Hyaluronan deposition and correlation with inflammation in a murine ovalbumin model of asthma

Asthma is a chronic inflammatory disease of the airways characterized by airway remodeling, which includes changes in the extracellular matrix (ECM). However the role of the ECM in mediating these changes is poorly understood. Hyaluronan (HA), a major component of the ECM, has been implicated in asthma as well as in many other biological processes. Our study investigates the processes involved in HA synthesis, deposition, localization and degradation during an acute and chronic murine model of ovalbumin (OVA)-induced allergic pulmonary inflammation. Mice were sensitized, challenged to OVA and sacrificed at various time points during an 8-week challenge protocol. Bronchoalveolar lavage (BAL) fluids, blood, and lung tissue were collected for study. RNA, HA, protein and histopathology were analyzed. Analyses of lung sections and BAL fluids revealed an early deposition and an increase in HA levels within 24 h of antigen exposure. HA levels peaked at day 8 in BAL, while inflammatory cell recovery peaked at day 6. Hyaluronan synthase (HAS)1 and HAS2 on RNA levels peaked within 2 h of antigen exposure, while hyaluronidase (HYAL)1 and HYAL2 on RNA levels decreased. Both inflammatory cell infiltrates and collagen deposition co-localized with HA deposition within the lungs. These data support a role for HA in the pathogenesis of inflammation and airway remodeling in a murine model of asthma. HA deposition appears largely due to up regulation of HAS1 and HAS2. In addition, HA appears to provide the scaffolding for inflammatory cell accumulation as well as for new collagen synthesis and deposition.     

Is there a ‘plenhaptic’ function?

One approach to gauge the complexity of the computational problem underlying haptic perception is to determine the number of dimensions needed to describe it. In vision, the number of dimensions can be estimated to be seven. This observation raises the question of what is the number of dimensions needed to describe touch. Only with certain simplified representations of mechanical interactions can this number be estimated, because it is in general infinite. Organisms must be sensitive to considerably reduced subsets of all possible measurements. These reductions are discussed by considering the sensing apparatuses of some animals and the underlying mechanisms of two haptic illusions.     

Non-indigenous microorganisms in the Antarctic: assessing the risks

The Antarctic continent is frequently cited as the last pristine continent on Earth. However, this view is misleading for several reasons. First, there has been a rapid increase in visitors to Antarctica, with large increases at research bases and their environs and to sites of major tourist interest (e.g. historical sites and concentrations of megafauna). Second, although substantial efforts are made to avoid physical disturbance and contamination by chemical, human and other wastes at these sites, little has been done to prevent the introduction of non-indigenous microorganisms. Here, we analyse the extent and significance of anthropogenic introduction of microbial 'contaminants' to the Antarctic continent. We conclude that such processes are unlikely to have any immediate gross impact on microbiological community structure or function, but that increased efforts are required to protect the unique ecosystems of Antarctica from microbial and genetic contamination and homogenisation.     

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.     

Lysophosphatidic acid is a modulator of cyst growth in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the slow growth of multiple fluid-filled cysts predominately in the kidney tubules and liver bile ducts. Elucidation of mechanisms that control cyst growth will provide the basis for rational therapeutic intervention. We used electrophysiological methods to identify lysophosphatidic acid (LPA) as a component of cyst fluid and serum that stimulates secretory Cl- transport in the epithelial cell type that lines renal cysts. LPA effects are manifested through receptors located on the basolateral membrane of the epithelial cells resulting in stimulation of channel activity in the apical membrane. Concentrations of LPA measured in human ADPKD cyst fluid and in normal serum are sufficient to maximally stimulate ion transport. Thus, cyst fluid seepage and/or leakage of vascular LPA into the interstitial space are capable of stimulating epithelial cell secretion resulting in cyst enlargement. These observations are particularly relevant to the rapid decline in renal function in late-stage disease and to the "third hit" hypothesis that renal injury exacerbates cyst growth.     

Phylogenetic group- and species-specific oligonucleotide probes for single-cell detection of lactic acid bacteria in oral biofilms

Background  

The purpose of this study was to design and evaluate fluorescent in situ hybridization (FISH) probes for the single-cell detection and enumeration of lactic acid bacteria, in particular organisms belonging to the major phylogenetic groups and species of oral lactobacilli and to Abiotrophia/Granulicatella.     

Venturia inaequalis: the causal agent of apple scab

The fungus Venturia inaequalis infects members of the Maloideae, and causes the disease apple scab, the most important disease of apple worldwide. The early elucidation of the gene-for-gene relationship between V. inaequalis and its host Malus has intrigued plant pathologists ever since, with the identification of 17 resistance (R)-avirulence (Avr) gene pairings. The Avr gene products are presumably a subset of the total effector arsenal of V. inaequalis (predominantly proteins secreted in planta assumed to facilitate infection). The supposition that effectors from V. inaequalis act as suppressors of plant defence is supported by the ability of the pathogen to penetrate the cuticle and differentiate into large pseudoparenchymatous structures, termed stromata, in the subcuticular space, without the initiation of an effective plant defence response. If effectors can be identified that are essential for pathogenicity, the corresponding R genes will be durable and would add significant value to breeding programmes. An R gene cluster in Malus has been cloned, but no V. inaequalis effectors have been characterized at the molecular level. However, the identification of effectors is likely to be facilitated by the resolution of the whole genome sequence of V. inaequalis. TAXONOMY: Teleomorph: Venturia inaequalis Cooke (Wint.); Kingdom Fungi; Phylum Ascomycota; Subphylum Euascomycota; Class Dothideomycetes; Family Venturiaceae; genus Venturia; species inaequalis. Anamorph: Fusicladium pomi (Fr.) Lind or Spilocaea pomi (Fr.). LIFE CYCLE: V. inaequalis is a hemibiotroph and overwinters as pseudothecia (sexual fruiting bodies) following a phase of saprobic growth in fallen leaf tissues. The primary inoculum consists of ascospores, which germinate and penetrate the cuticle. Stromata are formed above the epidermal cells but do not penetrate them. Cell wall-degrading enzymes are only produced late in the infection cycle, raising the as yet unanswered question as to how V. inaequalis gains nutrients from the host. Conidia (secondary inoculum) arise from the upper surface of the stromata, and are produced throughout the growing season, initiating multiple rounds of infection. VENTURIA INAEQUALIS AS A MODEL PATHOGEN OF A WOODY HOST: V. inaequalis can be cultured and is amenable to crossing in vitro, enabling map-based cloning strategies. It can be transformed readily, and functional analyses can be conducted by gene silencing. Expressed sequence tag collections are available to aid in gene identification. These will be complemented by the whole genome sequence, which, in turn, will contribute to the comparative analysis of different races of V. inaequalis and plant pathogens within the Dothideomycetes.     

Heat for nothing or activity for free? Evidence and implications of activity-thermoregulatory heat substitution

If heat generated through activity can substitute for heat required for thermoregulation, then activity in cold environments may be energetically free for endotherms. Although the possibility of activity-thermoregulatory heat substitution has been long recognized, its empirical generality and ecological implications remain unclear. We combine a review of the literature and a model of heat exchange to explore the generality of activity-thermoregulatory heat substitution, to assess the extent to which substitution is likely to vary with body size and ambient temperature, and to examine some potential macroecological implications. A majority of the 51 studies we located showed evidence of activity-thermoregulatory heat substitution (35 of 51 studies), with 28 of 32 species examined characterized by substitution in one or more study. Among studies that did detect substitution, the average magnitude of substitution was 57%, but its occurrence and extent varied taxonomically, allometrically, and with ambient temperature. Modeling of heat production and dissipation suggests that large birds and mammals, engaged in intense activity and exposed to relatively warm conditions, have more scope for substitution than do smaller endotherms engaged in less intense activity and experiencing cooler conditions. However, ambient temperature has to be less than the lower critical temperature (the lower bound of the thermal neutral zone) for activity-thermoregulatory heat substitution to occur and this threshold is lower in large endotherms than in small endotherms. Thus, in nature, substitution is most likely to be observed in intermediate-sized birds and mammals experiencing intermediate ambient temperatures. Activity-thermoregulatory heat substitution may be an important determinant of the activity patterns and metabolic ecology of endotherms. For example, a pattern of widely varying field metabolic rates (FMR) at low latitudes that converges to higher and less variable FMR at high latitudes has been interpreted as suggesting that warm environments at low latitudes allow a greater variety of feasible metabolic niches than do cool, high-latitude environments. However, activity-thermoregulatory heat substitution will generate this pattern of latitudinal FMR variation even if endotherms from cold and warm climates are metabolically and behaviorally identical, because the metabolic rates of resting and active animals are more similar in cold than in warm environments. Activity-thermoregulatory heat substitution is an understudied aspect of endotherm thermal biology that is apt to be a major influence on the physiological, behavioral and ecological responses of free-ranging endotherms to variation in temperature.