Dipeptide repeat pathology in C9orf72-ALS Is associated with redox, mitochondrial and NRF2 pathway imbalance

The hexanucleotide expansion of the C9orf72 gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from C9orf72 patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from C9orf72 ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to C9orf72 pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring C9orf72 expansion repeats. Keywords: NRF2; amyotrophic lateral sclerosis; C9orf72; dipeptide repeat protein

Dietary α‐Linolenic Acid, Marine ω‐3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study

Background: Epidemiological evidence suggests a cardioprotective role of α‐linolenic acid (ALA), a plant‐derived ω‐3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ω‐3 fatty acids (long‐chain n‐3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all‐cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long‐chain n‐3 polyunsaturated fatty acids (≥500 mg/day). Methods and Results: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable‐adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9‐y follow‐up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56–0.92) for all‐cause mortality and 0.95 (95% CI 0.58–1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long‐chain n‐3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67–1.05) for all‐cause mortality, 0.61 (95% CI 0.39–0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29–0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22–1.01) for sudden cardiac death. The highest reduction in all‐cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45–0.87]). Conclusions: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all‐cause mortality, whereas protection from cardiac mortality is limited to fish‐derived long‐chain n‐3 polyunsaturated fatty acids. Clinical Trial Registration URL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639

A minimalistic approach to identify substrate binding features in B1 Metallo-beta-lactamases

International audienceThe 2-oxoazetidinylacetate sodium salt was synthesized as a model of a minimal P-lactam drug. This compound and the monobactam aztreonam were assayed as substrates of the Metallo-p-lactamase Bell. None of them was hydrolyzed by the enzyme. While the azetidinone was not able to bind Bell, aztreonam was shown to bind in a nonproductive mode. These results provide an explanation for the unability of Metallo-beta-lactamases to inactive monobactams and give some clues for inhibitor design

Polyvinyl alcohol/chitosan wound dressings loaded with antiseptics

Wound care remains a challenge in healthcare. This work aimed to develop a new polyvinyl alcohol (PVA)/chitosan (Ch) based wound dressing able to ensure protection, hydration and a controlled release of antiseptics, as alternative to actual treatments. Two distinct formulations (1:1 and 3:1, w/w) were prepared, sterilized by autoclaving and characterized concerning surface morphology, degradation over the time, mechanical properties and hydrophilicity. Both dressings revealed adequate properties for the intended purpose. The dressings were loaded with chlorhexidine (CHX) and polyhexanide (PHMB) and the drug release profiles were determined using Franz diffusion cells. The release of PHMB was more sustained than CHX, lasting for 2 days. As the amounts of drugs released by PVA/Ch 1:1 were greater, the biological tests were done only with this formulation. The drug loaded dressings revealed antibacterial activity against S. aureus and S. epidermidis, but only the ones loaded with PHMB showed adequate properties in terms of cytotoxicity and irritability. The application of this elastic dressing in the treatment of wounds in a dog led to faster recovery than conventional treatment, suggesting that the material can be a promising alternative in wound care.info:eu-repo/semantics/publishedVersio

Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease

10.1002/ana.21405Annals of Neurology64188-92ANNE

XMM-Newton-discovered Fast X-ray Transients: host galaxies and limits on contemporaneous detections of optical counterparts

Extragalactic fast X-ray transients (FXTs) are a class of soft (0.3–10 keV) X-ray transients lasting a few hundred seconds to several hours. Several progenitor mechanisms have been suggested to produce FXTs, including supernova shock breakouts, binary neutron star mergers, or tidal disruptions involving an intermediate-mass black hole and a white dwarf. We present detailed host studies, including spectroscopic observations of the host galaxies of seven XMM-Newton-discovered FXTs. The candidate hosts lie at redshifts 0.0928 <z < 0.645 implying peak X-ray luminosities of 1043 erg s−1<LX < 1045 erg s−1 and physical offsets of 1 kpc < rproj < 22 kpc. These observations increase the number of FXTs with a spectroscopic redshift measurement by a factor of 2, although we note that one event is re-identified as a Galactic flare star. We infer host star formation rates and stellar masses by fitting the combined spectroscopic and archival photometric data. We also report on a contemporaneous optical counterpart search to the FXTs in Pan-STARRS and ATLAS by performing forced photometry at the position of the FXTs. We do not find any counterpart in our search. Given our constraints, including peak X-ray luminosities, optical limits, and host properties, we find that XRT 110 621 is consistent with an supernova shock breakout (SN SBO) event. Spectroscopic redshifts of likely host galaxies for four events imply peak X-ray luminosities that are too high to be consistent with SN SBOs, but we are unable to discard either the binary neutron star or white dwarf–intermediate-mass black hole tidal disruption event scenarios for these FXTs. © 2023 The Author(s).Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]