Microglia and the aging brain:are senescent microglia the key to neurodegeneration?

The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer's disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer's disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron-overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.</p

Enhancing reductive cleavage of aromatic carboxamides

[GRAPHICS] A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)amine in most cases in nearly quantitative yields, Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH4 are given

Paradoxical Role of Prion Protein Aggregates in Redox-Iron Induced Toxicity

Imbalance of iron homeostasis has been reported in sporadic Creutzfeldt-Jakob-disease (sCJD) affected human and scrapie infected animal brains, but the contribution of this phenotype to disease associated neurotoxicity is unclear.Using cell models of familial prion disorders, we demonstrate that exposure of cells expressing normal prion protein (PrP(C)) or mutant PrP forms to a source of redox-iron induces aggregation of PrP(C) and specific mutant PrP forms. Initially this response is cytoprotective, but becomes increasingly toxic with time due to accumulation of PrP-ferritin aggregates. Mutant PrP forms that do not aggregate are not cytoprotective, and cells show signs of acute toxicity. Intracellular PrP-ferritin aggregates induce the expression of LC3-II, indicating stimulation of autophagy in these cells. Similar observations are noted in sCJD and scrapie infected hamster brains, lending credence to these results. Furthermore, phagocytosis of PrP-ferritin aggregates by astrocytes is cytoprotective, while culture in astrocyte conditioned medium (CM) shows no measurable effect. Exposure to H(2)O(2), on the other hand, does not cause aggregation of PrP, and cells show acute toxicity that is alleviated by CM.These observations suggest that aggregation of PrP in response to redox-iron is cytoprotective. However, subsequent co-aggregation of PrP with ferritin induces intracellular toxicity unless the aggregates are degraded by autophagosomes or phagocytosed by adjacent scavenger cells. H(2)O(2), on the other hand, does not cause aggregation of PrP, and induces toxicity through extra-cellular free radicals. Together with previous observations demonstrating imbalance of iron homeostasis in prion disease affected brains, these observations provide insight into the mechanism of neurotoxicity by redox-iron, and the role of PrP in this process

Explaining oscillations and variability in the p53-Mdm2 system

<p>Abstract</p> <p>Background</p> <p>In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14^ARFwhich sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing.</p> <p>Results</p> <p>The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells.</p> <p>Conclusion</p> <p>The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.</p

Need for recovery amongst emergency physicians in the UK and Ireland: A cross-sectional survey

OBJECTIVES: To determine the need for recovery (NFR) among emergency physicians and to identify demographic and occupational characteristics associated with higher NFR scores. DESIGN: Cross-sectional electronic survey. SETTING: Emergency departments (EDs) (n=112) in the UK and Ireland. PARTICIPANTS: Emergency physicians, defined as any registered physician working principally within the ED, responding between June and July 2019. MAIN OUTCOME MEASURE: NFR Scale, an 11-item self-administered questionnaire that assesses how work demands affect intershift recovery. RESULTS: The median NFR Score for all 4247 eligible, consented participants with a valid NFR Score was 70.0 (95% CI: 65.5 to 74.5), with an IQR of 45.5-90.0. A linear regression model indicated statistically significant associations between gender, health conditions, type of ED, clinical grade, access to annual and study leave, and time spent working out-of-hours. Groups including male physicians, consultants, general practitioners (GPs) within the ED, those working in paediatric EDs and those with no long-term health condition or disability had a lower NFR Score. After adjusting for these characteristics, the NFR Score increased by 3.7 (95% CI: 0.3 to 7.1) and 6.43 (95% CI: 2.0 to 10.8) for those with difficulty accessing annual and study leave, respectively. Increased percentage of out-of-hours work increased NFR Score almost linearly: 26%-50% out-of-hours work=5.7 (95% CI: 3.1 to 8.4); 51%-75% out-of-hours work=10.3 (95% CI: 7.6 to 13.0); 76%-100% out-of-hours work=14.5 (95% CI: 11.0 to 17.9). CONCLUSION: Higher NFR scores were observed among emergency physicians than reported in any other profession or population to date. While out-of-hours working is unavoidable, the linear relationship observed suggests that any reduction may result in NFR improvement. Evidence-based strategies to improve well-being such as proportional out-of-hours working and improved access to annual and study leave should be carefully considered and implemented where feasible

An electron spin resonance study of gamma-irradiated citrus fruits.

The ESR spectra of the stalks and skins of a selection of unirradiated and γ-irradiated citrus fruits have been obtained. The spectra from the stalks and skins of unirradiated fruits exhibit only a single line, the intensity of which varies markedly from fruit to fruit. The spectra from irradiated stalks exhibit extra features which can be used to detect irradiation, particularly at higher doses. The spectra obtained from the skins of the irradiated fruits also exhibit radiation-induced features which can easily be used to detect irradiation even at the lowest dose examined (2 kGy). The spectra from the irradiated skins show a high degree of reproducibility from fruit to fruit. These observations suggest that ESR spectroscopy could form the basis of a viable test to determine the radiation history of these fruits

ESR spin-trap study of the radicals present during the thermolysis of some novel dialkyl peroxides.

The thermolysis of two bifunctional dialkyl peroxides [2,5-dimethyl-2,5-bis(tert-butylperoxy)hexane (1) and 2,5-dimethyl-2,5-bis(tert-butylperoxy)-3-hexyne (2)] and two novel monofunctional dialkyl peroxides [2-methyl-(2-tert-amylperoxy)pentan-4-ol (3) and 2-methyl-(2-tert-butylperoxy)pentan-4-ol (4)] was undertaken, in various solvents, between 353 and 383 K and the radicals generated trapped employing DMPO, PBN-d14 and 2,4,6-tri-tert-butylnitrosobenzene (TTBNB). We established that both 1 and 2 release the tert-butoxyl radical (and the methyl radical via -scission) following cleavage of one of the O - O bonds. During the thermolysis of 1 a ·CH2R radical was trapped which we assign to the 3-methyl-3-(tert-butylperoxy)butyl radical (6). We found no evidence for the presence of an alkynyl radical during the thermolysis of 2. The tert-amyloxyl (and the ethyl radical via -scission) and the tert-butoxyl radical (and the methyl radical via -scission) were trapped during the thermolysis of 3 and 4, respectively. The 2-hydroxypropyl radical (10) was trapped employing TTBNB during the thermolysis of both 3 and 4 with its adduct exhibiting two magnetically non-equivalent -protons as a consequence of the adjacent chiral carbon atom. Reaction schemes for the thermolysis all four peroxides are proposed based on the nature of the trapped radicals

A high-field 13C-NMR study of the aqueous copolymerisations of acrylonitrile and vinyl acetate. Microstructural observations.

A detailed examination has been undertaken of the high field 13C-NMR spectrum of various acrylonitrile/vinyl acetate copolymers prepared by radical initiation in a heterogeneous aqueous batch reaction (taken to low conversion). It has been possible to establish the triad, tetrad and pentad sequences for copolymers employing sequence patterns and peak fractions as an aid to peak assignments. These results indicate that the copolymer cotacticity is virtually independent of the comonomer feed ratio