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The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the S kp1, C UL1, and F -box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle progression, identifying cyclin F-bound SCF complex (SCF Cyclin F ) substrates has remained challenging. Since cyclin F overexpression rescues a yeast mutant in the cdc4 gene, we considered the possibility that other genes that genetically modify cdc4 mutant lethality could also encode cyclin F substrates. We identified the mitochondrial and cytosolic deacylating enzyme sirtuin 5 (SIRT5) as a novel cyclin F substrate. SIRT5 has been implicated in metabolic processes, but its connection to the cell cycle is not known. We show that cyclin F interacts with and controls the ubiquitination, abundance, and stability of SIRT5. We show SIRT5 knockout results in a diminished G 1 population and a subsequent increase in both S and G 2 /M. Global proteomic analyses reveal cyclin-dependent kinase (CDK) signaling changes congruent with the cell cycle changes in SIRT5 knockout cells. Together, these data demonstrate that SIRT5 is regulated by cyclin F and suggest a connection between SIRT5, cell cycle regulation, and metabolism., (Copyright © 2021 American Society for Microbiology.)

ProZES is a software tool for estimating the probability that a given cancer was caused by preceding exposure to ionising radiation. ProZES calculates this probability, the assigned share, for solid cancers and hematopoietic malignant diseases, in cases of exposures to low-LET radiation, and for lung cancer in cases of exposure to radon. User-specified inputs include birth year, sex, type of diagnosed cancer, age at diagnosis, radiation exposure history and characteristics, and smoking behaviour for lung cancer. Cancer risk models are an essential part of ProZES. Linking disease and exposure to radiation involves several methodological aspects, and assessment of uncertainties received particular attention. ProZES systematically uses the principle of multi-model inference. Models of radiation risk were either newly developed or critically re-evaluated for ProZES, including dedicated models for frequent types of cancer and, for less common diseases, models for groups of functionally similar cancer sites. The low-LET models originate mostly from the study of atomic bomb survivors in Hiroshima and Nagasaki. Risks predicted by these models are adjusted to be applicable to the population of Germany and to different time periods. Adjustment factors for low dose rates and for a reduced risk during the minimum latency time between exposure and cancer are also applied. The development of the methodology and software was initiated and supported by the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) taking up advice by the German Commission on Radiological Protection (SSK, Strahlenschutzkommission). These provide the scientific basis to support decision making on compensation claims regarding malignancies following occupational exposure to radiation in Germany.

This paper summarises the view of the German Commission on Radiological Protection ("Strahlenschutzkommission", SSK) on the rationale behind the currently valid dose limits and dose constraints for workers recommended by the International Commission on Radiological Protection (ICRP). The paper includes a discussion of the reasoning behind current dose limits followed by a discussion of the detriment used by ICRP as a measure for stochastic health effects. Studies on radiation-induced cancer are reviewed because this endpoint represents the most important contribution to detriment. Recent findings on radiation-induced circulatory disease that are currently not included in detriment calculation are also reviewed. It appeared that for detriment calculations the contribution of circulatory diseases plays only a secondary role, although the uncertainties involved in their risk estimates are considerable. These discussions are complemented by a review of the procedures currently in use in Germany, or in discussion elsewhere, to define limits for genotoxic carcinogens. To put these concepts in perspective, actual occupational radiation exposures are exemplified with data from Germany, for the year 2012, and regulations in Germany are compared to the recommendations issued by ICRP. Conclusions include, among others, considerations on radiation protection concepts currently in use and recommendations of the SSK on the limitation of annual effective dose and effective dose cumulated over a whole working life.

To maintain tissue homeostasis, cells transition between cell cycle quiescence and proliferation. An essential G1 process is minichromosome maintenance complex (MCM) loading at DNA replication origins to prepare for S phase, known as origin licensing. A p53-dependent origin licensing checkpoint normally ensures sufficient MCM loading before S phase entry. We used quantitative flow cytometry and live cell imaging to compare MCM loading during the long first G1 upon cell cycle entry and the shorter G1 phases in the second and subsequent cycles. We discovered that despite the longer G1 phase, the first G1 after cell cycle re-entry is significantly underlicensed. Consequently, the first S phase cells are hypersensitive to replication stress. This underlicensing results from a combination of slow MCM loading with a severely compromised origin licensing checkpoint. The hypersensitivity to replication stress increases over repeated rounds of quiescence. Thus, underlicensing after cell cycle re-entry from quiescence distinguishes a higher-risk first cell cycle that likely promotes genome instability., (© 2019 Matson et al.)

Introduction: Severe hypoglycaemia (SH), when blood glucose falls too low to support brain function, is the most feared acute complication of insulin therapy for type 1 diabetes mellitus (T1DM). 10% of people with T1DM contribute nearly 70% of all episodes, with impaired awareness of hypoglycaemia (IAH) a major risk factor. People with IAH may be refractory to conventional approaches to reduce SH, with evidence for cognitive barriers to hypoglycaemia avoidance. This paper describes the protocol for the Hypoglycaemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic Hypoglycaemia Persisting Despite Optimised Self-care (HARPdoc) study, a trial to assess the impact on hypoglycaemia experience of a novel intervention that addresses cognitive barriers to hypoglycaemia avoidance, compared with an existing control intervention, recommended by the National Institute of Health and Care Excellence., Methods and Analysis: A randomised parallel two-arm trial of two group therapies: HARPdoc versus Blood Glucose Awareness Training, among 96 adults with T1DM and problematic hypoglycaemia, despite attendance at education with or without technology use, in four centres providing specialist T1DM services. The primary outcome will be the SH rate at 12 and/or 24 months after randomisation to either course. Secondary outcomes include rates of SH requiring parenteral therapy, involving unconsciousness or needing emergency services; hypoglycaemia awareness status, overall diabetes control and quality of life measures. An implementation study to evaluate how the interventions are delivered and how implementation impacts on clinical effectiveness is planned as a parallel study, with its own protocol., Ethics and Dissemination: The protocol was approved by the London Dulwich Research Ethics Committee, the Health Research Authority, National Health Service R&D and the Institutional Review Board of the Joslin Diabetes Center in the USA. Study findings will be disseminated to study participants and through peer-reviewed publications and conference presentations, including user groups., Trial Registration Number: NCY02940873; Pre-results., Competing Interests: Competing interests: SA is a member of the International Hypoglycaemia Study Group and has served on advisory panels for Roche, Medtronic and NovoNordisk. AB has received honoraria from Astra Zeneca and Sanofi for speaking at educational events and sponsorship from Lilly and Janssen to attend conferences. SH has served as a consultant or speaker from Lilly, Novo Nordisk, Takeda, Boeringher Ingelheim, Mannkind, Sanofi, Zealand Pharma and UN-EEG. NS is the Director of London Safety and Training Solutions Ltd, which provides quality and safety training and advisory services on a consultancy basis to healthcare organisation globally., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Statins have proven efficacy in reducing vascular disease, but statin-induced myalgia is relatively common in clinical practice, and can sometimes leave patients who are high risk for vascular disease unable to take these important preventative treatments. Low or intermittent dose rosuvastatin has been shown to be useful in lowering cholesterol with fewer side-effects. Supplementation with co-enzyme Q10 is suggested to reduce statin-induced myalgia., Materials and Methods: A retrospective review of patients attending a tertiary referral lipid clinic with statin-induced myalgia was carried out. Patients were counseled on commencing low-dose rosuvastatin, titrated at monthly intervals, and supplemented by co-enzyme Q10 100 mg daily., Results: Forty Three patients were reviewed. Six were unable to tolerate the regime at all. The remaining 37 patients tolerated rosuvastatin between 5 mg weekly and 20 mg daily. Total and LDL-cholesterol levels fell by a mean of 29.1% and 27.5%, respectively. 62.2% of patients achieved total cholesterol under 5.0 mmol/L., Conclusions: In this retrospective review of clinical practice, "low and slow" rosuvastatin supplemented by co-enzyme Q10 led to clinically meaningful reductions in total and LDL-cholesterol in patients with statin-induced myalgia.

Functionalized solid-liquid interfaces were analyzed by X-ray standing waves (XSW) combined with streaming current measurements to study surface charges, interfacial potential, and ion distributions. Thin films of aqueous solution containing Br(-) anions and Fe(3+) cations at a concentration of 10 mg/L were prepared on functionalized silicon wafers. Functionalization of Si surfaces was accomplished by aminosilane groups shifting the interfacial potential toward positive values. The ion distribution was measured with nanometer resolution, which allows distinguishing between absorbed and mobile ions at the surface and in the diffusive layer, respectively. For Br(-), different degrees of ion attraction were measured for the pH values 5.7 and 2.8. The ion Debye length values of the diffuse layer were 4 and 2 nm, respectively.

This paper presents the results of an effort to evaluate anthropogenic doses in bricks from old buildings located on the banks of the Techa River. The river area was contaminated in 1949-1956 as a result of radioactive waste releases by the Mayak plutonium facility (Southern Urals, Russia). Absorbed doses were determined by luminescence measurements of quartz extracted from the near-surface layers of bricks sampled in 1991-1997 from three remained buildings (a mill, a granary and a church). These buildings are located in the former residence area of Metlino, which was the settlement located closest to the release site (residents of Metlino were relocated from the contaminated river in 1956). The measured anthropogenic dose in the three buildings was found to be comparable: minimum values were equal to 0.5-0.9 Gy and maximum values amounted to about 3-4 Gy. Unfortunately, the geometry of gamma-exposure of the brick samples changed significantly in 1956 as a result of creation of an artificial reservoir downstream of the Metlinsky pond. Since luminescence data provide absorbed dose in the investigated samples accumulated over the whole period of irradiation, for interpretation of the data obtained it is important to know the exposure geometry for the period of maximal exposure, which was in the early 1950s. In 2005, archival data describing configuration of contaminated water streams and shorelines (which were the main sources of gamma-irradiation) were published. Comparison of these data with the results of the luminescence study presented here showed that the bricks with the highest thermoluminescence (TL)-based doses faced contaminated shores and were located close to them. In contrast, the bricks with lower values of measured dose were opposite to contaminated shores and/or being shielded. This demonstrates that the luminescence method allowed reconstruction of the anthropogenic dose distribution in the former settlement center. The obtained results suggest new options for further luminescence studies in Metlino aimed at the reconstruction of the external exposures of the affected population.

The two-stage clonal expansion (TSCE) model of carcinogenesis has been applied to cancer mortality data from the atomic bomb survivors, to examine the possible influence of radiation-induced cell inactivation on excess relative risk (ERR) and excess absolute risk (EAR) estimates. Cell survival curve forms being either conventional or allowing for low-dose hypersensitivity (LDH) were investigated. Quality-of-fit tests for non-nested models were used in comparisons with the types of empirical risk models applied at the Radiation Effects Research Foundation (RERF) in Hiroshima. In general the TSCE model was found to represent the data more economically (i.e., with fewer parameters for a similarly good description of the data) than the empirical risk model. However, the data are not strong enough to give a clear preference to one of the very different model types used. Central ERR and EAR estimates (at 1 Sv, for age at exposure 30 and age attained 70) from TSCE and empirical models were in good agreement with each other and with previously published estimates. However, the TSCE models including radiation-induced cell inactivation resulted in a lower estimate of the relative risk at young ages at exposure (0-15 years) than the empirical model. Also the TSCE model allowing for radiation-induced cell inactivation with a conventional cell survival curve resulted at 0.2 Sv in significantly lower risk estimates than the model with LDH. These model differences have been used here to suggest risk estimates which include model uncertainty as well as the usual statistical uncertainty. Model uncertainties were small for central estimates and larger for other values of the variables. Applying the proposed method to excess risk for all solid cancer at 1 Sv, age at exposure 10 and age attained 70, results in total uncertainty ranges that are wider than the pure statistical uncertainty range by about 30% for both ERR and EAR.

Objective: Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterised by focal brain activation. Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders., Methods: Patients suffering from chronic tinnitus underwent a [ (18)F]deoxyglucose-PET (positron emission tomography). Fusioning of the individual PET scan with the structural MRI-scan (magnetic resonance imaging, T1, MPRAGE) revealed an increased metabolic activation in the primary auditory cortex as target point for rTMS. A neuronavigational system enabled the positioning of the figure of eight coil in relation to the target area. rTMS (110 % motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design., Results: Following active rTMS there was a moderate improvement of tinnitus perception. Treatment effects lasted up to six months in some patients., Conclusions: Neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

Objective: Disturbed GABA-B mediated inhibitory cortical processes are discussed to be involved both in schizophrenia as well as in chronic tinnitus. Transcranial magnetic stimulation (TMS) provides an intriguing in vivo method to investigate GABA-B associated aspects of cortical inhibition, thus allowing to detect disease-related cortical inhibitory processes., Method: Parameters of cortical excitability were measured by TMS in drug-naive first-episode schizophrenic patients and in patients suffering from chronic tinnitus., Results: The cortical silent period as measured by TMS indicated a dysfunctional GABA-B mediated cortical inhibition in both groups of patients., Conclusions: TMS offers new insights into the pathophysiology of neuropsychiatric disorders. Parameters of this technique point to changes in GABA-B associated inhibitory processes within thalamocortial circuits both in schizophrenia and chronic tinnitus. These data are in line with current models of disturbed thalamic gating in phantom perceptions like auditory hallucinations, chronic tinnitus and central pain.

Within the track structure code PARTRAC, DNA strand break induction by direct and indirect radiation action was calculated for the E. coli catabolite gene activator protein (CAP) DNA complex with (125)I located at the position of the H(5) atom of the cytosine near the center. The shape of the resulting DNA fragment size distributions was found to be in reasonable agreement with corresponding experimental results. However, the calculated yield was considerably lower than the measured one. To study possible reasons for this, recently published experimental data on DNA strand breaks in a 41-mer synthetic oligodeoxynucleotide (oligoDNA) with incorporated (125)I were analyzed aiming at an evaluation of the non-radiation-related component due to the neutralization of the initially highly charged (125m)Te daughter ion. This was done by assuming that the differences between simulated radiation-induced distribution and the measured total fragment size distributions were due to the neutralization process. The neutralization effect defined in this way was found to dominate the strand breakage frequency within a range of 5-7 base pairs around the (125)I decay site on both strands. After implementing this neutralization effect derived from the oligoDNA analysis into the PARTRAC simulation for the CAP-DNA complex, the agreement of the calculated DNA fragment distributions with the corresponding experimental data was considerably improved. The results indicate that DNA conformation may be explored by incorporation of (125)I into the DNA, measurement of fragment size distributions, and comparison with simulation calculation for various hypothetical DNA models.