A pathogenic variant in the FLCN gene presenting with pure dementia: is autophagy at the intersection between neurodegeneration and cancer?

IntroductionFolliculin, encoded by FLCN gene, plays a role in the mTORC1 autophagy cascade and its alterations are responsible for the Birt–Hogg–Dubé (BHD) syndrome, characterized by follicle hamartomas, kidney tumors and pneumothorax.Patient and resultsWe report a 74-years-old woman diagnosed with dementia and carrying a FLCN alteration in absence of any sign of BHD. She also carried an alteration of MAT1A gene, which is also implicated in the regulation of mTORC1.DiscussionThe MAT1A variant could have prevented the development of a FLCN-related oncological phenotype. Conversely, our patient presented with dementia that, to date, has yet to be documented in BHD. Folliculin belongs to the DENN family proteins, which includes C9orf72 whose alteration has been associated to neurodegeneration. The folliculin perturbation could affect the C9orf72 activity and our patient could represent the first human model of a relationship between FLCN and C9orf72 across the path of autophagy

The impact of the revised 17 O(p, \u3b1)14 N reaction rate on 17 O stellar abundances and yields

Context. Material processed by the CNO cycle in stellar interiors is enriched in 17O. When mixing processes from the stellar surface reach these layers, as occurs when stars become red giants and undergo the first dredge up, the abundance of 17O increases. Such an occurrence explains the drop of the 16O/17O observed in RGB stars with mass larger than solar mass 1:5M solar mass. As a consequence, the interstellar medium is continuously polluted by the wind of evolved stars enriched in 17O . Aims. Recently, the Laboratory for Underground Nuclear Astrophysics (LUNA) collaboration released an improved rate of the 17O(p; a)14N reaction. In this paper we discuss the impact that the revised rate has on the 16O/17O ratio at the stellar surface and on 17O stellar yields. Methods.We computed stellar models of initial mass between 1 and 20M solar mass and compared the results obtained by adopting the revised rate of the 17O(p; a)14N to those obtained using previous rates. Results. The post-first dredge up 16O/17O ratios are about 20% larger than previously obtained. Negligible variations are found in the case of the second and the third dredge up. In spite of the larger 17O(p; a)14N rate, we confirm previous claims that an extra-mixing process on the red giant branch, commonly invoked to explain the low carbon isotopic ratio observed in bright low-mass giant stars, marginally affects the 16O/17O ratio. Possible effects on AGB extra-mixing episodes are also discussed. As a whole, a substantial reduction of 17O stellar yields is found. In particular, the net yield of stars with mass ranging between 2 and 20 solar mass is 15 to 40% smaller than previously estimated. Conclusions. The revision of the 17O(p; a)14N rate has a major impact on the interpretation of the 16O/17O observed in evolved giants, in stardust grains and on the 17O stellar yields

BIOHOT (BIOphysical characterization of Helium and Oxygen ion beams for hadronTherapy

Hadrontherapy (HT) presently uses protons and 12C ions to treat deep-seated and radioresistant tumors due to their favorable inverse dose-depth profile and, in the case of 12C ions, their higher relative biological effectiveness (RBE). However, particles of intermediate and higher charge, 4He and 16O ions, may improve dose localization and tumor control. A knowledge gap exists between predictions and available data. BIOHOT will study the biophysical properties of these ions through an integrated approach by in vitro measurements of clinically useful endpoints, cellular radioresponse predictive models, and microdosimetry. 4He ions at clinically relevant energies (≅ 250 MeV/n) present reduced lateral scattering and range straggling, with a higher linear energy transfer (LET) compared to protons, hence better spatial selectivity and increased RBE, with still negligible fragmentation beyond the Spread-Out Bragg Peak (SOBP). This is attractive for pediatric patients, where lowering the risk of radiotherapy-induced secondary cancers is mandatory. Heavier ions such as 16O, on the other hand, offer an even smaller later-scattering-generated penumbra and greater LET than 12C ions across the entire target volume, making them in principle more effective at counteracting hypoxia-induced radioresistance. In addition, at the entrance (plateau), the physical dose to normal tissue could be further decreased thanks to the higher RBE, partly offsetting the bigger fragmentation tail. As the choice of the “optimal” ion depends on several factors, e.g. type of tumor and healthy tissue, target position and depth, and beam ballistics, biologically and LET-optimized SOBPs require a thorough biophysical characterization.Therefore, we shall measure normoxic and hypoxic cancer cell death and migration, DNA damage induction and repair proficiency in cells of tumors prospectively benefitting from 4He and 16O ions, i.e., osteosarcoma and pancreatic cancer. The former is most common among children, hence a candidate for 4He-based HT; the latter is already treated with 12C ions due to its radioresistance. Normal-tissue toxicity, a limiting factor for curative dose, will be evaluated using endpoints related to late sequelae, e.g. senescence and inflammation. An innovative 3D model will be also used for a better mimicry of the in vivo environment. Monte Carlo simulations coupled with microdosimetric measurements will complete the biophysical characterization of 4He and 16O beams in terms of LET profile, secondary productions and model-verified biological and physical parameters. Activities will be carried out at Heidelberg Ion- Therapy center (HIT), where 4He-based HT is starting, and at CNAO, where a new source is planned for 2023 as use of both ions is considered. Clinical SOBPs will be thus available at both facilities during the project. Obtained data will help evidence-based, disease-specific ion type selection and serve as facility intercomparison between HIT and CNAO

Insights into rhamnolipid amendment towards enhancing microbial electrochemical treatment of petroleum hydrocarbon contaminated soil

Environmental pollution by hydrophobic hydrocarbons is increasing, notably nowadays due to a large amount of industrial activity. Microbial electrochemical technologies (MET) are promising bio-based systems which can oxidize hydrophobic hydrocarbon pollutants and produce bioelectricity simultaneously. However, MET faces some issues in terms of soil remediation, including low mass transfer, limited electro-activity of anodes as electron acceptors, low bioavailability of hydrocarbons, and the limited activity of beneficial bacteria and inefficient electron transport. This study aims to investigate the role of the addition of rhamnolipid as an analyte solution to the MET to enhance the efficacy and concurrently solve the abovementioned issues. In this regard, a novel long chain of RL was produced by using low-cost carbon winery waste through non-pathogenic Burkholderia thailandensis E264 strains. Different doses of RL were tested, including 10, 50, and 100 mg/L. A maximum enhancement in the oxidation of hydrophobic hydrocarbons was found to be up to 72.5%, while the current density reached 9.5 Am-2 for the MET reactor having a dose of 100 mg/L. The biosurfactants induced a unique microbial enrichment associated with Geobacter, Desulfovibrio, Klebsiella, and Comamona on the anode surface, as well as Pseudomonas, Acinetobacter, and Franconibacter in soil MET, indicating the occurrence of a metabolic pathway in microbes working with the anode and soil bioelectrochemical remediation system. According to cyclic voltammetry analysis, redox peaks appeared, showing a minor shift in redox MET-biosurfactant compared to the bare MET system. Furthermore, the phytotoxicity of polluted soil to L. sativum seeds after and before MET remediation shows a decrease in phytotoxicity of 77.5% and 5% for MET-biosurfactant system and MET only, respectively. With MET as a tool, this study confirmed for the first time that novel long-chain RL produced from non-Pseudomonas bacteria could remarkably facilitate the degradation of petroleum hydrocarbon via extracellular electron transfer, which provides novel insights to understand the mechanisms of RL regulating petroleum hydrocarbon degradation

Dominant and Nondominant Leg Kinematics During Kicking in Young Soccer Players: A Cross-Sectional Study

The goal of the study is to analyze the kinematics and provide an EMG analysis of the support limb during an instep kick in adolescent players. We set a video camera, two torque transducers on the knee, and EMG sensors. A sample of 16 adolescent soccer players between 10 and 12 years old performed kicks. The kinematics shows a p = .039 on frontal plane (dominant 15.4 ± 1.8, nondominant 18.8 ± 1.7); the EMG analysis shows a p = .04 on muscular activation timing for the vastus medialis. A difference between the legs on the frontal plane emerges. Moreover, a huge difference on sagittal plane between the adolescent pattern and adult pattern exists (15° in adolescent population, 40° in adult population). The result shows a greater activation of the vastus medialis in the nondominant leg; probably, in this immature pattern, the adolescents use this muscle more than necessary

Small Hexokinase 1 Peptide against Toxic SOD1 G93A Mitochondrial Accumulation in ALS Rescues the ATP-Related Respiration

Mutations in Cu/Zn Superoxide Dismutase (SOD1) gene represent one of the most common causes of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that specifically affects motor neurons (MNs). The dismutase-active SOD1 G93A mutant is responsible for the formation of toxic aggregates onto the mitochondrial surface, using the Voltage-Dependent Anion Channel 1 (VDAC1) as an anchor point to the organelle. VDAC1 is the master regulator of cellular bioenergetics and by binding to hexokinases (HKs) it controls apoptosis. In ALS, however, SOD1 G93A impairs VDAC1 activity and displaces HK1 from mitochondria, promoting organelle dysfunction, and cell death. Using an ALS cell model, we demonstrate that a small synthetic peptide derived from the HK1 sequence (NHK1) recovers the cell viability in a dose–response manner and the defective mitochondrial respiration profile relative to the ADP phosphorylation. This correlates with an unexpected increase of VDAC1 expression and a reduction of SOD1 mutant accumulation at the mitochondrial level. Overall, our findings provide important new insights into the development of therapeutic molecules to fight ALS and help to better define the link between altered mitochondrial metabolism and MNs death in the disease

Enhanced Exoelectrogenic Activity of Cupriavidus metallidurans in Bioelectrochemical Systems through the Expression of a Constitutively Active Diguanylate Cyclase

Electroactive bacteria have a wide range of applications, including electricity production, bioremediation, and the sensing of toxic compounds. Bacterial biofilm formation is often mediated by the second messenger cyclic guanosine monophosphate (c-di-GMP) synthesized by a diguanylate cyclase (DGC). The role of c-di-GMP in the expression of c-type cytochromes has been previously reported. The aim of this study was to determine the bioelectrogenic activity of Cupriavidus metallidurans strain CH34 pJBpleD*, which possesses a constitutively active DGC that increases c-di-GMP levels. Notably, the heterologous expression of the constitutively active DGC in C. metallidurans strain CH34 pJBpleD* showed a higher biofilm formation and increased the electrical current production up to 560%. In addition, C. metallidurans CH34 pJBpleD* showed increased levels of c-type cytochrome-associated transcripts compared with the wild-type strain CH34. Scanning electron microscopies revealed a denser extracellular matrix with an increased exopolymeric substance content in the CH34 pJBpleD* biofilm on the electrode surface. The results of this study suggest that higher levels of c-di-GMP synthesized by a constitutively active diguanylate cyclase in C. metallidurans strain CH34 pJBpleD* activated the formation of an electroactive biofilm on the electrode, enhancing its exoelectrogenic activity

Enhanced Exoelectrogenic Activity of <i>Cupriavidus metallidurans</i> in Bioelectrochemical Systems through the Expression of a Constitutively Active Diguanylate Cyclase

Electroactive bacteria have a wide range of applications, including electricity production, bioremediation, and the sensing of toxic compounds. Bacterial biofilm formation is often mediated by the second messenger cyclic guanosine monophosphate (c-di-GMP) synthesized by a diguanylate cyclase (DGC). The role of c-di-GMP in the expression of c-type cytochromes has been previously reported. The aim of this study was to determine the bioelectrogenic activity of Cupriavidus metallidurans strain CH34 pJBpleD*, which possesses a constitutively active DGC that increases c-di-GMP levels. Notably, the heterologous expression of the constitutively active DGC in C. metallidurans strain CH34 pJBpleD* showed a higher biofilm formation and increased the electrical current production up to 560%. In addition, C. metallidurans CH34 pJBpleD* showed increased levels of c-type cytochrome-associated transcripts compared with the wild-type strain CH34. Scanning electron microscopies revealed a denser extracellular matrix with an increased exopolymeric substance content in the CH34 pJBpleD* biofilm on the electrode surface. The results of this study suggest that higher levels of c-di-GMP synthesized by a constitutively active diguanylate cyclase in C. metallidurans strain CH34 pJBpleD* activated the formation of an electroactive biofilm on the electrode, enhancing its exoelectrogenic activity

Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in &beta;-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins&rsquo; synthesis and lipoproteins&rsquo; assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (A&beta;) assemblies on this process is not fully understood. In this study, we investigated how of A&beta;1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins&rsquo; levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood&ndash;brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs