Influenza A virus strains adopt different host specificities mainly depending on their hemagglutinin (HA) protein. Via HA, the virus binds sialic acid receptors of the host cell and, upon endocytic ...uptake, HA triggers fusion between the viral envelope bilayer and the endosomal membrane by a low pH-induced conformational change leading to the release of the viral genome into the host cell cytoplasm. Both functions are crucial for viral infection enabling the genesis of new progeny virus.
Adaptation to different hosts in vitro was shown to require mutations within HA altering the receptor binding and/or fusion behavior of the respective virus strain. Human adapted influenza virus strains (H1N1, H3N2, H2N2) as well as recent avian influenza virus strains (H5, H7 and H9 subtypes) which gained the ability to infect humans mostly contained mutations in the receptor binding site (RBS) of HA enabling increased binding affinity of these viruses to human type (α-2,6 linked sialic acid) receptors. Thus, the receptor binding specificity seems to be the major requirement for successful adaptation to the human host; however, the RBS is not the only determinant of host specificity. Increased binding to a certain cell type does not always correlate with infection efficiency. Furthermore, viruses carrying mutations in the RBS often resulted in reduced viral fitness and were still unable to transmit between mammals. Recently, the pH stability of HA was reported to affect the transmissibility of influenza viruses. This review summarizes recent findings on the adaptation of influenza A viruses to the human host and related amino acid substitutions resulting in altered receptor binding specificity and/or modulated fusion pH of HA. Furthermore, the role of these properties (receptor specificity and pH stability of HA) for adaptation to and transmissibility in the human host is discussed. This article is part of a Special Issue entitled: Viral Membrane Protiens -- Channels for Cellular Networking.
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•Adaptation to the human host requires altered receptor binding and membrane fusion behavior of HA.•The receptor specificity is determined by the amino acid composition of the receptor binding site.•The pH of fusion is controlled by intrinsic interactions within HA determining its stability.•Viral uptake and thus, infection efficiency is also controlled by other cell specific factors.•Infection of and transmissibility between humans seem to require a low pH of membrane fusion.
Background Approximately 5% to 10% of asthmatic patients achieve incomplete symptom control on current therapies. The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity ...suggests a potential benefit of anti–IL-13 therapy in refractory asthma. GSK679586, a humanized mAb, inhibits IL-13 binding to both IL-13 receptor α1 and α2. Objectives We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids. Methods Patients who remained symptomatic (Asthma Control Questionnaire score ≥1.5) after uptitration to 1000 μg/d fluticasone propionate or greater were randomized to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 (n = 99) or placebo (n = 99). Results Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Questionnaire symptom scores (the primary end point; GSK679586 = −0.31, placebo = −0.17, P = .058) and FEV1 (GSK679586 = −0.01, placebo = 0.03, P = .276). Similar analyses in patients with increased serum IgE levels, blood eosinophil counts, or both were also negative. Incidence of asthma exacerbations was similar between treatments. Most adverse events were nonserious and unrelated to treatment. Two GSK679586-treated patients had treatment-related serious adverse events (lethargy and supraventricular extrasystoles). Conclusions Although well tolerated, GSK679586 did not demonstrate clinically meaningful improvements in asthma control, pulmonary function, or exacerbations in patients with severe asthma. Further studies are needed to determine whether therapies targeting IL-13, the functionally related IL-4 cytokine, or both can provide clinical benefit in patients with severe refractory asthma or a subpopulation of these patients beyond that achievable with high-dose corticosteroids.
Obesity is a prevalent global public health issue characterized by excess body fat. Adipose tissue is now recognized as an important endocrine organ releasing an abundance of bioactive adipokines ...including, but not limited to, leptin, adiponectin and resistin. Obesity is a common comorbidity amongst pulmonary arterial hypertension patients, with 30% to 40% reported as obese, independent of other comorbidities associated with pulmonary arterial hypertension (e.g. obstructive sleep apnoea). An ‘obesity paradox’ has been observed, where obesity has been associated with subclinical right ventricular dysfunction but paradoxically may confer a protective effect on right ventricular function once pulmonary hypertension develops. Obesity and pulmonary arterial hypertension share multiple pathophysiological mechanisms including inflammation, oxidative stress, elevated leptin (proinflammatory) and reduced adiponectin (anti-inflammatory). The female prevalence of pulmonary arterial hypertension has instigated the hypothesis that estrogens may play a causative role in its development. Adipose tissue, a major site for storage and metabolism of sex steroids, is the primary source of estrogens and circulating estrogens levels which are elevated in postmenopausal women and men with pulmonary arterial hypertension. This review discusses the functions of adipose tissue in both health and obesity and the links between obesity and pulmonary arterial hypertension. Shared pathophysiological mechanisms and the contribution of specific fat depots, metabolic and sex-dependent differences are discussed.
Proteins undergo dynamic structural changes to function within the range of physical and chemical conditions of their microenvironments. Changes in these environments affect their activity unless the ...respective mutations preserve their proper function. Here, we examine the influenza A virus spike protein hemagglutinin (HA), which undergoes a dynamic conformational change that is essential to the viral life cycle and is dependent on endosomal pH. Since the cells of different potential hosts exhibit different levels of pH, the virus can only cross species barriers if HA undergoes mutations that still permit the structural change to occur. This key event occurs after influenza A enters the host cell via the endocytic route, during its intracellular transport inside endosomes. The acidic pH inside these vesicles triggers a major structural transition of HA that induces fusion of the viral envelope and the endosomal membrane, and permits the release of the viral genome. HA experiences specific mutations that alter its pH stability and allow the conformational changes required for fusion in different hosts, despite the differences in the degree of acidification of their endosomes. Experimental and theoretical studies over the past few years have provided detailed insights into the structural aspects of the mutational changes that alter its susceptibility to different pH thresholds. We will illustrate how such mutations modify the protein’s structure and consequently its pH stability. These changes make HA an excellent model of the way subtle structural modifications affect a protein’s stability and enable it to function in diverse environments.
To evaluate the prevalence of severe acute respiratory syndrome coronavirus-2 infection in patients presenting with epistaxis to a tertiary otolaryngology unit.
A prospective study was conducted of ...40 consecutive patients presenting with epistaxis referred to our tertiary otolaryngology unit. A group of 40 age-matched controls were also included. All patients underwent real-time reverse transcriptase polymerase chain reaction testing for severe acute respiratory syndrome coronavirus-2. Symptoms of fever, cough and anosmia were noted in the study group.
The mean age was 66.5 ± 22.4 years in the study group. There were 22 males (55 per cent) and 18 females (45 per cent). The mean age in the control group was 66.3 ± 22.4 years (p = 0.935). There were six positive cases for severe acute respiratory syndrome coronavirus-2 (15 per cent) in the epistaxis group and one case (2.5 per cent) in the control group. The difference was statistically significant (p = 0.05).
Epistaxis may represent a presenting symptom of severe acute respiratory syndrome coronavirus-2 infection. This may serve as a useful additional criterion for screening patients.
Idiopathic and familial forms of pulmonary arterial hypertension (PAH) occur more frequently in women than men. However, the reason for this remains unknown. Both the calcium binding protein ...S100A4/Mts1 (Mts1) and its endogenous receptor (receptor for advanced glycosylation end products; RAGE) have been implicated in the development of PAH. We wished to investigate if the Mts1/RAGE pathway may play a role in the gender bias associated with PAH.
We investigated the effects of gender on development of PAH in mice over-expressing Mts1 (Mts1+ mice) via measurement of pulmonary arterial remodeling, systolic right ventricular pressure (sRVP) and right ventricular hypertrophy (RVH). Gender differences in pulmonary arterial Mts1 and RAGE expression were assessed by qRT-PCR and immunohistochemistry. Western blotting and cell counts were used to investigate interactions between 17β-estradiol, Mts1 and RAGE on proliferation of human pulmonary artery smooth muscle cells (hPASMCs). Statistical analysis was by one-way analysis of variance with Dunnetts post test or two-way analysis of variance with Bonferronis post test, as appropriate.
Female Mts1+ mice developed increased sRVP and pulmonary vascular remodeling, whereas male Mts1+ mice remained unaffected. The development of plexiform-like lesions in Mts1+ mice was specific to females. These lesions stained positive for both Mts1 and RAGE in the endothelial and adventitial layers. Expression of pulmonary arterial Mts1 was greater in female than male Mts1+ mice, and was localised to the medial and adventitial layers in non plexiform-like pulmonary arteries. RAGE gene expression and immunoreactivity were similar between male and female Mts1+ mice and RAGE staining was localised to the endothelial layer in non plexiform-like pulmonary arteries adjacent to airways. In non-plexiform like pulmonary arteries not associated with airways RAGE staining was present in the medial and adventitial layers. Physiological concentrations of 17β-estradiol increased Mts1 expression in hPASMCs. 17β-estradiol-induced hPASMC proliferation was inhibited by soluble RAGE, which antagonises the membrane bound form of RAGE.
Mts1 over-expression combined with female gender is permissive to the development of experimental PAH in mice. Up-regulation of Mts1 and subsequent activation of RAGE may contribute to 17β-estradiol-induced proliferation of hPASMCs.
Pulmonary arterial hypertension (PAH) is a hyperproliferative vascular disorder observed predominantly in women. Estrogen is a potent mitogen in human pulmonary artery smooth muscle cells and ...contributes to PAH in vivo; however, the mechanisms attributed to this causation remain obscure. Curiously, heightened expression of the estrogen-metabolizing enzyme cytochrome P450 1B1 (CYP1B1) is reported in idiopathic PAH and murine models of PAH.
Here, we investigated the putative pathogenic role of CYP1B1 in PAH. Quantitative reverse transcription-polymerase chain reaction, immunoblotting, and in situ analysis revealed that pulmonary CYP1B1 is increased in hypoxic PAH, hypoxic+SU5416 PAH, and human PAH and is highly expressed within the pulmonary vascular wall. PAH was assessed in mice via measurement of right ventricular hypertrophy, pulmonary vascular remodeling, and right ventricular systolic pressure. Hypoxic PAH was attenuated in CYP1B1(-/-) mice, and the potent CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS; 3 mg · kg(-1) · d(-1) IP) significantly attenuated hypoxic PAH and hypoxic+SU5416 PAH in vivo. TMS also abolished estrogen-induced proliferation in human pulmonary artery smooth muscle cells and PAH-pulmonary artery smooth muscle cells. The estrogen metabolite 16α-hydroxyestrone provoked human pulmonary artery smooth muscle cell proliferation, and this mitogenic effect was greatly pronounced in PAH-pulmonary artery smooth muscle cells. ELISA analysis revealed that 16α-hydroxyestrone concentration was elevated in PAH, consistent with CYP1B1 overexpression and activity. Finally, administration of the CYP1B1 metabolite 16α-hydroxyestrone (1.5 mg · kg(-1) · d(-1) IP) caused the development of PAH in mice.
Increased CYP1B1-mediated estrogen metabolism promotes the development of PAH, likely via the formation of mitogens, including 16α-hydroxyestrone. Collectively, this study reveals a possible novel therapeutic target in clinical PAH.
Long term planning of urban water infrastructure requires acknowledgement that transitions in the water system are driven by changes in the urban environment, as well as societal dynamics. Inherent ...to the complexity of these underlying processes is that the dynamics of a system's evolution cannot be explained by linear cause-effect relationships and cannot be predicted under narrow sets of assumptions. Planning therefore needs to consider the functional behaviour and performance of integrated flexible infrastructure systems under a wide range of future conditions. This paper presents the first step towards a new generation of integrated planning tools that take such an exploratory planning approach. The spatially explicit model, denoted DAnCE4Water, integrates urban development patterns, water infrastructure changes and the dynamics of socio-institutional changes. While the individual components of the DAnCE4Water model (i.e. modules for simulation of urban development, societal dynamics and evolution/performance of water infrastructure) have been developed elsewhere, this paper presents their integration into a single model. We explain the modelling framework of DAnCE4Water, its potential utility and its software implementation. The integrated model is validated for the case study of an urban catchment located in Melbourne, Australia.
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•Long term planning of urban water infrastructure needs to account for transitions.•DAnCe4Water links urban and societal dynamics with infrastructure evolution.•The complexity of the system requires an exploratory planning approach.•The model was able to predict transition towards decentralized drainage solutions.
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