Connexin communication compartments and wound repair in epithelial tissue

Epithelial tissues line the lumen of tracts and ducts connecting to the external environment. They are critical in forming an interface between the internal and external environment and, following assault from environmental factors and pathogens, they must rapidly repair to maintain cellular homeostasis. These tissue networks, that range from a single cell layer, such as in airway epithelium, to highly stratified and differentiated epithelial surfaces, such as the epidermis, are held together by a junctional nexus of proteins including adherens, tight and gap junctions, often forming unique and localised communication compartments activated for localised tissue repair. This review focuses on the dynamic changes that occur in connexins, the constituent proteins of the intercellular gap junction channel, during wound-healing processes and in localised inflammation, with an emphasis on the lung and skin. Current developments in targeting connexins as corrective therapies to improve wound closure and resolve localised inflammation are also discussed. Finally, we consider the emergence of the zebrafish as a concerted whole-animal model to study, visualise and track the events of wound repair and regeneration in real-time living model systems

Enhancement of thermoelectric properties by energy filtering: Theoretical potential and experimental reality in nanostructured ZnSb

Energy filtering has been suggested by many authors as a means to improve thermoelectric properties. The idea is to filter away low-energy charge carriers in order to increase Seebeck coefficient without compromising electronic conductivity. This concept was investigated in the present paper for a specific material (ZnSb) by a combination of first-principles atomic-scale calculations, Boltzmann transport theory, and experimental studies of the same system. The potential of filtering in this material was first quantified, and it was as an example found that the power factor could be enhanced by an order of magnitude when the filter barrier height was 0.5~eV. Measured values of the Hall carrier concentration in bulk ZnSb were then used to calibrate the transport calculations, and nanostructured ZnSb with average grain size around 70~nm was processed to achieve filtering as suggested previously in the literature. Various scattering mechanisms were employed in the transport calculations and compared with the measured transport properties in nanostructured ZnSb as a function of temperature. Reasonable correspondence between theory and experiment could be achieved when a combination of constant lifetime scattering and energy filtering with a 0.25~eV barrier was employed. However, the difference between bulk and nanostructured samples was not sufficient to justify the introduction of an energy filtering mechanism. The reasons for this and possibilities to achieve filtering were discussed in the paper

Connexins and the epithelial tissue barrier: a focus on Connexin 26

Epithelial tissue responds rapidly to environmental triggers and is constantly renewed. This tissue is also highly accessible for therapeutic targeting. This review highlights the role of connexin mediated communication in avascular epithelial tissue. These proteins form communication conduits with the extracellular space (hemichannels) and between neighboring cells (gap junctions). Regulated exchange of small metabolites less than 1kDa aide the co-ordination of cellular activities and in spatial communication compartments segregating tissue networks. Dysregulation of connexin expression and function has profound impact on physiological processes in epithelial tissue including wound healing. Connexin 26, one of the smallest connexins, is expressed in diverse epithelial tissue and mutations in this protein are associated with hearing loss, skin and eye conditions of differing severity. The functional consequences of dysregulated connexin activity is discussed and the development of connexin targeted therapeutic strategies highlighted

Control of protein synthesis by the reovirus S4 gene

Mammalian reoviruses have been used as a model to study the control of host cell protein synthesis following infection. The reovirus genome is composed of 10 segments of double stranded RNA each of which, with one exception, encodes a single protein. The three serotypes of the virus show marked differences in their effects on host cell protein synthesis following viral infection. Serotypes 2 and 3 give pronounced inhibition and serotype 1 has little effect. Genetic studies using intertypic reassortants have mapped this property to the S4 gene of the virus which encodes the major outer capsid polypeptide σ3. The S4 gene of serotypes 1 and 3 have been sequenced and show 96 % homology at the amino acid level. Full length cDNA clones of the S4 gene of serotypes 1 and 3 (S4-1 and S4-3) were used to develop in vitro and in vivo assay systems to study the mechanism underlying the differential effects on host cell protein synthesis of the corresponding σ3 proteins. The ability of σ3 to inhibit host cell protein synthesis was investigated in two in vitro translation systems: the rabbit reticulocyte lysate system and S-10 cell extracts prepared from uninfected and type 1 and type 3 infected L-cells. Σ3 had no effect on either the translation of B-actin when used as a marker for eukaryotic protein synthesis, or endogenous protein synthesis in either of these systems. In vivo assay systems made use of the HIVLTR/tat inducible reporter system to drive σ3 expression. The effects of σ3 on the expression of two reporter genes, chloramphenicol acetyltransferase (CAT) and B-galactosidase were investigated in transient in vivo assay systems. Σ3 expressed from S4-3 cDNA caused a significant stimulation of reporter gene expression. In contrast σ3 from S4-1 cDNA had no effect on gene expression, suggesting a domain of S4-3 was responsible for this stimulation. In an attempt to domain map this property two hybrids were constructed, one containing the S' 800 base pairs of S4-1 and the 3' 400 base pairs of S4-3 (HY-1), and the other, HY-3, the converse of this. Σ3 synthesised from HY-1 stimulated reporter gene expression whereas that from HY-3 had no effect. Σ3 was readily detected in cells transiently expressing either the parental type 3 S4 cDNA or the HY-1 hybrid by immunoprecipitation and immunofluorescence. By contrast only very small amounts of oi were detected when either the S4 cDNA from type 1 or the HY-3 were used. Pulse-chase experiments indicated that the σ3 from type 1 virus is less stable than the type 3 protein and that the domain responsible for this stability is in the 3' terminus of the S4 gene. This domain is also that shown by others to be responsible for the ability of σ3 to bind dsRNA

The relationship between duration of initial alcohol exposure and persistence of molecular tolerance is markedly nonlinear

The neuronal calcium- and voltage-activated BK potassium channel is modulated by ethanol, and plays a role in behavioral tolerance in vertebrates and invertebrates. We examine the influence of temporal parameters of alcohol exposure on the characteristics of BK molecular tolerance in the ventral striatum, an important component of brain reward circuitry. BK channels in striatal neurons of C57BL/6J mice exhibited molecular tolerance whose duration was a function of exposure time. After 6 h exposure to 20 mm (0.09 mg%) ethanol, alcohol sensitivity was suppressed beyond 24 h after withdrawal, while after a 1 or 3 h exposure, sensitivity had significantly recovered after 4 h. This temporally controlled transition to persistent molecular tolerance parallels changes in BK channel isoform profile. After withdrawal from 6 h, but not 3 h alcohol exposure, mRNA levels of the alcohol-insensitive STREX (stress axis-regulated exon) splice variant were increased. Moreover, the biophysical properties of BK channels during withdrawal from 6 h exposure were altered, and match the properties of STREX channels exogenously expressed in HEK 293 cells. Our results suggest a temporally triggered shift in BK isoform identity. Once activated, the transition does not require the continued presence of alcohol. We next determined whether the results obtained using cultured striatal neurons could be observed in acutely dissociated striatal neurons, after alcohol administration in the living mouse. The results were in remarkable agreement with the striatal culture data, showing persistent molecular tolerance after injections producing 6 h of intoxication, but not after injections producing only 3 h of intoxication

Palliative care needs in patients hospitalized with heart failure (PCHF) study: rationale and design

Abstract Aims The primary aim of this study is to provide data to inform the design of a randomized controlled clinical trial (RCT) of a palliative care (PC) intervention in heart failure (HF). We will identify an appropriate study population with a high prevalence of PC needs defined using quantifiable measures. We will also identify which components a specific and targeted PC intervention in HF should include and attempt to define the most relevant trial outcomes. Methods An unselected, prospective, near-consecutive, cohort of patients admitted to hospital with acute decompensated HF will be enrolled over a 2-year period. All potential participants will be screened using B-type natriuretic peptide and echocardiography, and all those enrolled will be extensively characterized in terms of their HF status, comorbidity, and PC needs. Quantitative assessment of PC needs will include evaluation of general and disease-specific quality of life, mood, symptom burden, caregiver burden, and end of life care. Inpatient assessments will be performed and after discharge outpatient assessments will be carried out every 4 months for up to 2.5 years. Participants will be followed up for a minimum of 1 year for hospital admissions, and place and cause of death. Methods for identifying patients with HF with PC needs will be evaluated, and estimates of healthcare utilisation performed. Conclusion By assessing the prevalence of these needs, describing how these needs change over time, and evaluating how best PC needs can be identified, we will provide the foundation for designing an RCT of a PC intervention in HF

An economic analysis of a contingency model utilising vaccination for the control of equine influenza in a non-endemic country

BACKGROUND:Equine influenza (EI) is an infectious respiratory disease of horses that has never been reported in New Zealand (NZ). However, the 2007 EI outbreak in Australia, previously EI free, spurred the NZ government and stakeholders into evaluating alternative EI control strategies in order to economically justify any future decision to eradicate or manage EI. To build on the policy debate, this paper presents an epinomic (epidemiologic and economic) modelling approach to evaluate alternative control strategies. An epidemiologic model to determine how alternative EI control strategies influence the distribution of EI. Model results were then input into a cost-benefit analysis framework, to identify the return and feasibility of alternative EI eradication strategies in NZ. METHODS:The article explores nine alternative eradication scenarios and two baseline strategies. The alternative scenarios consisted of three vaccination strategies (suppressive, protective or targeted) starting at three time points to reflect the commercial breeding-cycle. These alternatives were compared to two breeding-cycle adjusted baselines: movement restriction in the breeding season (August to January) or non-breeding season (February to July). The economic loss parameters were incursion response, impact to the commercial racing industry (breeding, sales and racing), horse morbidity and mortality, and compensation to industry participants. RESULTS AND CONCLUSIONS:Results suggest that the economic viability of the EI eradication programme is dependent on when within the breeding-cycle the EI outbreak occurs. If an outbreak were to occur, the return on each dollar invested for protective or suppressive vaccination strategies would be between NZD$3.67 to NZD$4.89 and between NZD$3.08 to NZD$3.50 in the breeding and non-breeding seasons, respectively. Therefore, protective or suppressive vaccination strategies could be prioritised, regardless of season. As multiple industry stakeholders benefit from these strategies, the study will enable policy development and to better formulate a user-pays eradication programme

Re-examination of the I-5 dust storm

The infamous dust storm over the thanksgiving holiday of 1991 that led to loss of life from numerous automobile accidents on Interstate 5 (I-5) has been re-examined. Pauley et al. (1996) conducted an earlier investigation of this dust storm following the tenets of Danielsen's paradigm—a paradigm that links the tropopause fold phenomenon and a balanced thermally indirect circulation about the upper level jet stream. However, a cursory examination of mesoscale structures in the storm from the North American Regional Reanalysis (NARR) indicated evidence of a low-level unbalanced thermally direct circulation that demanded further investigation using a high-resolution Weather Research and Forecasting (WRF) model simulation. Principal results from the present study follow: (1) Although the model simulation showed evidence of a weak indirect circulation in the upper troposphere in support of the Danielsen's paradigm, the dynamic control of the storm stemmed from the lower tropospheric mesoscale response to geostrophic imbalance. (2) A lower tropospheric direct circulation led to mass/temperature adjustments that were confirmed by upper air observations at locations in proximity to the accident site, and (3) boundary layer deepening and destabilization due to these mesoscale processes pinpointed the timing and location of the dust storm. Although the present study does not underestimate the value of analyses that focus on the larger/synoptic scales of motion, it does bring to light the value of investigation that makes use of the mesoscale resources in order to clarify synoptic-mesoscale interactions