DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites

The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development

Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress

Acknowledgments We thank Alexander Johnson (yhb1D/D), Karl Kuchler (sodD/D mutants), Janet Quinn (hog1D/D, hog1/cap1D/D, trx1D/D) and Peter Staib (ssu1D/D) for providing mutant strains. We acknowledge helpful discussions with our colleagues from the Microbial Pathogenicity Mechanisms Department, Fungal Septomics and the Microbial Biochemistry and Physiology Research Group at the Hans Kno¨ll Institute (HKI), specially Ilse D. Jacobsen, Duncan Wilson, Sascha Brunke, Lydia Kasper, Franziska Gerwien, Sea´na Duggan, Katrin Haupt, Kerstin Hu¨nniger, and Matthias Brock, as well as from our partners in the FINSysB Network. Author Contributions Conceived and designed the experiments: PM HW IMB AJPB OK BH. Performed the experiments: PM CD HW. Analyzed the data: PM HW IMB AJPB OK BH. Wrote the paper: PM HW OK AJPB BH.Peer reviewedPublisher PD

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Αξιολόγηση εξωτερικοτήτων εγκαταστάσεων βιοαερίου

Fusarium oxysporum f. sp. cubense tropical race 4 (TR4) is reported for the first time in northern Queensland, the centre of Australia’s commercial banana production. The identity of the pathogen was confirmed by vegetative compatibility group testing, TR4 specific PCR tests and sequencing. Although presently confined to a single property, the disease poses a serious threat to Australia’s banana industry

Stress corrosion cracking in Al-Zn-Mg-Cu aluminum alloys in saline environments

Copyright 2013 ASM International. This paper was published in Metallurgical and Materials Transactions A, 44A(3), 1230 - 1253, and is made available as an electronic reprint with the permission of ASM International. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplications of any material in this paper for a fee or for commercial purposes, or modification of the content of this paper are prohibited.Stress corrosion cracking of Al-Zn-Mg-Cu (AA7xxx) aluminum alloys exposed to saline environments at temperatures ranging from 293 K to 353 K (20 °C to 80 °C) has been reviewed with particular attention to the influences of alloy composition and temper, and bulk and local environmental conditions. Stress corrosion crack (SCC) growth rates at room temperature for peak- and over-aged tempers in saline environments are minimized for Al-Zn-Mg-Cu alloys containing less than ~8 wt pct Zn when Zn/Mg ratios are ranging from 2 to 3, excess magnesium levels are less than 1 wt pct, and copper content is either less than ~0.2 wt pct or ranging from 1.3 to 2 wt pct. A minimum chloride ion concentration of ~0.01 M is required for crack growth rates to exceed those in distilled water, which insures that the local solution pH in crack-tip regions can be maintained at less than 4. Crack growth rates in saline solution without other additions gradually increase with bulk chloride ion concentrations up to around 0.6 M NaCl, whereas in solutions with sufficiently low dichromate (or chromate), inhibitor additions are insensitive to the bulk chloride concentration and are typically at least double those observed without the additions. DCB specimens, fatigue pre-cracked in air before immersion in a saline environment, show an initial period with no detectible crack growth, followed by crack growth at the distilled water rate, and then transition to a higher crack growth rate typical of region 2 crack growth in the saline environment. Time spent in each stage depends on the type of pre-crack (“pop-in” vs fatigue), applied stress intensity factor, alloy chemistry, bulk environment, and, if applied, the external polarization. Apparent activation energies (E a) for SCC growth in Al-Zn-Mg-Cu alloys exposed to 0.6 M NaCl over the temperatures ranging from 293 K to 353 K (20 °C to 80 °C) for under-, peak-, and over-aged low-copper-containing alloys (~0.8 wt pct), they are typically ranging from 20 to 40 kJ/mol for under- and peak-aged alloys, and based on limited data, around 85 kJ/mol for over-aged tempers. This means that crack propagation in saline environments is most likely to occur by a hydrogen-related process for low-copper-containing Al-Zn-Mg-Cu alloys in under-, peak- and over-aged tempers, and for high-copper alloys in under- and peak-aged tempers. For over-aged high-copper-containing alloys, cracking is most probably under anodic dissolution control. Future stress corrosion studies should focus on understanding the factors that control crack initiation, and insuring that the next generation of higher performance Al-Zn-Mg-Cu alloys has similar longer crack initiation times and crack propagation rates to those of the incumbent alloys in an over-aged condition where crack rates are less than 1 mm/month at a high stress intensity factor

Blow-off mechanisms of turbulent premixed bluff-body stabilised flames operated with vapourised kerosene fuels

The lean blow-off (LBO) behaviour of unconfined lean premixed blu -body stabilised flames with various fuels was investigated. Methane and vapourised ethanol, heptane, Jet-A1, and an alternative alcohol-derived kerosene (Gevo) were used. OH* chemiluminescence (5 kHz), OH- and Fuel-PLIF (5 kHz), and CH2O-PLIF (10 Hz) were deployed. For all fuels, as the flame approached LBO fragmentation was observed downstream, the two sides of the flame merged at the axis, pockets of OH and CH2O were found in the recirculation zone (RZ), and eventually the individual fragments extinguished. The CH2O seemed to enter into the RZ from downstream early in the LBO process, with reactants following suit at times closer to LBO. During LBO, the integrated OH* signal decreased slowly to zero and the duration of this transition was 25 (d=UBO) in the methane and ethanol flames and 60 (d=UBO) in flames operated with heptane and the two kerosenes (where d is the blu -body diameter and UBO the LBO velocity). This large di erence could be due to re-ignitions of partially-quenched fluid inside the RZ during the LBO event. Additionally, for the same bulk velocity, the kerosene flames blow-o at higher equivalence ratios than the single-component fuelled flames, which is possibly due to the higher Lewis number and lower extinction strain rates of these fuels. The results suggest that the blow-o mechanism is qualitatively similar for each of the fuels; however, the complex chemistry associated with heavy hydrocarbons appears to result in a prolonged LBO event.Cambridge Trust

miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity

miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity

Predicting Energy Requirement for Cooling the Building Using Artificial Neural Network

This paper explores total cooling load during summers and total carbon emissions of a six storey building by using artificial neural network (ANN). Parameters used for the calculation were conduction losses, ventilation losses, solar heat gain and internal gain. The standard back-propagation learning algorithm has been used in the network. The energy performance in buildings is influenced by many factors, such as ambient weather conditions, building structure and characteristics, the operation of sub-level components like lighting and HVAC systems, occupancy and their behavior. This complex situation makes it very difficult to accurately implement the prediction of building energy consumption. The calculated cooling load was 0.87 million kW per year. ANN application showed that data was best fit for the regression coefficient of 0.9955 with best validation performance of 0.41231 in case of conduction losses. To meet out this energy demand various fuel options are presented along with their cost and carbon emission

Ignition probability and lean ignition behaviour of a swirled premixed bluff body stabilised annular combustor

Abstract An experimental investigation was performed in a premixed annular combustor equipped with multiple swirl, bluff body burners to assess the ignition probability and to provide insights into the mechanisms of failure and of successful propagation. The experiments are done at conditions that are close to the lean blow-off limit (LBO) and hence the ignition is difficult and close to the limiting condition when ignition is not possible. Two configurations were employed, with 12 and 18 burners, the mixture velocity was varied between 10 and 30 m/s, and the equivalence ratio (ϕ) between 0.58 and 0.68. Ignition was initiated by a sequence of sparks (2 mm gap, 10 sparks of 10 ms each) and “ignition” is defined as successful ignition of the whole annular combustor. The mechanism of success and failure of the ignition process and the flame propagation patterns were investigated via high-speed imaging (10 kHz) of OH* chemiluminescence. The lean ignition limits were evaluated and compared to the lean blow-off limits, finding the 12-burner configuration is more stable than the 18-burner. It was found that failure is linked to the trapping of the initial flame kernel inside the inner recirculation zone (IRZ) of a single burner adjacent to the spark, followed by localised quenching on the bluff body probably due to heat losses. In contrast, for a successful ignition, it was necessary for the flame kernel to propagate to the adjacent burner or for a flame pocket to be convected downstream in the chamber to grow and start propagating upwards. Finally, the ignition probability (Pign) was obtained for different spark locations. It was found that sparking inside the recirculation zone resulted in Pign ∼ 0 for most conditions, while Pign increased moving the spark away from the bluff-body or placing it between two burners and peaked to Pign ∼ 1 when the spark was located downstream in the combustion chamber, where the velocities are lower and the turbulence less intense. The results provide information on the most favourable conditions for achieving ignition in a complex multi-burner geometry and could help the design and optimisation of realistic gas turbine combustors.EU Project ANNULIGHT (765998