Circularity in fisheries data weakens real world prediction

The systematic substitution of direct observational data with synthesized data derived from models during the stock assessment process has emerged as a low-cost alternative to direct data collection efforts. What is not widely appreciated, however, is how the use of such synthesized data can overestimate predictive skill when forecasting recruitment is part of the assessment process. Using a global database of stock assessments, we show that Standard Fisheries Models (SFMs) can successfully predict synthesized data based on presumed stock-recruitment relationships, however, they are generally less skillful at predicting observational data that are either raw or minimally filtered (denoised without using explicit stock-recruitment models). Additionally, we find that an equation-free approach that does not presume a specific stock-recruitment relationship is better than SFMs at predicting synthesized data, and moreover it can also predict observational recruitment data very well. Thus, while synthesized datasets are cheaper in the short term, they carry costs that can limit their utility in predicting real world recruitment.https://www.nature.com/articles/s41598-020-63773-3Published versio

Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cells

Neurons rely on the release and subsequent cleavage of GSH to cysteinylglycine (CysGly) by astrocytes in order to maintain optimal intracellular GSH levels. In neurodegenerative diseases characterised by oxidative stress, neurons need an optimal GSH supply to defend themselves against free radicals released from activated microglia and astroglia. The rate of GSH synthesis is controlled largely by the activity of γ-glutamyl cysteine ligase. Expression of γ-glutamyl cysteine ligase and of the Xc- system, which facilitates cystine uptake, is regulated by the redox-sensitive transcription factor, nuclear factor erythroid-2-related factor 2 (Nrf2). Compounds that can activate the Nrf2-ARE pathway, referred to as ‘Nrf2 activators’ are receiving growing attention due to their potential as GSH-boosting drugs. This study compares four known Nrf2 activators, R-α-Lipoic acid (LA), tert-butylhydroquinone (TBHQ), sulforaphane (SFN) and Polygonum cuspidatum extract containing 50% resveratrol (PC-Res) for their effects on astroglial release of GSH and CysGly. GSH levels increased dose-dependently in response to all four drugs. Sulforaphane produced the most potent effect, increasing GSH by up to 2.4-fold. PC-Res increased GSH up to 1.6-fold, followed by TBHQ (1.5-fold) and LA (1.4-fold). GSH is processed by the ectoenzyme, γ-glutamyl transpeptidase, to form CysGly. Once again, SFN produced the most potent effect, increasing CysGly by up to 1.7-fold, compared to control cells. TBHQ and PC-Res both induced fold increases of 1.3, followed by LA with a fold increase of 1.2. The results from the present study showed that sulforaphane, followed by lipoic acid, resveratrol and Polygonum multiflorum were all identified as potent “GSH and Cys-Gly boosters”

Development of a high-performance liquid chromatography method for the simultaneous quantitation of glutathione and related thiols

The development of drugs with the ability to increase the level of the antioxidant glutathione and related metabolites has become an important research area for many age-related diseases. Here we describe a high-performance liquid chromatography (HPLC) method that uses the thiol-specific, fluorogenic reagent 4-fluoro-7-aminosulfonylbenzofurazan (ABD-F) for the simultaneous determination of total glutathione (GSH), cysteine (Cys), cysteinylglycine (CysGly), and homocysteine (Hcys) in cell culture medium. ABD-F-labeled thiols were separated using an isocratic mobile phase consisting of 14% methanol and 86% 0.1M acetate buffer at pH4.0. The method was validated for linearity, accuracy, and intra- and interday precision, and the lower and upper limits of quantitation (LLOQ and ULOQ, respectively) were determined using a Dionex RF-2000 detector set to medium sensitivity. In addition, the suitability of N-acetylcysteine (NAC) as an internal standard was evaluated by external and internal standard calibration methods. Although both calibration methods showed acceptable linearity (correlation coefficients\u3e0.99) and intra- and interday precision (relative standard deviations=10.2 and 6.6%, respectively), the external standard calibration method performed better in terms of accuracy (recovery=93.7-125%) and also had lower LLOQ values for all analytes (Cys=6.3μM, CysGly=0.8μM, Hcys=0.8μM, and GSH=1.6μM)

Cytoprotective properties of traditional Chinese medicinal herbal extracts in hydrogen peroxide challenged human U373 astroglia cells

Age is the leading risk factor for many of the most prevalent and devastating diseases including neurodegenerative diseases. A number of herbal medicines have been used for centuries to ameliorate the deleterious effects of ageing-related diseases and increase longevity. Oxidative stress is believed to play a role in normal ageing as well as in neurodegenerative processes. Since many of the constituents of herbal extracts are known antioxidants, it is believed that restoring oxidative balance may be one of the underlying mechanisms by which medicinal herbs can protect against ageing and cognitive decline. Based on the premise that astrocytes are key modulators in the progression of oxidative stress associated neurodegenerative diseases, 13 herbal extracts purported to possess anti-ageing properties were tested for their ability to protect U373 human astrocytes from hydrogen peroxide induced cell death. To determine the contribution of antioxidant activity to the cytoprotective ability of extracts, total phenol content and radical scavenging capacities of extracts were examined. Polygonum multiflorum, amongst others, was identified as possessing potent antioxidant and cytoprotective properties. Not surprisingly, total phenol content of extracts was strongly correlated with antioxidant capacity. Interestingly, when total phenol content and radical scavenging capacities of extracts were compared to the cytoprotective properties of extracts, only moderately strong correlations were observed. This finding suggests the involvement of multiple protective mechanisms in the beneficial effects of these medicinal herbs

Generation of hydrogen peroxide-resistant murine neuroblastoma cells: a target discovery platform for novel neuroprotective genes

Oxidative stress has been suggested to play an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer’s disease (AD). Hydrogen peroxide (H2O2), one of the main reactive oxygen species, is converted into the highly toxic ·OH radical in the presence of redox-active transition metals, which then oxidises nucleic acids, lipids and proteins, leading to neurodegeneration and cell death. There is an urgent need to gain more knowledge about relevant therapeutic targets to combat oxidative stress and it neurotoxic effects, and how this knowledge can be utilized to develop novel neuroprotective therapies for AD. One way to identify new mechanisms combating oxidative stress was via the creation of H2O2-resistant cell lines and identification of the mechanisms responsible for their resistance. However, in most cases catalase overexpression or increased glutathione content was identified as the primary mode of H2O2 resistance in these cell lines. In this study, we have generated six different resistant neuronal cell lines or populations (from the same original murine Neuro2a neuroblastoma line) by exposing cells to increasing concentrations of H2O2 and performing continuous selection for survivors over a period of several months, which appear to have acquired H2O2 resistance based on other, novel mechanisms. These six populations showed a significant, but differential resistance against H2O2 when compared with the parental cell line. Using combinations of catalase-, glutathione synthesis- and glutathione peroxidase-inhibitors it was shown that the increased resistance of Neuro2a-HR cells is not solely based on an increased activity of catalase or the glutathione system, suggesting that their resistance might be based on yet unknown, novel defence mechanisms

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer\u27s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that leads to a progressive decline in a person’s memory and ability to communicate and carry out daily activities. The brain pathology in AD is characterized by extensive neuronal loss, particularly of cholinergic neurons, intracellular neurofibrillary tangles composed of the tau protein (NFTs) and extracellular deposition of plaques composed of β-amyloid (Aβ), a cleavage product of the amyloid precursor protein (APP). These two insoluble protein aggregates are accompanied by a chronic inflammatory response and extensive oxidative damage. Whereas dys-regulation of APP expression or processing appears to be important for the familial, early-onset form of AD, controversy exists between the “Baptists” (in favour of Aβ) and the “Tauists” (in favour of tau) as to which of these two protein dysfunctions occur at the earliest stages or are the most important contributors to the disease process in sporadic AD. However, more and more “non-amyloid” and “non-tau” causes have been proposed, including, glycation, inflammation, oxidative stress and dys-regulation of the cell cycle. However, to get an insight into the ultimate cause of AD, and to prove that any drug target is valuable in AD, disease-relevant models giving insight into the pathogenic processes in AD are urgently needed. In the absence of a good animal model for sporadic AD, we propose in this review that induced pluripotent stem cells, derived from dermal fibroblasts of AD patients, and differentiated into cholinergic neurons, might be a promising novel tool for disease modelling and drug discovery for the sporadic form of AD