottlenecked populations, the reduction in inbreeding load under dominance and overdominance loci cannot be easily distinguished. However, while purging depletes inbreeding load from dominant loci, slowing inbreeding depression and leading to partial fitness recovery, for overdominant loci fitness declines monotonically.
