A comprehensive review of the proline mimic azetidine-2-carboxylic acid (A2C).

The imino acid azetidine-2-carboxylic acid (A2C), a proline homologue, was first identified in liliaceous plants in 1955. Its ability to exchange for proline in protein synthesis is responsible for its teratogenic effects and has made it a very useful tool for generating non-native proteins to study proteotoxic stress and ER stress. The tRNA synthetases from some A2C-producing plants can discriminate between proline and A2C, but for most plants and for mammalian cells, A2C is mistakenly used in protein synthesis in place of proline and can avoid cell proof-reading mechanisms. Human exposure to A2C would be very limited had it not been for the development of sugar beets as an alternative source of dietary sucrose to sugar cane, and the widespread use of the plentiful byproducts as livestock fodder. Fodder beets, a very high yielding forage crop, are also used as livestock fodder particularly for lactating cows. It is therefore possible for A2C to enter the human food chain and impact human health. It was hypothesised that its ability to replace proline in protein synthesis generates immunogenic neo-epitopes in myelin basic protein and could therefore be a causative factor for multiple sclerosis. In this review we discuss the distribution of A2C in nature, what is known about its toxicity, and the impact of the proline to A2C exchange on protein structure and function and in particular the proteins collagen and myelin basic protein. We summarise analytical approaches that can be used to quantify A2C in complex biological samples and the adaptations made by some organisms to avoid its toxic effects. We summarise the evidence for human exposure to A2C and the geographical and temporal links to higher incidences of MS. Finally, we highlight gaps in our knowledge that require addressing before we can determine if this non-protein amino acid is a threat to human health

Role of P-selectin in platelet sequestration in pulmonary capillaries during endotoxemia

Background: There is growing evidence that platelets accumulate in the lung and contribute to the pathogenesis of acute lung injury during endotoxemia. The aims of the present study were to localize platelet sequestration in the pulmonary microcirculation and to investigate the role of P-selectin as a molecular mechanism of platelet endothelial cell interaction. Methods: We used in vivo fluorescence microscopy to quantify the kinetics of fluorescently labeled erythrocytes and platelets in alveolar capillary networks in rabbit lungs. Results: Six hours after onset of endotoxin infusion we observed a massive rolling along and firm adherence of platelets to lung capillary endothelial cells whereas under control conditions no platelet sequestration was detected. P-selectin was expressed on the surface of separated platelets which were incubated with endotoxin and in lung tissue. Pretreatment of platelets with fucoidin, a P-selectin antagonist, significantly attenuated the endotoxin-induced platelet rolling and adherence. In contrast, intravenous infusion of fucoidin in endotoxin-treated rabbits did not inhibit platelet sequestration in pulmonary capillaries. Conclusion: We conclude that platelets accumulate in alveolar capillaries following endotoxemia. P-selectin expressed on the surface of platelets seems to play an important role in mediating this platelet-endothelial cell interaction. Copyright (c) 2006 S. Karger AG, Basel

Simultaneous determination of natural and synthetic steroid estrogens and their conjugates in aqueous matrices by liquid chromatography / mass spectrometry

An analytical method for the simultaneous determination of nine free and conjugated steroid estrogens was developed with application to environmental aqueous matrices. Solid phase extraction (SPE) was employed for isolation and concentration, with detection by liquid chromatography/mass spectrometry (LC/MS) using electrospray ionisation (ESI) in the negative mode. Method recoveries for various aqueous matrices (wastewater, lake and drinking water) were determined, recoveries proving to be sample dependent. When spiked at 50 ng/l concentrations in sewage influent, recoveries ranged from 62-89 % with relative standard deviations (RSD) < 8.1 %. In comparison, drinking water spiked at the same concentrations had recoveries between 82-100 % with an RSD < 5%. Ion suppression is a known phenomenon when using ESI; hence its impact on method recovery was elucidated for raw sewage. Both ion suppression from matrix interferences and the extraction procedure has bearing on the overall method recovery. Analysis of municipal raw sewage identified several of the analytes of interest at ng/l concentrations, estriol (E3) being the most abundant. Only one conjugate, estrone 3-sulphate (E1-3S) was observe

Correction: Steele et al. Misincorporation Proteomics Technologies: A Review. Proteomes 2021, 9, 2.

In the original publication, there was a mistake in Table 2 as published [...]

Misincorporation Proteomics Technologies: A Review.

Proteinopathies are diseases caused by factors that affect proteoform conformation. As such, a prevalent hypothesis is that the misincorporation of noncanonical amino acids into a proteoform results in detrimental structures. However, this hypothesis is missing proteomic evidence, specifically the detection of a noncanonical amino acid in a peptide sequence. This review aims to outline the current state of technology that can be used to investigate mistranslations and misincorporations whilst framing the pursuit as Misincorporation Proteomics (MiP). The current availability of technologies explored herein is mass spectrometry, sample enrichment/preparation, data analysis techniques, and the hyphenation of approaches. While many of these technologies show potential, our review reveals a need for further development and refinement of approaches is still required

The strengths and difficulties questionnaire as a predictor of parent-reported diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder

notes: PMCID: PMC3848967This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The Strengths and Difficulties Questionnaire (SDQ) is widely used as an international standardised instrument measuring child behaviour. The primary aim of our study was to examine whether behavioral symptoms measured by SDQ were elevated among children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) relative to the rest of the population, and to examine the predictive value of the SDQ for outcome of parent-reported clinical diagnosis of ASD/ADHD. A secondary aim was to examine the extent of overlap in symptoms between children diagnosed with these two disorders, as measured by the SDQ subscales. A cross-sectional secondary analysis of data from the Millennium Birth Cohort (n = 19,519), was conducted. Data were weighted to be representative of the UK population as a whole. ADHD or ASD identified by a medical doctor or health professional were reported by parents in 2008 and this was the case definition of diagnosis; (ADHD n = 173, ASD n = 209, excluding twins and triplets). Study children's ages ranged from 6.3-8.2 years; (mean 7.2 years). Logistic regression was used to examine the association between the parent-reported clinical diagnosis of ASD/ADHD and teacher and parent-reported SDQ subscales. All SDQ subscales were strongly associated with both ASD and ADHD. There was substantial co-occurrence of behavioral difficulties between children diagnosed with ASD and those diagnosed with ADHD. After adjustment for other subscales, the final model for ADHD, contained hyperactivity/inattention and impact symptoms only and had a sensitivity of 91% and specificity of 90%; (AUC) = 0.94 (95% CI, 0.90-0.97). The final model for ASD was composed of all subscales except the 'peer problems' scales, indicating of the complexity of behavioural difficulties that may accompany ASD. A threshold of 0.03 produced model sensitivity and specificity of 79% and 93% respectively; AUC = 0.90 (95% CI, 0.86-0.95). The results support changes to DSM-5 removing exclusivity clauses.ESRCNational Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsul

Setback distances as a conservation tool in wildlife-human interactions : testing their efficacy for birds affected by vehicles on open-coast sandy beaches

In some wilderness areas, wildlife encounter vehicles disrupt their behaviour and habitat use. Changing driver behaviour has been proposed where bans on vehicle use are politically unpalatable, but the efficacy of vehicle setbacks and reduced speeds remains largely untested. We characterised bird-vehicle encounters in terms of driver behaviour and the disturbance caused to birds, and tested whether spatial buffers or lower speeds reduced bird escape responses on open beaches. Focal observations showed that: i) most drivers did not create sizeable buffers between their vehicles and birds; ii) bird disturbance was frequent; and iii) predictors of probability of flushing (escape) were setback distance and vehicle type (buses flushed birds at higher rates than cars). Experiments demonstrated that substantial reductions in bird escape responses required buffers to be wide (&gt; 25 m) and vehicle speeds to be slow (&lt; 30 km h-1). Setback distances can reduce impacts on wildlife, provided that they are carefully designed and derived from empirical evidence. No speed or distance combination we tested, however, eliminated bird responses. Thus, while buffers reduce response rates, they are likely to be much less effective than vehicle-free zones (i.e. beach closures), and rely on changes to current driver behaviou

Setback distances as a conservation tool in wildlife-human interactions : testing their efficacy for birds affected by vehicles on open-coast sandy beaches

In some wilderness areas, wildlife encounter vehicles disrupt their behaviour and habitat use. Changing driver behaviour has been proposed where bans on vehicle use are politically unpalatable, but the efficacy of vehicle setbacks and reduced speeds remains largely untested. We characterised bird-vehicle encounters in terms of driver behaviour and the disturbance caused to birds, and tested whether spatial buffers or lower speeds reduced bird escape responses on open beaches. Focal observations showed that: i) most drivers did not create sizeable buffers between their vehicles and birds; ii) bird disturbance was frequent; and iii) predictors of probability of flushing (escape) were setback distance and vehicle type (buses flushed birds at higher rates than cars). Experiments demonstrated that substantial reductions in bird escape responses required buffers to be wide (&gt; 25 m) and vehicle speeds to be slow (&lt; 30 km h-1). Setback distances can reduce impacts on wildlife, provided that they are carefully designed and derived from empirical evidence. No speed or distance combination we tested, however, eliminated bird responses. Thus, while buffers reduce response rates, they are likely to be much less effective than vehicle-free zones (i.e. beach closures), and rely on changes to current driver behaviou

The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.

Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities