The mycotoxin phomoxanthone A disturbs the form and function of the inner mitochondrial membrane.

Mitochondria are cellular organelles with crucial functions in the generation and distribution of ATP, the buffering of cytosolic Ca2+ and the initiation of apoptosis. Compounds that interfere with these functions are termed mitochondrial toxins, many of which are derived from microbes, such as antimycin A, oligomycin A, and ionomycin. Here, we identify the mycotoxin phomoxanthone A (PXA), derived from the endophytic fungus Phomopsis longicolla, as a mitochondrial toxin. We show that PXA elicits a strong release of Ca2+ from the mitochondria but not from the ER. In addition, PXA depolarises the mitochondria similarly to protonophoric uncouplers such as CCCP, yet unlike these, it does not increase but rather inhibits cellular respiration and electron transport chain activity. The respiration-dependent mitochondrial network structure rapidly collapses into fragments upon PXA treatment. Surprisingly, this fragmentation is independent from the canonical mitochondrial fission and fusion mediators DRP1 and OPA1, and exclusively affects the inner mitochondrial membrane, leading to cristae disruption, release of pro-apoptotic proteins, and apoptosis. Taken together, our results suggest that PXA is a mitochondrial toxin with a novel mode of action that might prove a useful tool for the study of mitochondrial ion homoeostasis and membrane dynamics

Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

Development and Initial Validation of the Humor Climate in Sport Scale Running Head: Humor climate in sport

In sport teams, humor is an essential element that influences communication processes, and plays an important role in group dynamics. Despite this, no current instrument is presented in the literature to measure humor climate in sport teams. Therefore, the current study presents the development and initial validation of the Humor Climate in Sport Scale (HCSS). The aim was to assess content, structural and concurrent validity of the developed instrument, and to examine differential item functioning (DIF) as a function of sex. Three different phases were completed in this study. The first phase involved focus groups (n = 5) that explored humor as communication in a team sport context. In phase 2, information from the focus groups was used to create a pool of potential items for the questionnaire. Two discussion groups with sport science students contributed to the development of 80 potential items, that two different expert groups then assessed for item quality. The final version of the instrument after this phase contained 14 items, representing three different humor dimensions. In phase 3, two independent samples with a total number of 776 participants were recruited for the psychometric evaluation of the instrument. EFA, ICM-CFA, and ESEM analysis were performed, supporting a three-factor structure with positive humor, negative humor in-group, and negative humor out-group. In addition, partial DIF as a function of sex on the negative humor dimensions was found, indicating differences in how male and female interpret the negative humor items. The findings in the current study expand our understanding of humor in sport teams and may be a starting point for further research on humor climate in sport teams and its role in group function

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field

Creation of multiple nanodots by single ions

In the challenging search for tools that are able to modify surfaces on the nanometer scale, heavy ions with energies of several 10 MeV are becoming more and more attractive. In contrast to slow ions where nuclear stopping is important and the energy is dissipated into a large volume in the crystal, in the high energy regime the stopping is due to electronic excitations only. Because of the extremely local (< 1 nm) energy deposition with densities of up to 10E19 W/cm^2, nanoscaled hillocks can be created under normal incidence. Usually, each nanodot is due to the impact of a single ion and the dots are randomly distributed. We demonstrate that multiple periodically spaced dots separated by a few 10 nanometers can be created by a single ion if the sample is irradiated under grazing angles of incidence. By varying this angle the number of dots can be controlled.Comment: 12 pages, 6 figure

Dynamic and thermodynamic properties of the generalised diamond chain model for azurite

The natural mineral azurite Cu3(CO3)2(OH)2 is an interesting spin-1/2 quantum antiferromagnet. Recently, a generalised diamond chain model has been established as a good description of the magnetic properties of azurite with parameters placing it in a highly frustrated parameter regime. Here we explore further properties of this model for azurite. First, we determine the inelastic neutron scattering spectrum in the absence of a magnetic field and find good agreement with experiments, thus lending further support to the model. Furthermore, we present numerical data for the magnetocaloric effect and predict that strong cooling should be observed during adiabatic (de)magnetisation of azurite in magnetic fields slightly above 30T. Finally, the presence of a dominant dimer interaction in azurite suggests the use of effective Hamiltonians for an effective low-energy description and we propose that such an approach may be useful to fully account for the three-dimensional coupling geometry.Comment: 19 pages, 6 figures; to appear in: J. Phys.: Condens. Matter (special issue on geometrically frustrated magnetism

A systematic approach to designing reliable VV optimization methodology: Assessment of internal validity of echocardiographic, electrocardiographic and haemodynamic optimization of cardiac resynchronization therapy

AbstractBackgroundIn atrial fibrillation (AF), VV optimization of biventricular pacemakers can be examined in isolation. We used this approach to evaluate internal validity of three VV optimization methods by three criteria.Methods and resultsTwenty patients (16 men, age 75±7) in AF were optimized, at two paced heart rates, by LVOT VTI (flow), non-invasive arterial pressure, and ECG (minimizing QRS duration). Each optimization method was evaluated for: singularity (unique peak of function), reproducibility of optimum, and biological plausibility of the distribution of optima.The reproducibility (standard deviation of the difference, SDD) of the optimal VV delay was 10ms for pressure, versus 8ms (p=ns) for QRS and 34ms (p<0.01) for flow.Singularity of optimum was 85% for pressure, 63% for ECG and 45% for flow (Chi2=10.9, p<0.005).The distribution of pressure optima was biologically plausible, with 80% LV pre-excited (p=0.007). The distributions of ECG (55% LV pre-excitation) and flow (45% LV pre-excitation) optima were no different to random (p=ns).The pressure-derived optimal VV delay is unaffected by the paced rate: SDD between slow and fast heart rate is 9ms, no different from the reproducibility SDD at both heart rates.ConclusionsUsing non-invasive arterial pressure, VV delay optimization by parabolic fitting is achievable with good precision, satisfying all 3 criteria of internal validity. VV optimum is unaffected by heart rate. Neither QRS minimization nor LVOT VTI satisfy all validity criteria, and therefore seem weaker candidate modalities for VV optimization. AF, unlinking interventricular from atrioventricular delay, uniquely exposes resynchronization concepts to experimental scrutiny

Modeling Policy and Agricultural Decisions in Afghanistan

Afghanistan is responsible for the majority of the world's supply of poppy crops, which are often used to produce illegal narcotics like heroin. This paper presents an agent-based model that simulates policy scenarios to characterize how the production of poppy can be dampened and replaced with licit crops over time. The model is initialized with spatial data, including transportation network and satellite-derived land use data. Parameters representing national subsidies, insurgent influence, and trafficking blockades are varied to represent different conditions that might encourage or discourage poppy agriculture. Our model shows that boundary-level interventions, such as targeted trafficking blockades at border locations, are critical in reducing the attractiveness of growing this illicit crop. The principle of least effort implies that interventions decrease to a minimal non-regressive point, leading to the prediction that increases in insurgency or other changes are likely to lead to worsening conditions, and improvements require substantial jumps in intervention resources.Comment: 16 pages, 5 figures; GeoJournal, 2012, 10.1007/s10708-012-9453-

Thermoelectric properties of lead chalcogenide core-shell nanostructures

We present the full thermoelectric characterization of nanostructured bulk PbTe and PbTe-PbSe samples fabricated from colloidal core-shell nanoparticles followed by spark plasma sintering. An unusually large thermopower is found in both materials, and the possibility of energy filtering as opposed to grain boundary scattering as an explanation is discussed. A decreased Debye temperature and an increased molar specific heat are in accordance with recent predictions for nanostructured materials. On the basis of these results we propose suitable core-shell material combinations for future thermoelectric materials of large electric conductivities in combination with an increased thermopower by energy filtering.Comment: 12 pages, 8 figure