Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and "New Old Friends".

The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends.

The novel 5-lipoxygenase inhibitor ABT-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

OBJECTIVE: Eicosanoids have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Leukotrienes, 5-hydroxyperoxyeicosatetraenoic acid, and 5-hydroxyeicosatetraenoic acid are part of this group of substances, resulting from the 5-lipoxygenase activity on arachidonic acid metabolism. This study examined the effects of ABT-761, a new 5-lipoxygenase inhibitor, on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS: A total of 48 rabbits were assigned to one of six groups: SAH + placebo (n = 8), SAH + ABT-761 20 mg/kg (n = 8), SAH + ABT-761 30 mg/kg (n = 8), control + placebo (n = 8), control + ABT-761 20 mg/kg (n = 8), and control + ABT-761 30 mg/kg (n = 8). Drug administration was initiated 30 minutes after induction of SAH and repeated 24 hours later. The animals were killed 48 hours after SAH, using the perfusion-fixation method. The cross sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups of the individual samples. RESULTS: In placebo-treated animals, the average luminal cross sectional area of the basilar artery was reduced by 68% after SAH as compared with controls (P < 0.0001). After SAH, the vasospastic response was attenuated in animals treated with 20 or 30 mg/kg representing a 28 or 35% reduction, respectively (P = 0.0011 and P = 0.0038). CONCLUSION: The results demonstrated that ABT-761 is effective in attenuating experimental cerebral vasospasm, indicating that this new drug represents a potential therapeutic agent for the treatment of vasospasm after SAH

Unique activities of two overlapping PAX6 retinal enhancers

Enhancers play a critical role in development by precisely modulating spatial, temporal, and cell type-specific gene expression. Sequence variants in enhancers have been implicated in diseases; however, establishing the functional consequences of these variants is challenging because of a lack of understanding of precise cell types and developmental stages where the enhancers are normally active. PAX6 is the master regulator of eye development, with a regulatory landscape containing multiple enhancers driving the expression in the eye. Whether these enhancers perform additive, redundant or distinct functions is unknown. Here, we describe the precise cell types and regulatory activity of two PAX6 retinal enhancers, HS5 and NRE. Using a unique combination of live imaging and single-cell RNA sequencing in dual enhancer-reporter zebrafish embryos, we uncover differences in the spatiotemporal activity of these enhancers. Our results show that although overlapping, these enhancers have distinct activities in different cell types and therefore likely nonredundant functions. This work demonstrates that unique cell type-specific activities can be uncovered for apparently similar enhancers when investigated at high resolution in vivo

Schistosomes in the Lung: Immunobiology and Opportunity

This is the final version. Available on open access from Frontiers Media via the DOI in this recordSchistosome infection is a major cause of global morbidity, particularly in sub-Saharan Africa. However, there is no effective vaccine for this major neglected tropical disease, and re-infection routinely occurs after chemotherapeutic treatment. Following invasion through the skin, larval schistosomula enter the circulatory system and migrate through the lung before maturing to adulthood in the mesenteric or urogenital vasculature. Eggs released from adult worms can become trapped in various tissues, with resultant inflammatory responses leading to hepato-splenic, intestinal, or urogenital disease – processes that have been extensively studied in recent years. In contrast, although lung pathology can occur in both the acute and chronic phases of schistosomiasis, the mechanisms underlying pulmonary disease are particularly poorly understood. In chronic infection, egg-mediated fibrosis and vascular destruction can lead to the formation of portosystemic shunts through which eggs can embolise to the lungs, where they can trigger granulomatous disease. Acute schistosomiasis, or Katayama syndrome, which is primarily evident in non-endemic individuals, occurs during pulmonary larval migration, maturation, and initial egg-production, often involving fever and a cough with an accompanying immune cell infiltrate into the lung. Importantly, lung migrating larvae are not just a cause of inflammation and pathology but are a key target for future vaccine design. However, vaccine efforts are hindered by a limited understanding of what constitutes a protective immune response to larvae. In this review, we explore the current understanding of pulmonary immune responses and inflammatory pathology in schistosomiasis, highlighting important unanswered questions and areas for future research.Biotechnology and Biological Sciences Research Council (BBSRC)Manchester Collaborative Centre for Inflammation Research (MCCIR)Royal SocietyWellcome TrustMedical Research Council (MRC)University of Exete

The Value of p-Value in Biomedical Research

Significance tests and the corresponding p-values play a crucial role in decision making. In this commentary the meaning, interpretation and misinterpretation of p-values is presented. Alternatives for evaluating the reported evidence are also discussed

First measurement of the T-violating muon polarization in the decay K^+ --> mu^+ nu gamma

We present the result of the first measurement of the T-violating muon polarization P_T in the decay K^+ --> mu^+ nu gamma. This polarization is sensitive to new sources of CP-violation in the Higgs sector. Using data accumulated in the period 1996-98 we have obtained P_T = (-0.64 +- 1.85(stat) +- 0.10(syst))x10^{-2} which is consistent with no T-violation in this decay.Comment: 11 pages, 8 figure

Brezin-Gross-Witten model as "pure gauge" limit of Selberg integrals

The AGT relation identifies the Nekrasov functions for various N=2 SUSY gauge theories with the 2d conformal blocks, which possess explicit Dotsenko-Fateev matrix model (beta-ensemble) representations the latter being polylinear combinations of Selberg integrals. The "pure gauge" limit of these matrix models is, however, a non-trivial multiscaling large-N limit, which requires a separate investigation. We show that in this pure gauge limit the Selberg integrals turn into averages in a Brezin-Gross-Witten (BGW) model. Thus, the Nekrasov function for pure SU(2) theory acquires a form very much reminiscent of the AMM decomposition formula for some model X into a pair of the BGW models. At the same time, X, which still has to be found, is the pure gauge limit of the elliptic Selberg integral. Presumably, it is again a BGW model, only in the Dijkgraaf-Vafa double cut phase.Comment: 21 page