A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle.

BACKGROUND: Mitochondria are a vital component of eukaryotic cells and their dysfunction is implicated in a large number of metabolic, degenerative and age-related human diseases. The mechanism or these disorders can be difficult to elucidate due to the inherent complexity of mitochondrial metabolism. To understand how mitochondrial metabolic dysfunction contributes to these diseases, a metabolic model of a human heart mitochondrion was created. RESULTS: A new model of mitochondrial metabolism was built on the principle of metabolite availability using MitoMiner, a mitochondrial proteomics database, to evaluate the subcellular localisation of reactions that have evidence for mitochondrial localisation. Extensive curation and manual refinement was used to create a model called iAS253, containing 253 reactions, 245 metabolites and 89 transport steps across the inner mitochondrial membrane. To demonstrate the predictive abilities of the model, flux balance analysis was used to calculate metabolite fluxes under normal conditions and to simulate three metabolic disorders that affect the TCA cycle: fumarase deficiency, succinate dehydrogenase deficiency and α-ketoglutarate dehydrogenase deficiency. CONCLUSION: The results of simulations using the new model corresponded closely with phenotypic data under normal conditions and provided insight into the complicated and unintuitive phenotypes of the three disorders, including the effect of interventions that may be of therapeutic benefit, such as low glucose diets or amino acid supplements. The model offers the ability to investigate other mitochondrial disorders and can provide the framework for the integration of experimental data in future studies.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.

Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity

EFFECT OF RECREATIONAL TRAIL TRAFFIC LEVEL ON EASTERN RED-BACKED SALAMANDER (PLETHODON CINEREUS) RELATIVE ABUNDANCE

The effects of roads and trails on terrestrial salamanders, primarily plethodontids, can be important. The abundance of terrestrial salamanders often increases with distance from roads. Less is known about the effects of recreational or hiking trails on terrestrial salamanders than is known about the effects of roads. We explored how low and high traffic trails in a suburban biological reserve affect the relative abundance of Eastern Red-backed Salamanders (Plethodon cinereus). We found more salamanders under cover objects next to low traffic trails compared to either high traffic trails or wooded areas without trails. At wooded sites, we found only striped morphs whereas at high traffic sites we found only unstriped morphs. Low traffic sites included a range of color morph frequencies. The proportion of females found in each site did not differ, nor did the mean size of the salamanders. Our results suggest that the impact of recreational walking trails needs to be examined more closely to see how and why the distributions of P. cinereus, and potentially other woodland salamanders, are affected and what trail characteristics are important in driving the apparent effects. Such information will contribute to the design and maintenance of walking trails in natural areas that minimize effects on terrestrial salamanders, and likely other organisms

Home telehealth and paediatric palliative care: clinician perceptions of what is stopping us?

Background: Advances in technology have made the use of telehealth in the home setting a feasible option for palliative care clinicians to provide clinical care and support. However, despite being widely available and accessible, telehealth has still not been widely adopted either in Australia or internationally. The study aim was to investigate the barriers, enablers and perceived usefulness for an established home telehealth program in paediatric palliative care from the perspective of clinicians

Mission Not Accomplished: Unequal Opportunities and Outcomes for Black and Latinx Engineers

Engineering occupations are some of the highest-paying and most prestigious in the US labor market, but they are also some of the least diverse. Mission Not Accomplished: Unequal Opportunities and Outcomes for Black and Latinx Engineers finds that of the nearly 1.7 million prime-age engineering workers in the United States in 2019, 81% were either White or Asian, and 84% were men. A mere 3% of engineers working in the field in 2019 were either Black or Latinx women

Paediatric palliative care by video consultation at home: a cost minimisation analysis

Background: In the vast state of Queensland, Australia, access to specialist paediatric services are only available in the capital city of Brisbane, and are limited in regional and remote locations. During home-based palliative care, it is not always desirable or practical to move a patient to attend appointments, and so access to care may be even further limited. To address these problems, at the Royal Children's Hospital (RCH) in Brisbane, a Home Telehealth Program (HTP) has been successfully established to provide palliative care consultations to families throughout Queensland

A systematic review of the methodologies used to evaluate telemedicine service initiatives in hospital facilities

Background: The adoption of telemedicine into mainstream health services has been slower than expected. Many telemedicine projects tend not to progress beyond the trial phase; there are a large number of pilot or project publications and fewer 'service' publications. This issue has been noted since 1999 and continues to be acknowledged in the literature. While overall telemedicine uptake has been slow, some services have been successful. The reporting and evaluation of these successful services may help to improve future uptake and sustainability. The aim of this literature review was to identify peer reviewed publications of deployed telemedicine services in hospital facilities; and to report, and appraise, the methodology used to evaluate these services

Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection. The alteplase dose assessment for Pleural infection Therapy project

Rationale: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here. Objectives: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. Methods: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. Results: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22–58] to 16% [8–31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247–2,984] over 72 h of therapy; P <  0.05) and a reduction in blood C-reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. Conclusions: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pl

Impact of Using Different Stocking Rates of Goats Under Pine Plantation on Plant Species Occurrence and Animal Productivity

Abstract The study assessed the impact of using different stocking rates of goats under pine plantation on plant species occurrence and animal productivity. It was conducted on an 11 year-old loblolly pine plantation site in Epes, Alabama from July to October 2011. Thirty-six Kiko crossbred male goat kids of 4 to 5 months of age were assigned to different stocking rates, namely, low (4 goats/acre), medium (8 goats/acre), and high (12 goats/acre) with three replications each. Forage composition, animal daily gain (ADG) and blood urea nitrogen (BUN) were monitored. Bahia grass (Paspalum notatum) was the most dominant grass species across all treatments. Quantities of understory plant species decreased across all stocking densities with season, but there were no statistical differences (p \u3e 0.05); ADG and BUN were similar. Long-term studies need to be conducted before any meaningful inferences can be drawn. Keywords: Silvopasture, Loblolly Pine, Goats, Understory Species Compositio