The p53 binding protein PDCD5 is not rate-limiting in DNA damage induced cell death

The tumour suppressor p53 is an important mediator of cell cycle arrest and apoptosis in response to DNA damage, acting mainly by transcriptional regulation of specific target genes. The exact details how p53 modulates this decision on a molecular basis is still incompletely understood. One mechanism of regulation is acetylation of p53 on lysine K120 by the histone-acetyltransferase Tip60, resulting in preferential transcription of proapoptotic target genes. PDCD5, a protein with reported pro-apoptotic function, has recently been identified as regulator of Tip60-dependent p53-acetylation. In an effort to clarify the role of PDCD5 upon DNA damage, we generated cell lines in which PDCD5 expression was conditionally ablated by shRNAs and investigated their response to genotoxic stress. Surprisingly, we failed to note a rate-limiting role of PDCD5 in the DNA damage response. PDCD5 was dispensable for DNA damage induced apoptosis and cell cycle arrest and we observed no significant changes in p53 target gene transcription. While we were able to confirm interaction of PDCD5 with p53, we failed to do so for Tip60. Altogether, our results suggest a role of PDCD5 in the regulation of p53 function but unrelated to cell cycle arrest or apoptosis, at least in the cell types investigated.FP06 RTN ‘ApopTrain’Tyrolean Science FundKrebshilfe-Tyro

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Non-lethal control of the cariogenic potential of an agent-based model for dental plaque

Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments

Metabolic synergies in the biotransformation of organic and metallic toxic compounds by a saprotrophic soil fungus

The saprotrophic fungus Penicillium griseofulvum was chosen as model organism to study responses to a mixture of hexachlorocyclohexane (HCH) isomers (α-HCH, β-HCH, γ-HCH, δ-HCH) and of potentially toxic metals (vanadium, lead) in solid and liquid media. The P. griseofulvum FBL 500 strain was isolated from polluted soil containing high concentrations of HCH isomers and potentially toxic elements (Pb, V). Experiments were performed in order to analyse the tolerance/resistance of this fungus to xenobiotics, and to shed further light on fungal potential in inorganic and organic biotransformations. The aim was to examine the ecological and bioremedial potential of this fungus verifying the presence of mechanisms that allow it to transform HCH isomers and metals under different, extreme, test conditions. To our knowledge, this work is the first to provide evidence on the biotransformation of HCH mixtures, in combination with toxic metals, by a saprotrophic non-white-rot fungus and on the metabolic synergies involved

Hospital discharge data is not accurate enough to monitor the incidence of postpartum hemorrhage.

Postpartum hemorrhage remains a leading cause of maternal morbidity and mortality worldwide. Therefore, cumulative incidence of postpartum hemorrhage and severe postpartum hemorrhage are commonly monitored within and compared across maternity hospitals or countries for obstetrical safety improvement. These indicators are usually based on hospital discharge data though their accuracy is seldom assessed. We aimed to measure postpartum hemorrhage and severe postpartum hemorrhage using electronic health records and hospital discharge data separately and compare the detection accuracy of these methods to manual chart review, and to examine the temporal trends in cumulative incidence of these potentially avoidable adverse outcomes. We analyzed routinely collected data of 7904 singleton deliveries from a large Swiss university hospital for a three year period (2014-2016). We identified postpartum hemorrhage and severe postpartum hemorrhage in electronic health records by text mining discharge letters and operative reports and calculating drop in hemoglobin from laboratory tests. Diagnostic and procedure codes were used to identify cases in hospital discharge data. A sample of 334 charts was reviewed manually to provide a reference-standard and evaluate the accuracy of the other detection methods. Sensitivities of detection algorithms based on electronic health records and hospital discharge data were 95.2% (95% CI: 92.6% 97.8%) and 38.2% (33.3% to 43.0%), respectively for postpartum hemorrhage, and 87.5% (85.2% to 89.8%) and 36.2% (26.3% to 46.1%) for severe postpartum hemorrhage. Postpartum hemorrhage cumulative incidence based on electronic health records decreased from 15.6% (13.1% to 18.2%) to 8.5% (6.7% to 10.5%) from the beginning of 2014 to the end of 2016, with an average of 12.5% (11.8% to 13.3%). The cumulative incidence of severe postpartum hemorrhage remained at approximately 4% (3.5% to 4.4%). Hospital discharge data-based algorithms provided significantly underestimated incidences. Hospital discharge data is not accurate enough to assess the incidence of postpartum hemorrhage at hospital or national level. Instead, automated algorithms based on structured and textual data from electronic health records should be considered, as they provide accurate and timely estimates for monitoring and improvement in obstetrical safety. Furthermore, they have the potential to better code for postpartum hemorrhage thus improving hospital reimbursement

Reductions in Perceived Injustice are Associated with Reductions in Disability and Depressive Symptoms after Total Knee Arthroplasty

Introduction: Perceptions of injustice have been associated with problematic recovery outcomes in individuals with a wide range of debilitating pain conditions. It has been suggested that, in patients with chronic pain, perceptions of injustice might arise in response to experiences characterized by illness-related pain severity, depressive symptoms, and disability. If symptoms severity and disability are important contributors to perceived injustice (PI), it follows that interventions that yield reductions in symptom severity and disability should also contribute to reductions in perceptions of injustice. The present study examined the relative contributions of postsurgical reductions in pain severity, depressive symptoms, and disability to the prediction of reductions in perceptions of injustice. Methods: The study sample consisted of 110 individuals (69 women and 41 men) with osteoarthritis of the knee scheduled for total knee arthroplasty (TKA). Patients completed measures of perceived injustice, depressive symptoms, pain, and disability at their presurgical evaluation, and at 1-year follow-up. Results: The results revealed that reductions in depressive symptoms and disability, but not pain severity, were correlated with reductions in perceived injustice. Regression analyses revealed that reductions in disability and reductions in depressive symptoms contributed modest but significant unique variance to the prediction of postsurgical reductions in perceived injustice. Discussion: The present findings are consistent with current conceptualizations of injustice appraisals that propose a central role for symptom severity and disability as determinants of perceptions of injustice in patients with persistent pain. The results suggest that the inclusion of psychosocial interventions that target depressive symptoms and perceived injustice might augment the impact of rehabilitation programs made available for individuals recovering from TKA.</p

Combining regenerative medicine strategies to provide durable reconstructive options: auricular cartilage tissue engineering

Recent advances in regenerative medicine place us in a unique position to improve the quality of engineered tissue. We use auricular cartilage as an exemplar to illustrate how the use of tissue-specific adult stem cells, assembly through additive manufacturing and improved understanding of postnatal tissue maturation will allow us to more accurately replicate native tissue anisotropy. This review highlights the limitations of autologous auricular reconstruction, including donor site morbidity, technical considerations and long-term complications. Current tissue-engineered auricular constructs implanted into immune-competent animal models have been observed to undergo inflammation, fibrosis, foreign body reaction, calcification and degradation. Combining biomimetic regenerative medicine strategies will allow us to improve tissue-engineered auricular cartilage with respect to biochemical composition and functionality, as well as microstructural organization and overall shape. Creating functional and durable tissue has the potential to shift the paradigm in reconstructive surgery by obviating the need for donor sites

Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health. Department of Health and Human Services (contract HHSN266200400001C)National Institutes of Health. Department of Health and Human Services(contract HHSN2722009000018C)Brazil. National Council for Scientific and Technological Developmen