During apoptosis, phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and serves as an 'eat-me' signal to trigger ...phagocytosis. It is poorly understood how PS exposure is activated in apoptotic cells. Here we report that CED-8, a Caenorhabditis elegans protein implicated in controlling the kinetics of apoptosis and a homologue of the XK family proteins, is a substrate of the CED-3 caspase. Cleavage of CED-8 by CED-3 activates its proapoptotic function and generates a carboxyl-terminal cleavage product, acCED-8, that promotes PS externalization in apoptotic cells and can induce ectopic PS exposure in living cells. Consistent with its role in promoting PS externalization in apoptotic cells, ced-8 is important for cell corpse engulfment in C. elegans. Our finding identifies a crucial link between caspase activation and PS externalization, which triggers phagocytosis of apoptotic cells.
There is speculation that the volume of percutaneous coronary interventions (PCIs) has been decreasing over the past several years. Published studies of PCI volume have evaluated regional or hospital ...trends, but few have captured national data. This study describes the use of coronary angiography and revascularization methods in Medicare patients from 2001 to 2009.
This retrospective study used data from the Centers for Medicare & Medicaid Services from 2001 to 2009. The annual number of coronary angiograms, PCI, intravascular ultrasound, fractional flow reserve, and coronary artery bypass graft (CABG) surgery procedures were determined from billing data and adjusted for the number of Medicare recipients. From 2001 to 2009, the average year-to-year increase for PCI was 1.3% per 1000 beneficiaries, whereas the mean annual decrease for CABG surgery was 5%. However, the increase in PCI volume occurred primarily from 2001 to 2004, as there was a mean annual rate of decline of 2.5% from 2004 to 2009; similar trends were seen with diagnostic angiography. The use of intravascular ultrasound and fractional flow reserve steadily increased over time.
This study confirms recent speculation that PCI volume has begun to decrease. Although rates of CABG have waned for several decades, all forms of coronary revascularization have been declining since 2004.
Brown rot decay removes cellulose and hemicellulose from wood—residual lignin contributing up to 30% of forest soil carbon—and is derived from an ancestral white rot saprotrophy in which both lignin ...and cellulose are decomposed. Comparative and functional genomics of the "dry rot" fungus Serpula lacrymans, derived from forest ancestors, demonstrated that the evolution of both ectomycorrhizal biotrophy and brown rot saprotrophy were accompanied by reductions and losses in specific protein families, suggesting adaptation to an intercellular interaction with plant tissue. Transcriptome and proteome analysis also identified differences in wood decomposition in S. lacrymans relative to the brown rot Postia placenta. Furthermore, fungal nutritional mode diversification suggests that the boreal forest biome originated via genetic coevolution of above- and below-ground biota.
Agaricus bisporus is the model fungus for the adaptation, persistence, and growth in the humic-rich leaf-litter environment. Aside from its ecological role, A. bisporus has been an important ...component of the human diet for over 200 y and worldwide cultivation of the “button mushroom” forms a multibillion dollar industry. We present two A. bisporus genomes, their gene repertoires and transcript profiles on compost and during mushroom formation. The genomes encode a full repertoire of polysaccharide-degrading enzymes similar to that of wood-decayers. Comparative transcriptomics of mycelium grown on defined medium, casing-soil, and compost revealed genes encoding enzymes involved in xylan, cellulose, pectin, and protein degradation are more highly expressed in compost. The striking expansion of heme-thiolate peroxidases and β-etherases is distinctive from Agaricomycotina wood-decayers and suggests a broad attack on decaying lignin and related metabolites found in humic acid-rich environment. Similarly, up-regulation of these genes together with a lignolytic manganese peroxidase, multiple copper radical oxidases, and cytochrome P450s is consistent with challenges posed by complex humic-rich substrates. The gene repertoire and expression of hydrolytic enzymes in A. bisporus is substantially different from the taxonomically related ectomycorrhizal symbiont Laccaria bicolor . A common promoter motif was also identified in genes very highly expressed in humic-rich substrates. These observations reveal genetic and enzymatic mechanisms governing adaptation to the humic-rich ecological niche formed during plant degradation, further defining the critical role such fungi contribute to soil structure and carbon sequestration in terrestrial ecosystems. Genome sequence will expedite mushroom breeding for improved agronomic characteristics.
In 1993, a surgical protocol for dynamic upper airway reconstruction in patients with obstructive sleep apnea (OSA) was published, and it became commonly known as the Stanford phase 1 and 2 sleep ...surgery protocol. It served as a platform on which research and clinical studies have continued to perfect the surgical care of patients with OSA. However, relapse is inevitable in a chronic condition such as OSA, and a subset of previously cured surgical patients return with complaints of excessive daytime sleepiness. This report describes a patient who was successfully treated with phase 1 and 2 operations more than a decade previously. He returned at 65 years of age with relapse of moderate OSA, and after workup with polysomnography and drug-induced sleep endoscopy, he underwent upper airway stimulation of the hypoglossal nerve that resulted in a cure of OSA. This case shows why upper airway stimulation is an appropriate option for patients with OSA relapse, after previously successful maxillomandibular advancement.
Abstract Objective Obstructive sleep apnea (OSA) can be a challenging disorder to treat. Maxillomandibular advancements (MMAs) generally have high success rates; however, larger advancements have ...higher success and cure rates. Our aim is to present and to describe the current technique used by the senior authors, which has been successful for performing large advancements, thereby improving post-operative outcomes. Methods The senior authors have developed and modified their maxillomandibular advancement operative techniques significantly over the past 30 years. The current version of the Riley–Powell MMA technique is described in a step-by-step fashion in this article. Results Initially, as part of the MMAs, patients underwent maxillomandibular fixation with wires, lag screws and harvested split calvarial bone grafts. The current technique utilizes plates, screws, Erich Arch Bars, and suspension wires which are left in place for 5–6 weeks. Guiding elastics are worn for the first week. The MMA technique described in this article has yielded a success rate over 90% for patients with a body mass index (BMI) <40 kg/m2 and 81% for patients with a BMI ≥40 kg/m2. Conclusion Large advancements during maxillomandibular advancement surgeries can help improve post-operative obstructive sleep apnea outcomes.
The ability to use in vitro human cytochrome P450 (CYP) time-dependent inhibition (TDI) data for in vivo drug–drug interaction (DDI) predictions should be viewed as a prerequisite to generating the ...data. Important terms in making such predictions are kinact and KI but first-line screening assays typically involve characterisation of an IC50 value or a time dependent shift in IC50. In the work presented here, two key screening methods from the scientific literature were appraised both in terms of practicality and quality of kinact/KI estimation. The utility of TDI screening data in DDI predictions was investigated and particular reference given to a simple DDI simulation model based on a spreadsheet that calculates the systemic exposure of unbound inhibitor drug following the input of human pharmacokinetic parameters. Using several clinical mechanism-based CYP DDI examples, the effectiveness of the approach was assessed and compared to other widely available approaches (a simple algorithm that employs a single in vivo unbound inhibitor concentration, a seven-compartment physiologically based pharmacokinetic (PBPK) model that defines the extent of interaction as a result of hepatic inhibitor concentrations and the commercially available software SimCYP®). All the methods gave predictions that compared favourably with the observed DDIs, but various advantages and disadvantages of each were also given full consideration. The new model facilitates rapid sensitivity analysis (parameters can be easily input and altered to give a visual representation of the impact on the active enzyme concentration) and it was therefore used to derive “rules of thumb” demonstrating the relationship between extent of DDI, time-dependent IC50 and dose for typical acidic and basic drugs. Additionally, a TDI decision tree linking into reactive metabolite investigations is proposed for use in a Drug Discovery setting.
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