Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo. To address this unmet need, we synthesized and characterized a mitochondria-targeted redox cycler, MitoParaquat (MitoPQ) that comprises a triphenylphosphonium lipophilic cation conjugated to the redox cycler paraquat. MitoPQ accumulates selectively in the mitochondrial matrix driven by the membrane potential. Within the matrix, MitoPQ produces superoxide by redox cycling at the flavin site of complex I, selectively increasing superoxide production within mitochondria. MitoPQ increased mitochondrial superoxide in isolated mitochondria and cells in culture ~a thousand-fold more effectively than untargeted paraquat. MitoPQ was also more toxic than paraquat in the isolated perfused heart and in Drosophila in vivo. MitoPQ enables the selective generation of superoxide within mitochondria and is a useful tool to investigate the many roles of mitochondrial superoxide in pathology and redox signaling in cells and in vivo

3D multi-robot patrolling with a two-level coordination strategy

Teams of UGVs patrolling harsh and complex 3D environments can experience interference and spatial conflicts with one another. Neglecting the occurrence of these events crucially hinders both soundness and reliability of a patrolling process. This work presents a distributed multi-robot patrolling technique, which uses a two-level coordination strategy to minimize and explicitly manage the occurrence of conflicts and interference. The first level guides the agents to single out exclusive target nodes on a topological map. This target selection relies on a shared idleness representation and a coordination mechanism preventing topological conflicts. The second level hosts coordination strategies based on a metric representation of space and is supported by a 3D SLAM system. Here, each robot path planner negotiates spatial conflicts by applying a multi-robot traversability function. Continuous interactions between these two levels ensure coordination and conflicts resolution. Both simulations and real-world experiments are presented to validate the performances of the proposed patrolling strategy in 3D environments. Results show this is a promising solution for managing spatial conflicts and preventing deadlocks

Data and performances evaluation of the SPIDIA-DNA Pan-European External Quality Assessment: 2nd SPIDIA-DNA laboratory report.

AbstractWithin the EU-SPIDIA project (www.spidia.eu), the quality parameters of blood genomic DNA were defined [SPIDIA-DNA: an External Quality Assessment for the pre-analytical phase of blood samples used for DNA-based analyses – [1]; Influence of pre-analytical procedures on genomic DNA integrity in blood samples: the SPIDIA experience – [2]; Combining qualitative and quantitative imaging evaluation for the assessment of genomic DNA integrity: the SPIDIA experience – [3]. DNA quality parameters were used to evaluate the laboratory performance within an External Quality Assessment (EQA) [Second SPIDIA-DNA External Quality Assessment (EQA): Influence of pre-analytical phase of blood samples on genomic DNA quality – [4]. These parameters included DNA purity and yield by UV spectrophotometric measurements, the presence of PCR interferences by Kineret software and genomic DNA integrity analysis by Pulsed Field Gel Electrophoresis.Here we present the specific laboratory report of the 2nd SPIDIA-DNA EQA as an example of data and performances evaluation

Reviews

The following publications have been reviewed by the mentioned authors;Supporting Science, Design and Technology in the Early Years - reviewed by Alan CrossDazzle Plus - reviewed by David FosterDesign and Bake - Wheat and Other Cereals - reviewed by Marion RutlandDesign and Technology and the Historic Environment - reviewed by Michael LawrenceThe Millennium Train - reviewed by Chris SnellGCSE Food Technology for OCR: Pupil Book and Teacher's Resource File - reviewed by Roy BallamRaising Achievement in Design and Technology: Resistant Materials - reviewed by Roman M. GawelThe Possibilities Schools - A Blueprint for Education - reviewed by Andy BreckonKites Resource Pack: Key Stage 3 Design and Technology - reviewed by Mark HudsonICT and the Learning Revolution - reviewed by Les Porte

Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing

Reviews

The following publications have been reviewed by the mentioned authors;Let's Go Bananas with Fyffes - reviewed by Melanie FasciatoLiquids Mean Life - reviewed by Jonty KinsellaDesign and Make It! Food Technology for KS3 - reviewed by Dawn WilliamsFidget - reviewed by George AsquithFinding out about Managing Waste - reviewed by Ann MacGarryHands on! - reviewed by Les PorterSkills in Graphic Products and Teacher's Resource Pack - reviewed by Michael LawranceResistant Materials to GCSE - reviewed by Roman M. GawelInventing the Modern World - reviewed by David SpendloveC for PICmicro Microcontrollers - reviewed by David FosterHow Things Work Today - reviewed by Mark HudsonMachi-work: Education for Participation - reviewed by Maggie RogersOne Good Turn - reviewed by John Egglesto

Nonrandom Distribution of Interhomolog Recombination Events Induced by Breakage of a Dicentric Chromosome in Saccharomyces cerevisiae

Dicentric chromosomes undergo breakage in mitosis, resulting in chromosome deletions, duplications, and translocations. In this study, we map chromosome break sites of dicentrics in Saccharomyces cerevisiae by a mitotic recombination assay. The assay uses a diploid strain in which one homolog has a conditional centromere in addition to a wild-type centromere, and the other homolog has only the wild-type centromere; the conditional centromere is inactive when cells are grown in galactose and is activated when the cells are switched to glucose. In addition, the two homologs are distinguishable by multiple single-nucleotide polymorphisms (SNPs). Under conditions in which the conditional centromere is activated, the functionally dicentric chromosome undergoes double-stranded DNA breaks (DSBs) that can be repaired by mitotic recombination with the homolog. Such recombination events often lead to loss of heterozygosity (LOH) of SNPs that are centromere distal to the crossover. Using a PCR-based assay, we determined the position of LOH in multiple independent recombination events to a resolution of ∼4 kb. This analysis shows that dicentric chromosomes have recombination breakpoints that are broadly distributed between the two centromeres, although there is a clustering of breakpoints within 10 kb of the conditional centromere