Interatomic scattering in energy dependent photoelectron spectra of Ar clusters

Soft X-ray photoelectron spectra of Ar 2p levels of atomic argon and argon clusters are recorded over an extended range of photon energies. The Ar 2p intensity ratios between atomic argon and clusters’ surface and bulk components reveal oscillations similar to photoelectron extended X-ray absorption fine structure signal (PEXAFS). We demonstrate here that this technique allows us to analyze separately the PEXAFS signals from surface and bulk sites of free-standing, neutral clusters, revealing a bond contraction at the surface

Conformational changes and protein stability of the pro-apoptotic protein Bax

Pro-apoptotic Bax is a soluble and monomeric protein under normal physiological conditions. Upon its activation substantial structural rearrangements occur: The protein inserts into the mitochondrial outer membrane and forms higher molecular weight oligomers. Subsequently, the cells can undergo apoptosis. In our studies, we focused on the structural rearrangements of Bax during oligomerization and on the protein stability. Both protein conformations exhibit high stability against thermal denaturation, chemically induced unfolding and proteolytic processing. The oligomeric protein is stable up to 90 °C as well as in solutions of 8 M urea or 6 M guanidinium hydrochloride. Helix 9 appears accessible in the monomer but hidden in the oligomer assessed by proteolysis. Tryptophan fluorescence indicates that the environment of the C-terminal protein half becomes more apolar upon oligomerization, whereas the loop region between helices 1 and 2 gets solvent exposed

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

The Indigenous Australian Human Papillomavirus (HPV) Cohort Study 2, Continuation for 5 to 10 Years: Protocol for a Longitudinal Study

Background: Human papillomavirus (HPV) infection, a common sexually transmitted disease, is associated with cancers of the cervix, vulva, vagina, penis, anus, and head and neck. Oropharyngeal squamous cell carcinoma (OPSCC; throat cancer) is a type of cancer involving the head and neck area that is rapidly increasing across the globe. There are higher rates of OPSCC among Indigenous populations relative to non–Indigenous Australian populations, although the HPV-attributable fraction remains unknown. For the first time at a global level, we plan to extend an Indigenous Australian adult cohort to monitor, screen, and ultimately prevent HPV-associated OPSCC and to undertake extensive cost-effectiveness modelling around HPV vaccination. Objective: This study aims to (1) extend follow-up to a minimum of 7 years post recruitment to describe the prevalence, incidence, clearance, and persistence of oral HPV infection; and (2) conduct clinical examinations of the head and neck, oral cavity, and oropharynx and collect saliva samples for early-stage OPSCC testing. Methods: We will continue to implement a longitudinal design for the next study phase, where we will ascertain the prevalence, incidence, clearance, and persistence of oral HPV infection at 48, 60, and 72 months; undertake clinical examinations/saliva assessments to detect early-stage OPSCC; and refer for treatment. The primary outcome measures are changes in oral HPV infection status, biomarker measures of early HPV-related cancer, and clinical evidence of early-stage OPSCC. Results: Participant 48-month follow-up will commence in January 2023. The first results are expected to be submitted for publication 1 year after 48-month follow-up begins. Conclusions: Our findings have potential to change the way in which OPSCC among Australian Indigenous adults is managed, with desired impacts including cost-savings on expensive cancer treatments; improved nutritional, social, and emotional outcomes; and improved quality of life for both Indigenous adults and the Indigenous community more broadly. Continuing a large, representative Indigenous adult cohort to track oral HPV infection and monitor early OPSCC is essential to yield critical information to include in the management armamentarium of health and well-being recommendations for Australia’s First Nations.Joanne Hedges, Sneha Sethi, Gail Garvey, Lisa J Whop, Karen Canfell, Zell Dodd, Priscilla Larkins, Annika Antonsson, Megan A Smith, Murthy Mittinty, Catherine Leane, Nicolas Reid, Eng H Ooi, Xiangqun Ju, Richard Logan, Lisa Jamieso

Human papillomavirus and oropharyngeal cancer among Indigenous Australians: protocol for a prevalence study of oral-related human papillomavirus and cost-effectiveness of prevention

Background: Oropharyngeal cancer is an important, understudied cancer affecting Aboriginal and Torres Strait Islander Australians. The human papillomavirus (HPV) is a significant risk factor for oropharyngeal cancer. Current generation HPV vaccines are effective against the 2 most common types of high-risk HPVs in cancer (hrHPVs 16/18). Objectives: This study aims (1) to yield population estimates of oncogenic genotypes of HPV in the mouth and oropharynx of defined Aboriginal and Torres Strait Islander populations; (2) to estimate the proportion of oropharyngeal cancer attributable to HPV among these Australian citizens; (3) to estimate the impact of HPV vaccination as currently implemented on rates of oropharyngeal cancer among Aboriginal and Torres Strait Islander Australians; and (4) taking into account impact on oropharyngeal as well as cervical cancer, to evaluate efficacy and cost-effectiveness of targeted extended HPV vaccination to older ages, among our study population. Methods: Our study design and operation is straightforward, with minimal impost on participants. It involves testing for carriage of hrHPV in the mouth and oropharynx among 1000 Aboriginal South Australians by simple saliva collection and with follow-up at 12 and 24 months, collection of sexual history at baseline, collection of information for estimating health state (quality-of-life) utilities at baseline, genotyping of viruses, predictive outcome and cost-effectiveness modeling, data interpretation and development of vaccination, and follow-up management strategies driven by the Aboriginal community. Results: Participant recruitment for this study commenced in February 2018 and enrollment is ongoing. The first results are expected to be submitted for publication in 2019. Conclusions: The project will have a number of important outcomes. Synthesis of evidence will enable generation of estimates of the burden of oropharyngeal cancer among Aboriginal and Torres Strait Islander Australians and indicate the likely effectiveness and cost-effectiveness of prevention. This will be important for health services planning, and for Aboriginal health worker and patient education. The results will also point to important areas where research efforts should be focused to improve outcomes in Aboriginal and Torres Strait Islander Australians with oropharyngeal cancer. There will be a strong focus on community engagement and accounting for the preferences of individuals and the community in control of HPV-related cancers. The project has international relevance in that it will be the first to systematically evaluate prevention of both cervical and oropharyngeal cancer in a high-risk Indigenous population taking into account all population, testing, and surveillance options.Lisa Jamieson, Gail Garvey, Joanne Hedges, Amanda Mitchell, Terry Dunbar, Cathy Leane, Isaac Hill, Kate Warren, Alex Brown, Xiangqun Ju, David Roder, Richard Logan, Newell Johnson, Megan Smith, Annika Antonsson, Karen Canfel

Exploitation of Herpesviral Transactivation Allows Quantitative Reporter Gene-Based Assessment of Virus Entry and Neutralization

Herpesviral entry is a highly elaborated process requiring many proteins to act in precise conjunction. Neutralizing antibodies interfere with this process to abrogate viral infection. Based on promoter transactivation of a reporter gene we established a novel method to quantify herpesvirus entry and neutralization by antibodies. Following infection with mouse and human cytomegalovirus and Herpes simplex virus 1 we observed promoter transactivation resulting in substantial luciferase expression (>1000-fold). No induction was elicited by UV-inactivated viruses. The response was MOI-dependent and immunoblots confirmed a correlation between luciferase induction and pp72-IE1 expression. Monoclonal antibodies, immune sera and purified immunoglobulin preparations decreased virus-dependent luciferase induction dose-dependently, qualifying this approach as surrogate virus neutralization test. Besides the reduced hands-on time, this assay allows analysis of herpesvirus entry in semi-permissive and non-adherent cells, which were previously non-assessable but play significant roles in herpesvirus pathology

Construction and analysis of a modular model of caspase activation in apoptosis

<p>Abstract</p> <p>Background</p> <p>A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic) and intracellular (intrinsic) signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC) and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins.</p> <p>Results</p> <p>A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines.</p> <p>Conclusion</p> <p>Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.</p

The Alpine Cushion Plant Silene acaulis as Foundation Species: A Bug’s-Eye View to Facilitation and Microclimate

Alpine ecosystems are important globally with high levels of endemic and rare species. Given that they will be highly impacted by climate change, understanding biotic factors that maintain diversity is critical. Silene acaulis is a common alpine nurse plant shown to positively influence the diversity and abundance of organisms–predominantly other plant species. The hypothesis that cushion or nurse plants in general are important to multiple trophic levels has been proposed but rarely tested. Alpine arthropod diversity is also largely understudied worldwide, and the plant-arthropod interactions reported are mostly negative, that is,. herbivory. Plant and arthropod diversity and abundance were sampled on S. acaulis and at paired adjacent microsites with other non-cushion forming vegetation present on Whistler Mountain, B.C., Canada to examine the relative trophic effects of cushion plants. Plant species richness and abundance but not Simpson’s diversity index was higher on cushion microsites relative to other vegetation. Arthropod richness, abundance, and diversity were all higher on cushion microsites relative to other vegetated sites. On a microclimatic scale, S. acaulis ameliorated stressful conditions for plants and invertebrates living inside it, but the highest levels of arthropod diversity were observed on cushions with tall plant growth. Hence, alpine cushion plants can be foundation species not only for other plant species but other trophic levels, and these impacts are expressed through both direct and indirect effects associated with altered environmental conditions and localized productivity. Whilst this case study tests a limited subset of the membership of alpine animal communities, it clearly demonstrates that cushion-forming plant species are an important consideration in understanding resilience to global changes for many organisms in addition to other plants

Role of Mitofusin 2 in the Renal Stress Response

The role of mitofusin 2 (MFN2), a key regulator of mitochondrial morphology and function in the renal stress response is unknown. To assess its role, the MFN2 floxed gene was conditionally deleted in the kidney of mice (MFN2 cKO) by Pax2 promoter driven Cre expression (Pax2Cre). MFN2 cKO caused severe mitochondrial fragmentation in renal epithelial cells that are critical for normal kidney tubular function. However, despite a small (20%) decrease in nephron number, newborn cKO pups had organ or tubular function that did not differ from littermate Cre-negative pups. MFN2 deficiency in proximal tubule epithelial cells in primary culture induced mitochondrial fragmentation but did not significantly alter ATP turnover, maximal mitochondrial oxidative reserve capacity, or the low level of oxygen consumption during cyanide exposure. MFN2 deficiency also did not increase apoptosis of tubule epithelial cells under non-stress conditions. In contrast, metabolic stress caused by ATP depletion exacerbated mitochondrial outer membrane injury and increased apoptosis by 80% in MFN2 deficient vs. control cells. Despite similar stress-induced Bax 6A7 epitope exposure in MFN2 deficient and control cells, MFN2 deficiency significantly increased mitochondrial Bax accumulation and was associated with greater release of both apoptosis inducing factor and cytochrome c. In conclusion, MFN2 deficiency in the kidney causes mitochondrial fragmentation but does not affect kidney or tubular function during development or under non-stress conditions. However, MFN2 deficiency exacerbates renal epithelial cell injury by promoting Bax-mediated mitochondrial outer membrane injury and apoptosis