Atmospheric undular bores.

We show that a recently-derived model for the propagation of nonlinear waves in the atmosphere admits undular bores as travelling-wave solutions. These solutions represent waves consisting of a damped oscillation behind a front that is preceded by a uniform breeze-type flow. The generation of such wave profiles requires a jump in the heat source across the leading front of the wave, a feature that is consistent with observations.

On the propagation of nonlinear waves in the atmosphere.

Starting from the general equations of fluid dynamics that describe the atmosphere, and using asymptotic methods, we present the derivation of the leading-order equations for nonlinear wave propagation in the troposphere. The only simplifying assumption is that the flow in the atmosphere exists in a thin shell over a sphere. The systematic approach adopted here enables us to find a consistent balance of terms describing the propagation, and to identify the temperature and pressure gradients that drive the motion, as well as the heat sources required. This produces a new nonlinear propagation equation that is then examined in some detail. With the morning glory in mind, we construct a few exact solutions, which, separately, describe breezes, bores and oscillatory motion.

Application of the ideas and techniques of classical fluid mechanics to some problems in physical oceanography.

This review makes a case for describing many of the flows observed in our oceans, simply based on the Euler equation, with (piecewise) constant density and with suitable boundary conditions. The analyses start from the Euler and mass conservation equations, expressed in a rotating, spherical coordinate system (but the f-plane and ß-plane approximations are also mentioned); five examples are discussed. For three of them, a suitable non-dimensionalization is introduced, and a single small parameter is identified in each case. These three examples lead straightforwardly and directly to new results for: waves on the Pacific Equatorial Undercurrent (EUC) with a thermocline (in the f-plane); a nonlinear, three-dimensional model for EUC-type flows (in the ß-plane); and a detailed model for large gyres. The other two examples are exact solutions of the complete system: a flow which corresponds to the underlying structure of the Pacific EUC; and a flow based on the necessary requirement to use a non-conservative body force, which produces the type of flow observed in the Antarctic Circumpolar Current. (All these examples have been discussed in detail in the references cited.) This review concludes with a few comments on how these solutions can be extended and expanded.This article is part of the theme issue 'Nonlinear water waves'.

Large gyres as a shallow-water asymptotic solution of Euler's equation in spherical coordinates.

Starting from the Euler equation expressed in a rotating frame in spherical coordinates, coupled with the equation of mass conservation and the appropriate boundary conditions, a thin-layer (i.e. shallow water) asymptotic approximation is developed. The analysis is driven by a single, overarching assumption based on the smallness of one parameter: the ratio of the average depth of the oceans to the radius of the Earth. Consistent with this, the magnitude of the vertical velocity component through the layer is necessarily much smaller than the horizontal components along the layer. A choice of the size of this speed ratio is made, which corresponds, roughly, to the observational data for gyres; thus the problem is characterized by, and reduced to an analysis based on, a single small parameter. The nonlinear leading-order problem retains all the rotational contributions of the moving frame, describing motion in a thin spherical shell. There are many solutions of this system, corresponding to different vorticities, all described by a novel vorticity equation: this couples the vorticity generated by the spin of the Earth with the underlying vorticity due to the movement of the oceans. Some explicit solutions are obtained, which exhibit gyre-like flows of any size; indeed, the technique developed here allows for many different choices of the flow field and of any suitable free-surface profile. We comment briefly on the next order problem, which provides the structure through the layer. Some observations about the new vorticity equation are given, and a brief indication of how these results can be extended is offered.

Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism.

Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.

Cutaneous exposure to hypoxia does not affect skin perfusion in humans.

AIM: Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O2 availability. Specifically, a reduction in skin-surface PO2 attenuates transcutaneous O2 diffusion, and hence epidermal O2 supply. In response, epidermal HIF-1α expression increases and facilitates initial cutaneous vasoconstriction and subsequent nitric oxide-dependent vasodilation. Here, we investigated whether the same mechanism exists in humans. METHODS: In a first experiment, eight males rested twice for 8 h in a hypobaric chamber. Once, barometric pressure was reduced by 50%, while systemic oxygenation was preserved by O2 -enriched (42%) breathing gas (HypoxiaSkin ), and once barometric pressure and inspired O2 fraction were normal (Control1 ). In a second experiment, nine males rested for 8 h with both forearms wrapped in plastic bags. O2 was expelled from one bag by nitrogen flushing (AnoxiaSkin ), whereas the other bag was flushed with air (Control2 ). In both experiments, skin blood flux was assessed by laser Doppler on the dorsal forearm, and HIF-1α expression was determined by immunohistochemical staining in forearm skin biopsies. RESULTS: Skin blood flux during HypoxiaSkin and AnoxiaSkin remained similar to the corresponding Control trial (P = 0.67 and P = 0.81). Immunohistochemically stained epidermal HIF-1α was detected on 8.2 ± 6.1 and 5.3 ± 5.7% of the analysed area during HypoxiaSkin and Control1 (P = 0.30) and on 2.3 ± 1.8 and 2.4 ± 1.8% during AnoxiaSkin and Control2 (P = 0.90) respectively. CONCLUSION: Reductions in skin-surface PO2 do not affect skin perfusion in humans. The unchanged epidermal HIF-1α expression suggests that epidermal O2 homoeostasis was not disturbed by HypoxiaSkin /AnoxiaSkin , potentially due to compensatory increases in arterial O2 extraction.

The Perception of Threat from Emotions in Predicting Binge Eating Behaviours in People Who Are Obese and Seeking Treatment for Their Weight.

OBJECTIVE: The affect regulation theory suggests that people binge eat to regulate negative emotional states. In this study, we used a basic emotions perspective to consider the role of perceived threat of emotions, emotional suppression and reduced emotional expressiveness in predicting binge eating behaviours in people who are obese. METHOD: Treatment-seeking participants with obesity (N = 51, body mass index range from 30.8 to 60.2 kg m-2 ) completed measures of 'perception of threat from emotion' as well as 'emotional expressiveness' and binge eating. RESULTS: The results demonstrated that perceived threat of sadness predicted binge eating (ß = .55, p < .05). Additionally, a mediation analysis revealed that reduced emotional expressiveness mediated the relationship between perceived threat of fear and binge eating (ß = .25, 95%). DISCUSSION: These findings are contextualized within a theoretical perspective that suggests that individuals who binge eat are threatened by certain emotional states and they use binge eating to suppress certain, but not all, emotional states. Copyright © 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Considering basic emotions within binge eating should be a part of a psychological assessment and treatment. This should consider how emotions could often be perceived as being threatening and their expression is limited. It is possible that the emotions of fear and sadness appear to be particularly threatening within binge eating/obese populations.

Negative regulation of HIF in skeletal muscle of elite endurance athletes: a tentative mechanism promoting oxidative metabolism.

The transcription factor hypoxia-inducible factor (HIF) has been suggested as a candidate for mediating training adaptation in skeletal muscle. However, recent evidence rather associates HIF attenuation with a trained phenotype. For example, a muscle-specific HIF deletion increases endurance performance, partly through decreased levels of pyruvate dehydrogenase kinase 1 (PDK-1). HIF activity is regulated on multiple levels: modulation of protein stability, transactivation capacity, and target gene availability. Prolyl hydroxylases (PHD1-3) induces HIF degradation, whereas factor-inhibiting HIF (FIH) and the histone deacetylase sirtuin-6 (SIRT6) repress its transcriptional activity. Together, these negative regulators introduce a mechanism for moderating HIF activity in vivo. We hypothesized that long-term training induces their expression. Negative regulators of HIF were explored by comparing skeletal muscle tissue from moderately active individuals (MA) with elite athletes (EA). In elite athletes, expression of the negative regulators PHD2 (MA 73.54 ± 9.54, EA 98.03 ± 6.58), FIH (MA 4.31 ± 0.25, EA 30.96 ± 7.99) and SIRT6 (MA 0.24 ± 0.07, EA 11.42 ± 2.22) were all significantly higher, whereas the response gene, PDK-1 was lower (MA 0.12 ± 0.03, EA 0.04 ± 0.01). Similar results were observed in a separate 6-wk training study. In vitro, activation of HIF in human primary muscle cell culture by PHD inactivation strongly induced PDK-1 (0.84 ± 0.12 vs 4.70 ± 0.63), providing evidence of a regulatory link between PHD activity and PDK-1 levels in a relevant model system. Citrate synthase activity, closely associated with aerobic exercise adaptation, increased upon PDK-1 silencing. We suggest that training-induced negative regulation of HIF mediates the attenuation of PDK-1 and contributes to skeletal muscle adaptation to exercise.

Tumour oxygenation: implications for breast cancer prognosis.

There are areas of limited oxygen availability in most solid tumours, including breast cancer. Hypoxia in solid tumours is mainly a consequence of poor perfusion. Structural and functional abnormalities of newly formed tumour vessels cause spatial and temporal heterogeneity of tissue perfusion. The two principal mediators of hypoxia response, HIF-1 and HIF-2, are known to be stabilized at different oxygen levels and to have different temporal responses to hypoxia. Recently, stromal HIF-1 and HIF-2 have been suggested to have opposing roles in breast cancer progression. There is an established link between intralesional, severe hypoxia near areas of necrosis with high levels of HIF-1 and poor prognosis in breast cancer. However, the biological effects of moderate hypoxia and the hypoxic response of stromal cells are currently topics of intense investigation.

Models for the formation of a critical layer in water wave propagation.

A theory is presented which provides a model for the appearance of critical layers within the flow below a water wave. The wave propagates over constant depth, with constant (non-zero) vorticity. The mechanism described here involves adjusting the surface-pressure boundary condition; two models are discussed. In the first, the pressure at the surface is controlled (mimicking the movement of a low-pressure region associated with a storm) so that the speed and development of the pressure region ensure the appearance of a critical layer. In the second, the pressure boundary condition is allowed to accommodate the reduction of pressure with altitude, although the effects have to be greatly enhanced for this mechanism to produce a critical layer. These two problems are analysed using formal parameter asymptotics. In the second problem, this leads to a Korteweg-de Vries equation for the surface wave, and then the evolution of appropriate solutions of this equation gives rise to the appearance of a critical layer near the bottom; the corresponding problem at the surface can be formulated but not completely resolved. The appearance of a stagnation point and then a critical layer, either at the surface or the bottom, are discussed; the nature of the flow, and the corresponding streamlines are obtained and some typical flow fields are depicted.

Deep fungal dermatitis caused by the Chrysosporium anamorph of Nannizziopsis vriesii in captive coastal bearded dragons (Pogona barbata).

Deep fungal dermatitis caused by the Chrysosporium anamorph of Nannizziopsis vriesii (CANV) was diagnosed in a group of coastal bearded dragons (Pogona barbata). The outbreak extended over a 6-month period, with four of six lizards from the same zoological outdoor enclosure succumbing to infection. A fifth case of dermatomycosis was identified in a pet lizard originally sourced from the wild. Diagnosis of infection with the CANV was based on similar clinical signs and histopathology in all animals and confirmed by culture and sequencing of the fungus from one animal. This is the first report of the CANV causing disease in a terrestrial reptile species in Australia and the first in the coastal bearded dragon.

Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Müller cells.

AIMS/HYPOTHESIS: Retinal Müller cells are known to produce inflammatory and angiogenic cytokines, which play important roles in diabetic retinopathy. Hypoxia-inducible factor (HIF)-1 has been shown to play a crucial role in retinal inflammation and neovascularisation. We sought to determine the role of Müller cell-derived HIF-1 in oxygen-induced retinopathy (OIR) and diabetic retinopathy using conditional Hif-1α (also known as Hif1a) knockout (KO) mice. METHODS: Conditional Hif-1α KO mice were generated by crossing mice expressing cyclisation recombinase (cre, also known as P1_gp003) in Müller cells with floxed Hif-1α mice and used for OIR and streptozotocin-induced diabetes to induce retinal neovascularisation and inflammation, respectively. Abundance of HIF-1α and pro-angiogenic and pro-inflammatory factors was measured by immunoblotting and immunohistochemistry. Retinal neovascularisation was visualised by angiography and quantified by counting pre-retinal nuclei. Retinal inflammation was evaluated by leucostasis and vascular leakage. RESULTS: While the Hif-1α KO mice showed significantly decreased HIF-1α levels in the retina, they exhibited no apparent histological or visual functional abnormalities under normal conditions. Compared with wild-type counterparts, Hif-1α KO mice with OIR demonstrated attenuated overproduction of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1, reduced vascular leakage and alleviated neovascularisation in the retina. Under diabetes conditions, disruption of Hif-1α in Müller cells attenuated the increases of retinal vascular leakage and adherent leucocytes, as well as the overproduction of VEGF and ICAM-1. CONCLUSIONS/INTERPRETATION: Müller cell-derived HIF-1α is a key mediator of retinal neovascularisation, vascular leakage and inflammation, the major pathological changes in diabetic retinopathy. Müller cell-derived HIF-1α is therefore a promising therapeutic target for diabetic retinopathy.

Biology of HIF-1alpha.

The increase in body size of humans and other vertebrates requires a physiological infrastructure to provide adequate delivery of oxygen to tissues and cells to maintain oxygen homeostasis. The heart, lungs and the vasculature are all part of a highly regulated system that ensures the distribution of the precise amount of oxygen needed throughout the mammalian organism. Given its fundamental impact on physiology and pathology, it is no surprise that the response of cells to a lack of oxygen, termed hypoxia, has been the focus of many research groups worldwide for many decades now. The transcriptional complex hypoxia-inducible factor has emerged as a key regulator of the molecular hypoxic response, mediating a wide range of physiological and cellular mechanisms necessary to adapt to reduced oxygen.

Edge waves: theories past and present.

The problem of edge waves as an example within classical water-wave theory is described by presenting an overview of some of the theories that have been offered for this phenomenon. The appropriate governing equations and boundary conditions are formulated, and then the important discoveries of Stokes and Ursell, concerning the travelling edge wave, are presented. (We do not address the corresponding problem of standing waves.) Thus, the linear problem and its spectrum are constructed; in addition, we also present the linear long-wave approximation to the problem, as well as Whitham's weakly nonlinear extension to Stokes' original theory. All these discussions are based on the same formulation of the problem, allowing an immediate comparison of the results, whether this be in terms of different approximations or whether the theory be for an irrotational flow or not. Gerstner's exact solution of the water-wave problem is then briefly described, together with a transformation that produces an exact solution of the full equations for the edge wave. The form of this solution is then used as the basis for a multiple-scale description of the edge wave over a slowly varying depth; this leads to a version of the shallow-water equations which has an exact solution that corresponds to the edge wave. Some examples of the theoretical predictions for the run-up pattern are presented. We conclude with three variants of nonlinear model equations that may prove useful in the study of edge waves and, particularly, the interaction of different modes.

Loss of vascular endothelial growth factor expression reduces vascularization, but not growth, of tumors lacking the Von Hippel-Lindau tumor suppressor gene.

Individuals bearing germ line mutations in the Von Hippel-Lindau (VHL) tumor suppressor gene are predisposed to the development of highly angiogenic tumors. This is correlated with an increased expression of the angiogenic factor vascular endothelial growth factor (VEGF) in these tumors, which is in part caused by elevated expression of the HIF-1 hypoxia inducible transcription factors. We created malignant astrocytes with genetic deletions of the VHL gene and implanted them in subcutaneous and intracranial sites; these sites are respectively vessel poor and vessel-rich tissues. When grown in a vessel poor site, VEGF expression in VHL null cells was important for both vascularization and tumor growth. However, when the same cells are grown in the vessel-rich intracranial environment, loss of VEGF expression reduces vascularization, but does not affect tumor growth. This indicates that antiangiogenic therapies for tumors that express high levels of angiogenic factors such as VEGF may vary in their efficacy, with potentially lowered effectiveness in sites, such as the brain, that are inherently vessel rich.

Expression of VEGF isoforms by epiphyseal chondrocytes during low-oxygen tension is HIF-1 alpha dependent.

OBJECTIVE: To establish the role of hypoxia and HIF-1 alpha for VEGF expression of murine epiphyseal chondrocytes. To analyze the effect of hypoxia on VEGF isoform expression. MATERIALS AND METHODS: VEGF mRNA and VEGF isoform expression was investigated in epiphyses of murine newborns by in situ hybridization and real-time PCR. Further, epiphyseal chondrocytes were isolated from newborn mice with homozygous flanking of the HIF-1 alpha gene with lox-P sites. HIF-1 alpha was deleted by infection with adenovirus containing cre-recombinase. After chondrocytes reached confluency they were exposed to 0.5% or 20% oxygen, respectively. Total VEGF and VEGF isoform mRNA expression levels were measured by real-time PCR. Secreted VEGF protein was determined by ELISA. RESULTS: VEGF mRNA signals were detected in the hypertrophic zone and in the center of the proliferative zone of the murine epiphysis, which is considered to be hypoxic. Real-time PCR revealed that VEGF(120)is the dominant isoform in vivo. In cultured epiphyseal chondrocytes strongly increased VEGF gene expression levels were detected after exposure to hypoxia. Furthermore, secretion of VEGF protein was significantly enhanced under 0.5% oxygen. Remarkably, functional inactivation of HIF-1 alpha abolished the hypoxic increase of VEGF expression in chondrocytes completely. Furthermore, the soluble isoforms VEGF(120)and VEGF(164)are the most abundantly expressed splice variants in chondrocytes exposed to low oxygen levels. CONCLUSIONS: The data presented here clearly indicate that hypoxia is able to induce the synthesis of soluble VEGF isoforms by epiphyseal chondrocytes, most likely through stabilization of HIF-1 alpha. Thus it can be speculated that HIF-1 alpha is an essential prerequisite for hypoxic VEGF synthesis in the epiphysis, thereby contributing to the formation and invasion of blood vessels in long bone development.

c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation.

Sympathetic neurons depend on NGF binding to TrkA for their survival during vertebrate development. NGF deprivation initiates a transcription-dependent apoptotic response, which is suggested to require activation of the transcription factor c-Jun. Similarly, apoptosis can also be induced by selective activation of the p75 neurotrophin receptor. The transcriptional dependency of p75-mediated cell death has not been determined; however, c-Jun NH2-terminal kinase has been implicated as an essential component. Because the c-jun-null mutation is early embryonic lethal, thereby hindering a genetic analysis, we used the Cre-lox system to conditionally delete this gene. Sympathetic neurons isolated from postnatal day 1 c-jun-floxed mice were infected with an adenovirus expressing Cre recombinase or GFP and analyzed for their dependence on NGF for survival. Cre immunopositive neurons survived NGF withdrawal, whereas those expressing GFP or those uninfected underwent apoptosis within 48 h, as determined by DAPI staining. In contrast, brain-derived neurotrophic factor (BDNF) binding to p75 resulted in an equivalent level of apoptosis in neurons expressing Cre, GFP, and uninfected cells. Nevertheless, cycloheximide treatment prevented BDNF-mediated apoptosis. These results indicate that whereas c-jun is required for apoptosis in sympathetic neurons on NGF withdrawal, an alternate signaling pathway must be induced on p75 activation.

Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.

Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.

Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha.

Hypoxia-inducible factor-1alpha (HIF-1alpha) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1alpha is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1alpha overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1alpha in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1alpha did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1alpha overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1alpha could improve therapy of tissue ischemia.