Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A

Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load

Towards a new generation axion helioscope

We study the feasibility of a new generation axion helioscope, the most ambitious and promising detector of solar axions to date. We show that large improvements in magnetic field volume, x-ray focusing optics and detector backgrounds are possible beyond those achieved in the CERN Axion Solar Telescope (CAST). For hadronic models, a sensitivity to the axion-photon coupling of \gagamma\gtrsim {\rm few} \times 10^{-12} GeV$^{-1}$ is conceivable, 1--1.5 orders of magnitude beyond the CAST sensitivity. If axions also couple to electrons, the Sun produces a larger flux for the same value of the Peccei-Quinn scale, allowing one to probe a broader class of models. Except for the axion dark matter searches, this experiment will be the most sensitive axion search ever, reaching or surpassing the stringent bounds from SN1987A and possibly testing the axion interpretation of anomalous white-dwarf cooling that predicts $m_a$ of a few meV. Beyond axions, this new instrument will probe entirely unexplored ranges of parameters for a large variety of axion-like particles (ALPs) and other novel excitations at the low-energy frontier of elementary particle physics.Comment: 37 pages, 11 figures, accepted for publication in JCA

The International Axion Observatory (IAXO)

The International Axion Observatory (IAXO) is a new generation axion helioscope aiming at a sensitivity to the axion-photon coupling of a few 10$^{12}$ GeV$^{-1}$, i.e. 1 - 1.5 orders of magnitude beyond the one currently achieved by CAST. The project relies on improvements in magnetic field volume together with extensive use of x-ray focusing optics and low background detectors, innovations already successfully tested in CAST. Additional physics cases of IAXO could include the detection of electron-coupled axions invoked to solve the white dwarfs anomaly, relic axions, and a large variety of more generic axion-like particles (ALPs) and other novel excitations at the low-energy frontier of elementary particle physics. This contribution is a summary of our paper [1] to which we refer for further details.Comment: 4 pages, 2 figures. To appear in the proceedings of the 7th Patras Workshop on Axions, WIMPs and WISPs, Mykonos, Greece, 201

DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease

Deep Learning Analyses to Delineate the Molecular Remodeling Process after Myocardial Infarction

Specific proteins and processes have been identified in post-myocardial infarction (MI) pathological remodeling, but a comprehensive understanding of the complete molecular evolution is lacking. We generated microarray data from swine heart biopsies at baseline and 6, 30, and 45 days after infarction to feed machine-learning algorithms. We cross-validated the results using available clinical and experimental information. MI progression was accompanied by the regulation of adipogenesis, fatty acid metabolism, and epithelial-mesenchymal transition. The infarct core region was enriched in processes related to muscle contraction and membrane depolarization. Angiogenesis was among the first morphogenic responses detected as being sustained over time, but other processes suggesting post-ischemic recapitulation of embryogenic processes were also observed. Finally, protein-triggering analysis established the key genes mediating each process at each time point, as well as the complete adverse remodeling response. We modeled the behaviors of these genes, generating a description of the integrative mechanism of action for MI progression. This mechanistic analysis overlapped at different time points; the common pathways between the source proteins and cardiac remodeling involved IGF1R, RAF1, KPCA, JUN, and PTN11 as modulators. Thus, our data delineate a structured and comprehensive picture of the molecular remodeling process, identify new potential biomarkers or therapeutic targets, and establish therapeutic windows during disease progression

CAST solar axion search with 3^He buffer gas: Closing the hot dark matter gap

The CERN Axion Solar Telescope (CAST) has finished its search for solar axions with 3^He buffer gas, covering the search range 0.64 eV < m_a <1.17 eV. This closes the gap to the cosmological hot dark matter limit and actually overlaps with it. From the absence of excess X-rays when the magnet was pointing to the Sun we set a typical upper limit on the axion-photon coupling of g_ag < 3.3 x 10^{-10} GeV^{-1} at 95% CL, with the exact value depending on the pressure setting. Future direct solar axion searches will focus on increasing the sensitivity to smaller values of g_a, for example by the currently discussed next generation helioscope IAXO.Comment: 5 pages, 2 figures. Last version uploade

CAST constraints on the axion-electron coupling

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axio-recombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling g_ae and axion-photon interaction strength g_ag using the CAST phase-I data (vacuum phase). For m_a < 10 meV/c2 we find g_ag x g_ae< 8.1 x 10^-23 GeV^-1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo

Colouration in amphibians as a reflection of nutritional status : the case of tree frogs in Costa Rica

Colouration has been considered a cue for mating success in many species; ornaments in males often are related to carotenoid mobilization towards feathers and/or skin and can signal general health and nutrition status. However, there are several factors that can also link with status, such as physiological blood parameters and body condition, but there is not substantial evidence which supports the existence of these relationships and interactions in anurans. This study evaluated how body score and blood values interact with colouration in free-range Agalychnis callidryas and Agalychnis annae males. We found significant associations between body condition and plasmatic proteins and haematocrit, as well as between body condition and colour values from the chromaticity diagram. We also demonstrated that there is a significant relation between the glucose and plasmatic protein values that were reflected in the ventral colours of the animals, and haematocrit inversely affected most of those colour values. Significant differences were found between species as well as between populations of A. callidryas, suggesting that despite colour variation, there are also biochemical differences within animals from the same species located in different regions. These data provide information on underlying factors for colouration of male tree frogs in nature, provide insights about the dynamics of several nutrients in the amphibian model and how this could affect the reproductive output of the animals