A proteomic perspective on TNF-mediated signalling and cell death

The tumour necrosis factor (TNF) is the most potent inducer of cell death amongst cyto-kines. It is crucial for processes including homeostasis, the development of the immune system and fighting infections. However, high levels of TNF due to genetic disorders or persistent infections can contribute to autoinflammatory and autoimmune diseases or life-threatening conditions like sepsis. These diseases generally display increased levels of cell death, which, downstream of the TNF receptor, can either be caspase-dependent (apoptosis) or caspase-independent (necroptosis). Significant efforts have been invested in unravelling and manipulating signalling mechanisms regulating these two different types of cell death. Here I discuss how modern proteomic approaches like phosphopro-teomics and secretomics provide a novel perspective on this central cytokine and its effect on inflammation and cell survival

The Highway Patrol Officer as Expert Witness

Expert Witnes

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

Asymptotic Solutions of Fifth Order Over-Damped Nonlinear Systems with Cubic Nonlinearity

Many engineering problems and physical systems of fifth degrees of freedom are governed by the fifth order nonlinear differential equations which are over-damped. In this article a fifth order nonlinear differential equation modeling an over-damped symmetrical system is considered. A perturbation technique based on the KBM method and the work of Akbar et al. is developed for obtaining the transient response when the eigenvalues are in integral multiple. The results obtained by the presented technique agree with those results obtained by the numerical method nicely. An example is solved to illustrated method

Effectiveness, cost-effectiveness and cost-benefit of a single annual professional intervention for the prevention of childhood dental caries in a remote rural Indigenous community

Background The aim of the study is to reduce the high prevalence of tooth decay in children in a remote, rural Indigenous community in Australia, by application of a single annual dental preventive intervention. The study seeks to (1) assess the effectiveness of an annual oral health preventive intervention in slowing the incidence of dental caries in children in this community, (2) identify the mediating role of known risk factors for dental caries and (3) assess the cost-effectiveness and cost-benefit of the intervention. Methods/design The intervention is novel in that most dental preventive interventions require regular re-application, which is not possible in resource constrained communities. While tooth decay is preventable, self-care and healthy habits are lacking in these communities, placing more emphasis on health services to deliver an effective dental preventive intervention. Importantly, the study will assess cost-benefit and cost-effectiveness for broader implementation across similar communities in Australia and internationally. Discussion There is an urgent need to reduce the burden of dental decay in these communities, by implementing effective, cost-effective, feasible and sustainable dental prevention programs. Expected outcomes of this study include improved oral and general health of children within the community; an understanding of the costs associated with the intervention provided, and its comparison with the costs of allowing new lesions to develop, with associated treatment costs. Findings should be generalisable to similar communities around the world. The research is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number ACTRN12615000693527; date of registration: 3rd July 2015

Cortical thickness of the insula and prefrontal cortex relates to externalizing behavior: Cross-sectional and prospective findings

Externalizing behaviors (EBs) pertain to a diverse set of aggressive, antisocial, and potentially destructive behaviors directed toward the external environment. They range from nonclinical to clinical in severity, associated with opposition, aggression, hyperactivity, or impulsivity, and are considered a risk factor for the emergence of psychopathology later in adulthood. Focusing on community adolescents (N = 102; 49 female and 53 male adolescents; age range 12-19 years), this study aimed to explore the relations between EBs and the cortical thickness of regions of interest as well as to identify possible risk markers that could improve understanding of the EB construct. Using a mixed cross-sectional and prospective design (1-year follow-up), we report specific associations with cortical thickness of the left insular, right orbitofrontal, and left anterior cingulate cortex. Specifically, thinner left insular and right orbitofrontal cortex was associated with higher EBs, and thinner left anterior cingulate cortex predicted less reduction in EBs 1 year later. In addition, further examination of the aggression and rule-breaking subscales of the Youth/Adult Self-Report, used to assess EBs, revealed specific associations with insular subregions. Findings suggest that cortical structure morphology may significantly relate to the expression and maintenance of EBs within the general population of adolescents

A Comprehensive Case Study of Macrosegregation in a Steel Ingot

This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11663-015-0386-yA case study is presented that examines the macrosegregation and grain structure present in a 12-tonne steel ingot, which was cast for experimental purposes. Details of the casting procedure were well documented and the resulting ingot was characterized using a number of techniques that measured chemical segregation, shrinkage, and porosity. The formation of the porosity and segregation patterns is discussed in reference to the particular grain structure observed in the ingot. It is hoped that this case study can be used as a tool for the validation of future macromodels.This work was undertaken as part of a Project sponsored by Rolls-Royce Power Nuclear plc in collaboration with Sheffield Forgemasters International

Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling

Tumor necrosis factor (TNF) has various effects on phosphorylation-mediated cellular signaling. Combining phosphoproteomics, subcellular localization analyses and kinase inhibitor assays, the authors provide systems level insights into TNF signaling and identify modulators of TNF-induced cell death. Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. Here, we reason that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Therefore, we combine phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis to identify functional modules of protein phosphorylation. The majority of regulated phosphorylation events can be assigned to an upstream kinase by inhibiting master kinases. Spatial proteomics reveals phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovers a key role for transcriptional cyclin-dependent kinase activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. This resource of TNF-induced pathways and sites can be explored at

Perturbation solutions of fifth order oscillatory nonlinear systems

Oscillatory systems play an important role in the nature. Many engineering problems and physical systems of fifth degrees of freedom are oscillatory and their governing equations are fifth order nonlinear differential equations. To investigate the solution of fifth order weakly nonlinear oscillatory systems, in this article the Krylov–Bogoliubov–Mitropolskii (KBM) method has been extended and desired solution is found. An example is solved to illustrate the method. The results obtain by the extended KBM method show good agreement with those obtained by numerical method

Quantitative and Dynamic Catalogs of Proteins Released during Apoptotic and Necroptotic Cell Death

The inflammatory functions of the cytokine tumor necrosis factor (TNF) rely on its ability to induce cytokine production and to induce cell death. Caspase-dependent and caspase-independent pathways-apoptosis and necroptosis, respectively-regulate immunogenicity by the release of distinct sets of cellular proteins. To obtain an unbiased, systems-level understanding of this important process, we here applied mass spectrometry-based proteomics to dissect protein release during apoptosis and necroptosis. We report hundreds of proteins released from human myeloid cells in time course experiments. Both cell death types induce receptor shedding, but only apoptotic cells released nucleosome components. Conversely, necroptotic cells release lysosomal components by activating lysosomal exocytosis at early stages of necroptosis-induced membrane permeabilization and show reduced release of conventionally secreted cytokines