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SUMMARY Oxidative stress as a contributor to neuronal death during prion infection is supported by the fact that various oxidative damage markers accumulate in the brain during the course of this disease. The normal cellular substrate of the causative agent, the prion protein, is also linked with protective functions against oxidative stress. Our previous work has found that, in chronic prion infection, an apoptotic subpopulation of cells exhibit oxidative stress and the accumulation of oxidised lipid and protein aggregates with caspase recruitment. Given the likely failure of antioxidant defence mechanisms within apoptotic prion-infected cells, we aimed to investigate the role of the crucial antioxidant pathway components, superoxide dismutases (SOD) 1 and 2, in an in vitro model of chronic prion infection. Increased total SOD activity, attributable to SOD1, was found in the overall population coincident with a decrease in SOD2 protein levels. When apoptotic cells were separated from the total population, the induction of SOD activity in the infected apoptotic cells was lost, with activity reduced back to levels seen in mock-infected control cells. In addition, mitochondrial superoxide production was increased and mitochondrial numbers decreased in the infected apoptotic subpopulation. Furthermore, a pan-caspase probe colocalised with SOD2 outside of mitochondria within cytosolic aggregates in infected cells and inhibition of caspase activity was able to restore cellular levels of SOD2 in the whole unseparated infected population to those of mock-infected control cells. Our results suggest that prion propagation exacerbates an apoptotic pathway whereby mitochondrial dysfunction follows mislocalisation of SOD2 to cytosolic caspases, permitting its degradation. Eventually, cellular capacity to maintain oxidative homeostasis is overwhelmed, thus resulting in cell death

On the consistency of Lorentz invariance violation in QED induced by fermions in constant axial-vector background

We show for the first time that the induced parity--even Lorentz invariance violation can be unambiguously calculated in the physically justified and minimally broken dimensional regularization scheme, suitably tailored for a spontaneous Lorentz symmetry breaking in a field theory model. The quantization of the Lorentz invariance violating quantum electrodynamics is critically examined and shown to be consistent either for a light--like cosmic anisotropy axial--vector or for a time--like one, when in the presence of a bare photon mass.Comment: 10 pages, revised for publication in Phys.Lett.

The ‘Healthy Dads, Healthy Kids’ community effectiveness trial: study protocol of a community-based healthy lifestyle program for fathers and their children

Background: The \u27Healthy Dads, Healthy Kids\u27 program was designed to help overweight fathers lose weight and positively influence the health behaviors of their children. The aim of the current study was to evaluate the previously established program in a community setting, in a large effectiveness trial. Methods/Design: The Healthy Dads, Healthy Kids community trial consists of three stages: (i) Stage 1 - program refinement and resource development (ii) Stage 2 - community randomized controlled trial (iii) Stage 3 - community effectiveness trial. The program will be evaluated in five Local Government Areas in the Hunter Valley Region of NSW, Australia. For the community randomized controlled trial, 50 overweight/obese men (aged 18-65 years) from one Local Government Area with a child aged between 5-12 years of age will be recruited. Families will be randomized to either the program or a 6-month wait-list control group. Fathers and their children will be assessed at baseline, post-intervention (3-months) and 6-months. Inclusion criteria are: body mass index 25-40 kg/m2; no participation in other weight loss programs during the study; pass a health-screening questionnaire; and access to a computer with Internet facilities. In the community trial, the program will be evaluated using a non-randomized, prospective design in five Local Government Areas. The exclusion criteria is body mass index \u3c 25 kg/m2 or lack of doctor\u27s approval. Measures will be collected at baseline, 3-, 6- and 12-months. The program involves fathers attending seven face-to-face group sessions (three with children) over 3-months. Measures: The primary outcome is fathers\u27 weight. Secondary outcomes for both fathers and children include: waist circumference, blood pressure, resting heart rate, physical activity, sedentary behaviors and dietary intake. Father-only measures include portion size, alcohol consumption, parenting for physical activity and nutrition and parental engagement. Process evaluation will determine the fidelity, dose (delivered and received), reach, recruitment and context of the program. Discussion: As a unique approach to reducing obesity prevalence in men and improving lifestyle behaviours in children, our findings will provide important evidence relating to the translation of Healthy Dads, Healthy Kids, which will enable it to be delivered on a larger scale

The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles

Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6–9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane

Predicting COVID-19 infection risk in people who are immunocompromised by antibody testing.

People with blood cancers have an increased risk of severe COVID-19 disease despite booster vaccine doses.1 This group, like other disease groups at increased risk of severe COVID-19, includes individuals with highly heterogeneous immune responses to vaccination.2 Although vaccine response studies and population studies identify similar diseases and treatments associated with increased risk of severe COVID-19, a direct correlation between antibody levels after vaccination and infection risk has been difficult to define. Identification of a laboratory correlate of infection risk would allow doctors and policy makers to target additional COVID-19 treatment or prophylactic efforts to people who are most in need

Reducing Constraints in a Higher Dimensional Extension of the Randall and Sundrum Model

In order to investigate the phenomenological implications of warped spaces in more than five dimensions, we consider a $4+1+\delta$ dimensional extension to the Randall and Sundrum model in which the space is warped with respect to a single direction by the presence of an anisotropic bulk cosmological constant. The Einstein equations are solved, giving rise to a range of possible spaces in which the $\delta$ additional spaces are warped. Here we consider models in which the gauge fields are free to propagate into such spaces. After carrying out the Kaluza Klein (KK) decomposition of such fields it is found that the KK mass spectrum changes significantly depending on how the $\delta$ additional dimensions are warped. We proceed to compute the lower bound on the KK mass scale from electroweak observables for models with a bulk $SU(2)\times U(1)$ gauge symmetry and models with a bulk $SU(2)_R\times SU(2)_L\times U(1)$ gauge symmetry. It is found that in both cases the most favourable bounds are approximately $M_{KK}\gtrsim 2$ TeV, corresponding to a mass of the first gauge boson excitation of about 4-6 TeV. Hence additional warped dimensions offer a new way of reducing the constraints on the KK scale.Comment: 27 pages, 15 figures, v3: Additional comments in sections 1, 2 and 4. New appendix added. Five additional figures. References adde

Understanding and protecting vulnerable financial consumers

This article considers how consumer protection law and policy should address the interests of particularly vulnerable financial consumers. Specifically, the article proposes a taxonomy of vulnerability which helps to identify (a) what makes consumers particularly vulnerable, and (b) how consumer protection law and consumer policy (broadly understood) can respond to these causes in a way that provides such consumers with appropriate protection. Changes to economic conditions, legal requirements on traders and our understanding of consumer behaviour make discussion of these issues particularly topical. There is little doubt that finding solutions is extremely difficult. Trade-offs are necessary and some enduring factors that contribute to vulnerability, in particular poverty, sometimes appear intractable. Nevertheless, it is submitted that by identifying clearly both why consumers are vulnerable and how the factors that lead to such vulnerability can be addressed, it is possible to construct an environment which respects consumer choice while ensuring that the most vulnerable are protected appropriately

Screening archaeological bone for palaeogenetic and palaeoproteomic studies.

The recovery and analysis of ancient DNA and protein from archaeological bone is time-consuming and expensive to carry out, while it involves the partial or complete destruction of valuable or rare specimens. The fields of palaeogenetic and palaeoproteomic research would benefit greatly from techniques that can assess the molecular quality prior to sampling. To be relevant, such screening methods should be effective, minimally-destructive, and rapid. This study reports results based on spectroscopic (Fourier-transform infrared spectroscopy in attenuated total reflectance [FTIR-ATR]; n = 266), palaeoproteomic (collagen content; n = 226), and palaeogenetic (endogenous DNA content; n = 88) techniques. We establish thresholds for three different FTIR indices, a) the infrared splitting factor [IRSF] that assesses relative changes in bioapatite crystals' size and homogeneity; b) the carbonate-to-phosphate [C/P] ratio as a relative measure of carbonate content in bioapatite crystals; and c) the amide-to-phosphate ratio [Am/P] for assessing the relative organic content preserved in bone. These thresholds are both extremely reliable and easy to apply for the successful and rapid distinction between well- and poorly-preserved specimens. This is a milestone for choosing appropriate samples prior to genomic and collagen analyses, with important implications for biomolecular archaeology and palaeontology

Myeloid 12/15-LOX regulates B cell numbers and innate immune antibody levels in vivo

Background. The myeloid enzyme 12/15-lipoxygenase (LOX), which generates bioactive oxidized lipids, has been implicated in numerous inflammatory diseases, with several studies demonstrating an improvement in pathology in mice lacking the enzyme. However, the ability of 12/15-LOX to directly regulate B cell function has not been studied. Methods. The influence of 12/15-LOX on B cell phenotype and function, and IgM generation, was compared using wildtype (WT) and 12/15-LOX (Alox15-/-) deficient mice. The proliferative and functional capacity of splenic CD19+ B cells was measured in vitro in response to various toll-like receptor agonists. Results. WT and Alox15-/- displayed comparable responses. However in vivo, splenic B cell numbers were significantly elevated in Alox15-/- mice with a corresponding elevation in titres of total IgM in lung, gut and serum, and lower serum IgM directed against the 12/15-LOX product, 12-hydroxyeicosatetraenoic acid-phosphatidylethanolamine (HETE-PE). Discussion. Myeloid 12/15-LOX can regulate B cell numbers and innate immune antibody levels in vivo, potentially contributing to its ability to regulate inflammatory disease. Furthermore, the alterations seen in 12/15-LOX deficiency likely result from changes in the equilibrium of the immune system that develop from birth. Further studies in disease models are warranted to elucidate the contribution of 12/15-LOX mediated alterations in B cell numbers and innate immune antibody generation to driving inflammation in vivo