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

CapZ-lipid membrane interactions: a computer analysis

BACKGROUND: CapZ is a calcium-insensitive and lipid-dependent actin filament capping protein, the main function of which is to regulate the assembly of the actin cytoskeleton. CapZ is associated with membranes in cells and it is generally assumed that this interaction is mediated by polyphosphoinositides (PPI) particularly PIP(2), which has been characterized in vitro. RESULTS: We propose that non-PPI lipids also bind CapZ. Data from computer-aided sequence and structure analyses further suggest that CapZ could become partially buried in the lipid bilayer probably under mildly acidic conditions, in a manner that is not only dependent on the presence of PPIs. We show that lipid binding could involve a number of sites that are spread throughout the CapZ molecule i.e., alpha- and beta-subunits. However, a beta-subunit segment between residues 134–151 is most likely to be involved in interacting with and inserting into lipid membrane due to a slighly higher ratio of positively to negatively charged residues and also due to the presence of a small hydrophobic helix. CONCLUSION: CapZ may therefore play an essential role in providing a stable membrane anchor for actin filaments

The first widespread solar energetic particle event of solar cycle 25 on 2020 November 29 Shock wave properties and the wide distribution of solar energetic particles

Context. On 2020 November 29, an eruptive event occurred in an active region located behind the eastern solar limb as seen from Earth. The event consisted of an M4.4 class flare, a coronal mass ejection, an extreme ultraviolet (EUV) wave, and a white-light (WL) shock wave. The eruption gave rise to the first widespread solar energetic particle (SEP) event of solar cycle 25, which was observed at four widely separated heliospheric locations (similar to 230 degrees).Aims. Our aim is to better understand the source of this widespread SEP event, examine the role of the coronal shock wave in the wide distribution of SEPs, and investigate the shock wave properties at the field lines magnetically connected to the spacecraft.Methods. Using EUV and WL data, we reconstructed the global three-dimensional structure of the shock in the corona and computed its kinematics. We determined the magnetic field configurations in the corona and interplanetary space, inferred the magnetic connectivity of the spacecraft with the shock surface, and derived the evolution of the shock parameters at the connecting field lines.Results. Remote sensing observations show formation of the coronal shock wave occurring early during the eruption, and its rapid propagation to distant locations. The results of the shock wave modelling show multiple regions where a strong shock has formed and efficient particle acceleration is expected to take place. The pressure/shock wave is magnetically connected to all spacecraft locations before or during the estimated SEP release times. The release of the observed near-relativistic electrons occurs predominantly close to the time when the pressure/shock wave connects to the magnetic field lines or when the shock wave becomes supercritical, whereas the proton release is significantly delayed with respect to the time when the shock wave becomes supercritical, with the only exception being the proton release at the Parker Solar Probe.Conclusions. Our results suggest that the shock wave plays an important role in the spread of SEPs. Supercritical shock regions are connected to most of the spacecraft. The particle increase at Earth, which is barely connected to the wave, also suggests that the cross-field transport cannot be ignored. The release of energetic electrons seems to occur close to the time when the shock wave connects to, or becomes supercritical at, the field lines connecting to the spacecraft. Energetic protons are released with a time-delay relative to the time when the pressure/shock wave connects to the spacecraft locations. We attribute this delay to the time that it takes for the shock wave to accelerate protons efficiently.</p

Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity

AIMS/HYPOTHESIS: Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake. MATERIALS AND METHODS: Insulin sensitivity in Pten heterozygous (Pten(+/−)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/−) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3β (GSK3β), a substrate of PKB/Akt, was determined by western immunoblotting. RESULTS: Following i.p. insulin challenge, blood glucose levels in Pten(+/−) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/−) mice. Enhanced glucose uptake was observed both in Pten(+/−) myocytes and in skeletal muscle of Pten(+/−) mice by PET. PKB and GSK3β phosphorylation was enhanced and prolonged in Pten(+/−) myocytes. CONCLUSIONS/INTERPRETATION: Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/−) mice