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IntroductionDose perturbation of spot-scanning proton beams passing through a dislocated metallic port (MP) of a breast tissue expander may degrade target dose coverage or deliver excess dose to the ipsilateral lung and heart. The feasibility of utilizing daily cone-beam computed tomography (CBCT)–based synthetic CTs (synCTs) for dose reconstruction was evaluated, and the fractional and cumulative dosimetric impact due to daily MP dislocation is reported.MethodsThe synCT was generated by deforming the simulation CT to daily CBCT. The MP structure template was mapped onto all CTs on the basis of daily MP position. Proton treatment plans were generated with two and three fields on the planned CT (pCT, Plan A) and the first verification CT (vCT, Plan B), respectively, for a fractional dose of 1.8 Gy(RBE). Plan A and Plan B were used alternatively, as determined by the daily MP position. The reconstructed fractional doses were calculated with corresponding plans and synCTs, and the cumulative doses were summed with the rigid or deformed fractional doses on pCT and vCT.ResultsThe planned and reconstructed fractional dose demonstrated a low-dose socket around the planned MP position due to the use of field-specific targets (FSTs). Dose hot spots with >120% of the prescription due to MP dislocation were found behind the planned MP position on most reconstructed fractional doses. The reconstructed cumulative dose shows two low-dose sockets around the two planned MP positions reflecting the two plans used. The doses at the hot spots behind the planned MPs averaged out to 114% of the prescription. The cumulative D95% of the CTV_Chest Wall decreased by up to 2.4% and 4.0%, and the cumulative V20Gy(RBE) of the left lung decreased to 16.1% and 16.8% on pCT and vCT, respectively. The cumulative Dmean of the heart decreased to as low as 0.7 Gy(RBE) on pCT but increased to as high as 1.6 Gy(RBE) on vCT.ConclusionThe robustness of proton plans using FSTs around the magnet in the MP of the tissue expander can be improved by applying multiple fields and plans, which provides forgiveness of dose heterogeneity incurred from dislocation of high-Z materials in this single case.

Abstract In the Arctic, chemical contaminants, shipping, oil pollution, plastic pollution, changing habitats in relation to climate change and fisheries have been identified as environmental stressors to seabirds such as Fulmarus glacialis (northern fulmar; qaqulluk; ᖃᖁᓪᓗᖅ), but rarely have these stressors been considered within a cumulative effects framework in this species which is currently showing a declining populations trend. As a novel tool to understand cumulative effects within a conservation context, we applied a fuzzy cognitive mapping (FCM) approach that allows experts to arrange key factors and their interrelationships, organizing their understanding of the components of a complex issue into a graphical representation; a ‘cognitive map’. This process was grounded in local environment concerns as documented in several Nunavut‐specific reports and discussions, and worked with western‐trained seabird experts with knowledge of northern fulmar populations to assess the inter‐related environmental threats to fulmars as a way to combine these stressors in a cumulative effects framework and identify conservation actions and knowledge gaps. We found strong agreement that the main stressors affecting northern fulmar populations in Canada include pollution (11% total influence (TI)), shipping activities (16% TI), hunting and fishing (18% TI) and mining/oil and gas exploitation activities (22% TI). The indirect influence of threats on northern fulmar population size (57% TI) exceeded the total direct influence (43% TI), emphasizing the value of cognitive mapping in cumulative effects assessment for a more holistic understanding of interacting stressors. Participants expressed substantial uncertainty regarding the strong relationships leading from the concepts, commercial fishing activity in the BBDS and the North Atlantic fisheries activity, indicating that these potential stressors require more research. Similarly, uncertainty was expressed about the potential effects of zodiac traffic, ship strikes of northern fulmar, number of oil spills and magnitude of oil spills on northern fulmar. By characterizing individual factors as manageable or not, we determined that stressors are largely manageable with enforcement of existing policies (58% TI)—importantly, fishing activities were both highly influential on fulmars and deemed manageable, which will inform ongoing co‐management planning in the region.

Caloric restriction (CR) has been shown as an effective intervention to reduce tumorigenesis, but alternative less stringent dietary interventions have also been considered. Here, the authors show that in a murine model of breast cancer CR has a larger effect on preventing tumorigenesis and metastasis compared to periodic caloric cycling.

Objective: We designed and validated a wireless, low-cost, easy-to-use, mobile, dry-electrode headset for scalp electroencephalography (EEG) recordings for closed-loop brain–computer (BCI) interface and internet-of-things (IoT) applications. Approach: The EEG-based BCI headset was designed from commercial off-the-shelf (COTS) components using a multi-pronged approach that balanced interoperability, cost, portability, usability, form factor, reliability, and closed-loop operation. Main Results: The adjustable headset was designed to accommodate 90% of the population. A patent-pending self-positioning dry electrode bracket allowed for vertical self-positioning while parting the user’s hair to ensure contact of the electrode with the scalp. In the current prototype, five EEG electrodes were incorporated in the electrode bracket spanning the sensorimotor cortices bilaterally, and three skin sensors were included to measure eye movement and blinks. An inertial measurement unit (IMU) provides monitoring of head movements. The EEG amplifier operates with 24-bit resolution up to 500 Hz sampling frequency and can communicate with other devices using 802.11 b/g/n WiFi. It has high signal–to–noise ratio (SNR) and common–mode rejection ratio (CMRR) (121 dB and 110 dB, respectively) and low input noise. In closed-loop BCI mode, the system can operate at 40 Hz, including real-time adaptive noise cancellation and 512 MB of processor memory. It supports LabVIEW as a backend coding language and JavaScript (JS), Cascading Style Sheets (CSS), and HyperText Markup Language (HTML) as front-end coding languages and includes training and optimization of support vector machine (SVM) neural classifiers. Extensive bench testing supports the technical specifications and human-subject pilot testing of a closed-loop BCI application to support upper-limb rehabilitation and provides proof-of-concept validation for the device’s use at both the clinic and at home. Significance: The usability, interoperability, portability, reliability, and programmability of the proposed wireless closed-loop BCI system provides a low-cost solution for BCI and neurorehabilitation research and IoT applications.

Adaptive homeostasis enables rapid cellular signaling, leading to transcriptional and translational modifications (Davies, 2016) [1]. The Proteasome is one of the main cellular proteolytic enzymes that plays an essential role in the rapid clearance of oxidatively damaged cellular proteins, and is highly responsive to oxidative stress. Upon exposure to even very low, signaling levels of oxidants, the predominant form of the Proteasome becomes the ATP-independent 20S proteasome that enables rapid clearance of damaged proteins. Subsequently there is also a concurrent upregulation of de novo 20S proteasome synthesis. These cellular adaptations not only ensure effective and efficient removal of damaged proteins, but prepare cells to better cope with future, more severe oxidative insults. Male and female Drosophila melanogaster fruit flies were pretreated with an adaptive amount of an oxidant (10 µM hydrogen peroxide or 0.5 µM paraquat) to assess the changes in proteolytic capacity and the role of the 20S proteasome. Additionally, the adaptive signaling by non-damaging amounts of hydrogen peroxide or paraquat) were used to assess changes in male and female fruit flies, following a subsequent more toxic amount of the two oxidants. Further analysis and detailed results about the adaptive role of the 20S proteasome in multiple D. melanogaster strains can be found in “Sexual Dimorphism in Oxidant-Induced Adaptive Homeostasis in Multiple Wild-Type D. melanogaster Strains” (Pomatto et al., 2018) [2]. Keywords: 20S proteasome, Sexual-dimorphism, Adaptive homeostasis, Proteolysis, D. melanogaster

The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O2, as a model of accelerated ageing. Hyperoxia increased baseline levels of Nrf2 and multiple transcriptional targets (20S Proteasome, Immunoproteasome, Lon protease, NQO1, and HO-1), but resulted in loss of cellular ability to adapt to signaling levels (1.0 μM) of H2O2. In contrast, MEFs cultured at physiologically relevant conditions of 5% O2 exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following H2O2 treatment. Importantly, all of these effects have been seen in older cells and organisms. Levels of Two major Nrf2 inhibitors, Bach1 and c-Myc, were strongly elevated by hyperoxia and appeared to exert a ceiling on Nrf2 signaling. Bach1 and c-Myc also increase during ageing and may thus be the mechanism by which adaptive homeostasis is compromised with age. Keywords: Adaptive homeostasis, Hyperoxia, Nrf2, 20S proteasome, Immunoproteasome, NQO1, Bach1, c-Myc, Lon protease, OXR1

Abstract A 55–200 expansion of the CGG nucleotide repeat in the 5′-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the “premutation” as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived reactive oxygen species (ROS) may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n = 31, all FXTAS-free except 8), compared with age- and sex-matched controls (n = 25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals’ scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier-specific. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset.

Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55–200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150–180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother’s ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention.