The OSU Scheme for Congestion Avoidance in ATM Networks: Lessons Learnt and Extensions

The OSU scheme is a rate-based congestion avoidance scheme for ATM networks using explicit rate indication. This work was one of the first attempts to define explicit rate switch mechanisms and the Resource Management (RM) cell format in Asynchronous Transfer Mode (ATM) networks. The key features of the scheme include explicit rate feedback, congestion avoidance, fair operation while maintaining high utilization, use of input rate as a congestion metric, O(1) complexity. This paper presents an overview of the scheme, presents those features of the scheme that have now become common features of other switch algorithms and discusses three extensions of the scheme

Exterior Problem of a Finite Cylindrical Cavity in Elasto-Dynamics

The elasto-dynamic problem of a finite cylindrical cavity in an infinite elastic solid has been studied. In order to satisfy the radiation conditions at infinity, the solution has been assumed in terms of Spherical Hankel functions and in order to satisfy the conditions at the boundary of the cavity, the method of least square approximation has been used for the minimisation of the errors on the boundary. The radiation patterns of displacements are given for two sets of frequencies and aspect ratios

Antigenically intact hemagglutinin in circulating avian and swine influenza viruses and potential for H3N2 pandemic

The 2009 swine-origin H1N1 influenza, though antigenically novel to the population at the time, was antigenically similar to the 1918 H1N1 pandemic influenza, and consequently was considered to be “archived” in the swine species before reemerging in humans. Given that the H3N2 is another subtype that currently circulates in the human population and is high on WHO pandemic preparedness list, we assessed the likelihood of reemergence of H3N2 from a non-human host. Using HA sequence features relevant to immune recognition, receptor binding and transmission we have identified several recent H3 strains in avian and swine that present hallmarks of a reemerging virus. IgG polyclonal raised in rabbit with recent seasonal vaccine H3 fail to recognize these swine H3 strains suggesting that existing vaccines may not be effective in protecting against these strains. Vaccine strategies can mitigate risks associated with a potential H3N2 pandemic in humans.National Institutes of Health (U.S.) (R37 GM057073-13

Context-Specific Target Definition in Influenza A Virus Hemagglutinin-Glycan Receptor Interactions

Protein-glycan interactions are important regulators of a variety of biological processes, ranging from immune recognition to anticoagulation. An important area of active research is directed toward understanding the role of host cell surface glycans as recognition sites for pathogen protein receptors. Recognition of cell surface glycans is a widely employed strategy for a variety of pathogens, including bacteria, parasites, and viruses. We present here a representative example of such an interaction: the binding of influenza A hemagglutinin (HA) to specific sialylated glycans on the cell surface of human upper airway epithelial cells, which initiates the infection cycle. We detail a generalizable strategy to understand the nature of protein-glycan interactions both structurally and biochemically, using HA as a model system. This strategy combines a top-down approach using available structural information to define important contacts between glycans and HA, with a bottom-up approach using data-mining and informatics approaches to identify the common motifs that distinguish glycan binders from nonbinders. By probing protein-glycan interactions simultaneously through top-down and bottom-up approaches, we can scientifically validate a series of observations. This in turn provides additional confidence and surmounts known challenges in the study of protein-glycan interactions, such as accounting for multivalency, and thus truly defines concepts such as specificity, affinity, and avidity. With the advent of new technologies for glycomics—including glycan arrays, data-mining solutions, and robust algorithms to model protein-glycan interactions—we anticipate that such combination approaches will become tractable for a wide variety of protein-glycan interactions.National Institute of General Medical Sciences (U.S.) (GM 57073)National Institute of General Medical Sciences (U.S.) (U54 GM62116)Singapore-MIT Alliance for Research and Technolog

Broadly Neutralizing Influenza Hemagglutinin Stem-Specific Antibody CR8020 Targets Residues that Are Prone to Escape due to Host Selection Pressure

Broadly neutralizing antibodies (bNAb) that target a conserved region of a viral antigen hold significant therapeutic promise. CR8020 is a bNAb that targets the stem region of influenza A virus (IAV) hemagglutinin (HA). CR8020 is currently being evaluated for prophylactic use against group 2 IAVs in phase II studies. Structural and computational analyses reported here indicate that CR8020 targets HA residues that are prone to antigenic drift and host selection pressure. Critically, CR8020 escape mutation is seen in certain H7N9 viruses from recent outbreaks. Furthermore, the ability of the bNAb Fc region to effectively engage activating Fcγ receptors (FCγR) is essential for antibody efficacy. In this regard, our data indicate that the membrane could sterically hinder the formation of HA-CR8020-FcγRIIa/HA-IgG-FcγRIIIa ternary complexes. Altogether, our analyses suggest that epitope mutability and accessibility to immune complex assembly are important attributes to consider when evaluating bNAb candidates for clinical development.National Institutes of Health (U.S.) (Merit Award R37 GM057073-13)Singapore. National Research Foundation (Singapore-MIT Alliance for Research and Technology

Glycan receptor specificity as a useful tool for characterization and surveillance of influenza A virus

Influenza A viruses are rapidly evolving pathogens with the potential for novel strains to emerge and result in pandemic outbreaks in humans. Some avian-adapted subtypes have acquired the ability to bind to human glycan receptors and cause severe infections in humans but have yet to adapt to and transmit between humans. The emergence of new avian strains and their ability to infect humans has confounded their distinction from circulating human virus strains through linking receptor specificity to human adaptation. Herein we review the various structural and biochemical analyses of influenza hemagglutinin–glycan receptor interactions. We provide our perspectives on how receptor specificity can be used to monitor evolution of the virus to adapt to human hosts so as to facilitate improved surveillance and pandemic preparedness.National Institutes of Health (U.S.) (Merit Award R37 GM057073-13)Singapore. National Research Foundation (Singapore-MIT Alliance for Research and Technology)Skolkovo Institute of Science and Technolog

Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants

SummaryAvian H5N1 influenza viruses continue to spread in wild birds and domestic poultry with sporadic infection in humans. Receptor binding specificity changes are a prerequisite for H5N1 viruses and other zoonotic viruses to be transmitted among humans. Previous reported hemagglutinin (HA) mutants from ferret-transmissible H5N1 viruses of A/Vietnam/1203/2004 and A/Indonesia/5/2005 showed slightly increased, but still very weak, binding to human receptors. From mutagenesis and glycan array studies, we previously identified two H5N1 HA mutants that could more effectively switch receptor specificity to human-like α2-6-linked sialosides with avidity comparable to wild-type H5 HA binding to avian-like α2-3-linked sialosides. Here, crystal structures of these two H5 HA mutants free and in complex with human and avian glycan receptor analogs reveal the structural basis for their preferential binding to human receptors. These findings suggest continuous surveillance should be maintained to monitor and assess human-to-human transmission potential of H5N1 viruses

Decoding the Distribution of Glycan Receptors for Human-Adapted Influenza A Viruses in Ferret Respiratory Tract

Ferrets are widely used as animal models for studying influenza A viral pathogenesis and transmissibility. Human-adapted influenza A viruses primarily target the upper respiratory tract in humans (infection of the lower respiratory tract is observed less frequently), while in ferrets, upon intranasal inoculation both upper and lower respiratory tract are targeted. Viral tropism is governed by distribution of complex sialylated glycan receptors in various cells/tissues of the host that are specifically recognized by influenza A virus hemagglutinin (HA), a glycoprotein on viral surface. It is generally known that upper respiratory tract of humans and ferrets predominantly express α2→6 sialylated glycan receptors. However much less is known about the fine structure of these glycan receptors and their distribution in different regions of the ferret respiratory tract. In this study, we characterize distribution of glycan receptors going beyond terminal sialic acid linkage in the cranial and caudal regions of the ferret trachea (upper respiratory tract) and lung hilar region (lower respiratory tract) by multiplexing use of various plant lectins and human-adapted HAs to stain these tissue sections. Our findings show that the sialylated glycan receptors recognized by human-adapted HAs are predominantly distributed in submucosal gland of lung hilar region as a part of O-linked glycans. Our study has implications in understanding influenza A viral pathogenesis in ferrets and also in employing ferrets as animal models for developing therapeutic strategies against influenza.Singapore-MIT Alliance for Research and Technolog

A Single Base-Pair Change in 2009 H1N1 Hemagglutinin Increases Human Receptor Affinity and Leads to Efficient Airborne Viral Transmission in Ferrets

The 2009 H1N1 influenza A virus continues to circulate among the human population as the predominant H1N1 subtype. Epidemiological studies and airborne transmission studies using the ferret model have shown that the transmission efficiency of 2009 H1N1 viruses is lower than that of previous seasonal strains and the 1918 pandemic H1N1 strain. We recently correlated this reduced transmission efficiency to the lower binding affinity of the 2009 H1N1 hemagglutinin (HA) to α2→6 sialylated glycan receptors (human receptors). Here we report that a single point mutation (Ile219→Lys; a base pair change) in the glycan receptor-binding site (RBS) of a representative 2009 H1N1 influenza A virus, A/California/04/09 or CA04/09, quantitatively increases its human receptor-binding affinity. The increased human receptor-affinity is in the same range as that of the HA from highly transmissible seasonal and 1918 pandemic H1N1 viruses. Moreover, a 2009 H1N1 virus carrying this mutation in the RBS (generated using reverse genetics) transmits efficiently in ferrets by respiratory droplets thereby reestablishing our previously observed correlation between human receptor-binding affinity and transmission efficiency. These findings are significant in the context of monitoring the evolution of the currently circulating 2009 H1N1 viruses