Glucose-6-phosphate tips the balance in modulating apoptosis in cerebellar granule cells

AbstractA metabolic shift from oxidative phosphorylation to glycolysis (i.e. the Warburg effect) occurs in Alzheimer’s disease accompanied by an increase of both activity and level of HK-I. The findings reported here demonstrate that in the early phase of apoptosis VDAC1 activity, but not its protein level, progressively decreases, in concomitance with the physical interaction of HK-I with VDAC1. In the late phase of apoptosis, glucose-6-phosphate accumulation in the cell causes the dissociation of the two proteins, the re-opening of the channel and the recovery of VDAC1 function, resulting in a reawakening of the mitochondrial function, thus inevitably leading to cell death

Rtg signaling sustains mitochondrial respiratory capacity in hog1-dependent osmoadaptation

Mitochondrial RTG-dependent retrograde signaling, whose regulators have been characterized in Saccharomyces cerevisiae, plays a recognized role under various environmental stresses. Of special significance, the activity of the transcriptional complex Rtg1/3 has been shown to be modu-lated by Hog1, the master regulator of the high osmolarity glycerol pathway, in response to osmotic stress. The present work focuses on the role of RTG signaling in salt-induced osmotic stress and its interaction with HOG1. Wild-type and mutant cells, lacking HOG1 and/or RTG genes, are compared with respect to cell growth features, retrograde signaling activation and mitochondrial function in the presence and in the absence of high osmostress. We show that RTG2, the main upstream regulator of the RTG pathway, contributes to osmoadaptation in an HOG1-dependent manner and that, with RTG3, it is notably involved in a late phase of growth. Our data demonstrate that impairment of RTG signaling causes a decrease in mitochondrial respiratory capacity exclusively under os-mostress. Overall, these results suggest that HOG1 and the RTG pathway may interact sequentially in the stress signaling cascade and that the RTG pathway may play a role in inter-organellar metabolic communication for osmoadaptation

Communication between PHEV’s and Smart Grid using Zigbee Protocol

Plug-in-hybrid electric vehicles commonly known as PHEV’s are hybrid electric vehicles that use rechargeable batteries for operation. Since PHEV’s run on electric batteries, they require charging after the charge reaches a certain minimum level. The batteries can be charged using external sources usually a smart grid. This requires a wireless technology that can be used to send the information of the battery charge to the smart grid so that it can be charged. This paper is a detailed description of how this communication can be achieved using the ZigBee wireless technology. The battery level information can be sent to the smart grid using this technology and the smart grid operator can then decide whether the PHEV needs charging or not. If not, the battery can be used to provide Vehicle-to-grid (V2G) services i.e. the charge from the vehicle can be sent back to the grid depending on the will of the vehicle owner. Thus, in this way a system can be developed where in both the PHEV driver and the grid operator can benefit

Coded Aperture and Compton Imaging for the Development of 225^{225}Ac-based Radiopharmaceuticals

Targeted alpha-particle therapy (TAT) has great promise as a cancer treatment. Arguably the most promising TAT radionuclide that has been proposed is $^{225}$Ac. The development of $^{225}$Ac-based radiopharmaceuticals has been hampered due to the lack of effective means to study the daughter redistribution of these agents in small animals at the preclinical stage. The ability to directly image the daughters, namely $^{221}$Fr and $^{213}$Bi, via their gamma-ray emissions would be a boon for preclinical studies. That said, conventional medical imaging modalities, including single photon emission computed tomography (SPECT) based on pinhole collimation, cannot be employed due to sensitivity limitations. As an alternative, we propose the use of both coded aperture and Compton imaging with the former modality suited to the 218-keV gamma-ray emission of $^{221}$Fr and the latter suited to the 440-keV gamma-ray emission of $^{213}$Bi. This work includes coded aperture images of $^{221}$Fr and Compton images of $^{213}$Bi in tumor-bearing mice injected with $^{225}$Ac-based radiopharmaceuticals. These results are the first demonstration of visualizing and quantifying the $^{225}$Ac daughters in small animals via coded aperture and Compton imaging and serve as a stepping stone for future radiopharmaceutical studies

A peptide containing residues 26–44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator

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NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease.

Disarrangement in functions and quality control of mitochondria at synapses are early events in Alzheimer's disease (AD) pathobiology. We reported that a 20-22 kDa NH2-tau fragment mapping between 26 and 230 amino acids of the longest human tau isoform (aka NH2htau): (i) is detectable in cellular and animal AD models, as well in synaptic mitochondria and cerebrospinal fluids (CSF) from human AD subjects; (ii) is neurotoxic in primary hippocampal neurons; (iii) compromises the mitochondrial biology both directly, by inhibiting the ANT-1-dependent ADP/ATP exchange, and indirectly, by impairing their selective autophagic clearance (mitophagy). Here, we show that the extensive Parkin-dependent turnover of mitochondria occurring in NH2htau-expressing post-mitotic neurons plays a pro-death role and that UCHL-1, the cytosolic Ubiquitin-C-terminal hydrolase L1 which directs the physiological remodeling of synapses by controlling ubiquitin homeostasis, critically contributes to mitochondrial and synaptic failure in this in vitro AD model. Pharmacological or genetic suppression of improper mitophagy, either by inhibition of mitochondrial targeting to autophagosomes or by shRNA-mediated silencing of Parkin or UCHL-1 gene expression, restores synaptic and mitochondrial content providing partial but significant protection against the NH2htau-induced neuronal death. Moreover, in mitochondria from human AD synapses, the endogenous NH2htau is stably associated with Parkin and with UCHL-1. Taken together, our studies show a causative link between the excessive mitochondrial turnover and the NH2htau-induced in vitro neuronal death, suggesting that pathogenetic tau truncation may contribute to synaptic deterioration in AD by aberrant recruitment of Parkin and UCHL-1 to mitochondria making them more prone to detrimental autophagic clearance

Critical raw materials and the circular economy

This report is a background document used by several European Commission services to prepare the EC report on critical raw materials and the circular economy, a commitment of the European Commission made in its Communication ‘EU action plan for the Circular Economy’. It represents a JRC contribution to the Raw Material Initiative and to the EU Circular Economy Action Plan. It combines the results of several research programmes and activities of the JRC on critical raw materials in a context of circular economy, for which a large team has contributed in terms of data and knowledge developments. Circular use of critical raw materials in the EU is analysed, also taking a sectorial perspective. The following sectors are analysed in more detail: extractive waste, landfills, electric and electronic equipment, batteries, automotive, renewable energy, defence and chemicals and fertilisers. Conclusions and opportunities for further work are also presented

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy