Cascades of Dynamical Transitions in an Adaptive Population

In an adaptive population which models financial markets and distributed control, we consider how the dynamics depends on the diversity of the agents' initial preferences of strategies. When the diversity decreases, more agents tend to adapt their strategies together. This change in the environment results in dynamical transitions from vanishing to non-vanishing step sizes. When the diversity decreases further, we find a cascade of dynamical transitions for the different signal dimensions, supported by good agreement between simulations and theory. Besides, the signal of the largest step size at the steady state is likely to be the initial signal.Comment: 4 pages, 8 figure

Utilizing the K18-hACE2 mouse model to develop protective COVID-19 vaccines

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the respiratory virus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Similar to other respiratory viruses, SARS-CoV-2 is transmitted through inhalation of respiratory droplets and aerosols from infected individuals. Once inhaled, SARS-CoV-2 utilizes the receptor binding domain (RBD) on the spike protein to bind to human Angiotensin Converting Enzyme 2 (hACE2) receptor to gain entrance into host cells to begin viral replication. SARS-CoV-2 infection can result in mild to severe cases of COVID-19 ranging from asymptomatic infections, cold or flu like symptoms to respiratory failure. The onset of the pandemic in 2019 triggered a push to develop vaccines and therapeutics to prevent and treat SARS-CoV-2 infections. At the end of 2020, companies such as Moderna and Pfizer began to administer the first COVID-19 mRNA vaccines, and now in 2022, there are ten World Health Organization (WHO) approved vaccines with many more vaccines in clinical trials and pre-clinical development. At this time, approximately 12 billion doses have been administered worldwide accounting for 61% of the global population being fully vaccinated. However, with the continual emergence of SARS-CoV-2 variants of concern (VOC), each harboring new mutations that can negatively impact vaccine efficacy, there is a need to study and develop new vaccine approaches to improve immunity against VOC. Here, we devised three approaches to help improve vaccine efficacy against SARS-CoV-2 using the pre-clinical Keratin promoter 18-human Angiotensin Converting Enzyme 2 (K18-hACE2) mouse model. First, we evaluated the pathogenesis and response of VOC against human convalescent plasma (HCP) obtained from patients infected with the ancestral strain of SARS-CoV-2. Second, we assessed the vaccine efficacy of four adjuvanted Beta VOC or ancestral strain derived RBD Virus-like particle (VLP) vaccines against Alpha and Beta VOC challenge. Third, we evaluated intranasal administration of a RBD carrier protein-based vaccine adjuvanted with a lipid A mimetic. K18-hACE2 challenge models were used to establish SARS-CoV-2 VOC lethal challenge doses for Alpha, Beta, and Delta. Once a lethal viral dose was determined for each VOC, we evaluated the VOC response against polyclonal antibodies obtained from high titer HCP in a passive immunization study. The objective of the study was to assess the efficacy of antibodies derived from the ancestral strain on emerging VOC since binding and neutralizing antibodies against SARS-CoV-2 are the main correlates of protection for measuring immunity against SARS-CoV-2. Passive immunization of HCP and challenge using ancestral strain, Alpha, Beta or Delta resulted in protection against ancestral strain (100% survival), partial protection against Alpha (60%), and no protection against Beta or Delta challenge (0% survival). Survival outcomes of passive immunization and VOC challenge were also reflected on disease outcomes, viral RNA levels in the lung, brain, and nasal wash (Delta challenge only), and lung pathology. Despite poor outcomes, human RBD and nucleocapsid IgG levels remained stable in the serum and lung in the HCP treated and VOC challenged animals. Therefore, the VOC challenge mouse model established in this study was further used to study vaccine efficacy. Additionally, the HCP passive immunization study demonstrated to us that antibodies generated against the ancestral strain may not protect against VOC. Therefore, to better improve vaccine efficacy against VOC, Beta specific RBD antigens were utilized to study the efficacy of a VLP delivery approach in a murine challenge model. In this study, vaccines were formulated with RBD from either the ancestral strain (Wu) or Beta VOC conjugated to Hepatitis B surface antigen (HBsAg) VLP and adjuvanted with Aluminum hydroxide (Alum) or Squalene-in-water emulsion (SWE) and compared against Pfizer mRNA vaccine. Overall, all RBD-VLP vaccines generated RBD binding antibodies against multiple VOC RBD, broadly neutralizing antibodies against VOC RBD, decreased viral burden in the lung and brain, and lowered inflammation in the lung similar to Pfizer mRNA. However, only Beta and Wu RBD VLP adjuvanted with Alum, and Beta RBD VLP adjuvanted with SWE were able to protect mice (100% survival) against both Alpha and Beta challenge. Next, we evaluated intranasal (IN) vaccination as an approach to improve vaccine efficacy against SARS-CoV-2. We developed a prototype RBD vaccine conjugated to a diphtheria toxoid carrier protein Economical CRM197 (EcoCRM) and adjuvanted with a toll-like receptor agonist 4 (TRL4), Bacterial Enzymatic Combinatorial Chemistry (BECC) called BReC-CoV-2 (BECC+ RBD-EcoCRM COVID-19 vaccine). Overall, IN immunization with BReC-CoV-2 resulted in protection against SARS-CoV-2, decreased viral burden in the lung, brain and nasal wash, generated high levels of RBD IgG in the serum and lung that were capable of neutralizing VOC RBD, as well as induced mucosal IgA in the lung and nasal wash compared to intramuscular (IM) vaccination of BReC-CoV-2. Furthermore, heterologous IN prime and IM boost strategy with BReC-CoV-2 resulted in protection (100% survival) against a lethal Delta challenge. Altogether, the three approaches to improve vaccine efficacy demonstrated that the addition of VOC vaccine antigens accompanied with immunostimulatory adjuvants can improve vaccine responses to VOC and intranasal immunization can enhance vaccine protection by inducing mucosal antibody responses at the site of infection. Together, these vaccine approaches can help improve vaccine efficacy against emerging VOC in future COVID-19 vaccines

Inhibition of IFN-γ Signaling by an Epstein-Barr Virus Immediate-Early Protein

AbstractViruses have evolved elaborate mechanisms to target many aspects of the host's immune response. The cytokine IFN-γ plays a central role in resistance of the host to infection via direct antiviral effects as well as modulation of the immune response. In this study, we demonstrate that the Epstein-Barr virus (EBV) immediate-early protein, BZLF1, inhibits the IFN-γ signaling pathway. BZLF1 decreases the ability of IFN-γ to activate a variety of important downstream target genes, such as IRF-1, p48, and CIITA, and prevents IFN-γ-induced class II MHC surface expression. Additionally, BZLF1 inhibits IFN-γ-induced STAT1 tyrosine phosphorylation and nuclear translocation. Finally, we demonstrate that BZLF1 decreases expression of the IFN-γ receptor, suggesting a mechanism by which EBV may escape antiviral immune responses during primary infection

Mutation of a conserved, hydrophobic, cryptic epitope improves manufacturability and immunogenicity of the SARS-CoV-2 RBD

The supply of COVID-19 vaccine doses still lags behind the global demand for first time vaccination and booster doses. Distribution of vaccine doses has been far from equitable across the world given the steep prices and logistical challenges that low- and middle-income countries face. Subunit protein vaccine candidates have now been shown to elicit protective responses against SARS-CoV-2 infection, while providing additional benefits for manufacturing capability and stability requirements compared to many currently approved vaccines. Here we report a second-generation engineered RBD sequence variant with enhanced manufacturability and immunogenicity over the wild-type ancestral RBD and a first-generation engineered variant (RBD-L452K-F490W (RBD-J)). Introducing two additional mutations, S383D and L518D, to a hydrophobic cryptic epitope in the RBD core improved expression titers and biophysical stability compared to RBD-J. These two additional mutations in RBD-S383D-L452K-F490W-L518D (RBD-J6) ablated the interaction of two neutralizing antibodies, CR3022 and EY6A, targeting the class 4 epitope on the RBD core, but the protein is still bound by human convalescent sera. Mice immunized with a Beta sequence variant of RBD-J and RBD-J6 displayed on a virus-like particle were protected against challenges with Alpha and Beta variants of SARS-CoV-2. Sera from mice immunized with three doses of a RBD-J6 β – VLP showed comparable neutralizing activity to several variants of concern compared to two doses of Comirnaty. Please click Download on the upper right corner to see the full abstract

A prospective randomized, open-label trial comparing the safety and efficacy of dose sparing intradermal 2010/2011 trivalent influenza vaccine delivered by two different devices

Poster Abstract Session - Influenza Vaccines: no. 533BACKGROUND: We performed intradermal 2010/11 trivalent influenza vaccination (TIV) in adult subjects delivered by two different intradermal (ID) devices, using 20% and 60% of the standard dose and compared the immunogenicity and safety with full dose intramuscular (IM) immunization. METHODS: This is a prospective randomized trial conducted from December 2010 to March 2011, comprising chronically ill adults. Subjects were randomly assigned …postprin

Willingness of Hong Kong healthcare workers to accept pre-pandemic influenza vaccination at different WHO alert levels: two questionnaire surveys

Objective To assess the acceptability of pre-pandemic influenza vaccination among healthcare workers in public hospitals in Hong Kong and the effect of escalation in the World Health Organization’s alert level for an influenza pandemic

Generative adversarial networks in ophthalmology: what are these and how can they be used?

PURPOSE OF REVIEW: The development of deep learning (DL) systems requires a large amount of data, which may be limited by costs, protection of patient information and low prevalence of some conditions. Recent developments in artificial intelligence techniques have provided an innovative alternative to this challenge via the synthesis of biomedical images within a DL framework known as generative adversarial networks (GANs). This paper aims to introduce how GANs can be deployed for image synthesis in ophthalmology and to discuss the potential applications of GANs-produced images. RECENT FINDINGS: Image synthesis is the most relevant function of GANs to the medical field, and it has been widely used for generating 'new' medical images of various modalities. In ophthalmology, GANs have mainly been utilized for augmenting classification and predictive tasks, by synthesizing fundus images and optical coherence tomography images with and without pathologies such as age-related macular degeneration and diabetic retinopathy. Despite their ability to generate high-resolution images, the development of GANs remains data intensive, and there is a lack of consensus on how best to evaluate the outputs produced by GANs. SUMMARY: Although the problem of artificial biomedical data generation is of great interest, image synthesis by GANs represents an innovation with yet unclear relevance for ophthalmology

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Background: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. Methods: We aim to identify genetic risk factors by a “trio-based” exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Results: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Conclusions: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD

Can luminous Lyman alpha emitters at zz ≃\simeq 5.7 and zz ≃\simeq 6.6 suppress star formation?

Addressing how strong UV radiation affects galaxy formation is central to understanding their evolution. The quenching of star formation via strong UV radiation (from starbursts or AGN) has been proposed in various scenes to solve certain astrophysical problems. Around luminous sources, some evidence of decreased star formation has been found but is limited to a handful of individual cases. No direct, conclusive evidence on the actual role of strong UV radiation in quenching star formation has been found. Here we present statistical evidence of decreased number density of faint (AB magnitude $\geq$ 24.75 mag) Ly\alpha emitters (LAEs) around bright (AB magnitude < 24.75 mag) LAEs even when the radius goes up to 10 pMpc for $z$ $\simeq$ 5.7 LAEs. A similar trend is found for z $\simeq$ 6.6 LAEs but only within 1 pMpc radius from the bright LAEs. We use a large sample of 1077 (962) LAEs at $z$ $\simeq$ 5.7 ($z$ $\simeq$ 6.6) selected in total areas of 14 (21) deg$^2$ with Subaru/Hyper Suprime-Cam narrow-band data, and thus, the result is of statistical significance for the first time at these high redshift ranges. A simple analytical calculation indicates that the radiation from the central LAE is not enough to suppress LAEs with AB mag $\geq$ 24.75 mag around them, suggesting additional physical mechanisms we are unaware of are at work. Our results clearly show that the environment is at work for the galaxy formation at $z$ $\sim$ 6 in the Universe.Comment: Accepted for publication at MNRA