Chronic toxicity of an environmentally relevant and equitoxic ratio of five metals to two Antarctic marine microalgae shows complex mixture interactivity

© 2018 Metal contaminants are rarely present in the environment individually, yet environmental quality guidelines are derived from single-metal toxicity data. Few metal mixture studies have investigated more than binary mixtures and many are at unrealistically high effect concentrations to freshwater organisms. This study investigates the toxicity of five metals (Cd, Cu, Ni, Pb, and Zn) to the Antarctic marine microalgae Phaeocystis antarctica and Cryothecomonas armigera. Two mixtures were tested: (i) an equitoxic mixture of contaminants present at their single-metal EC10 concentrations, and (ii) an environmental mixture based on the ratio metal concentrations in a contaminated Antarctic marine bay. Observed toxicity, as chronic population growth rate inhibition, was compared to Independent Action (IA) and Concentration Addition (CA) predictions parameterised to use EC10 values. This allowed for the inclusion of metals with low toxicities. The biomarkers chlorophyll a fluorescence, cell size and complexity, and intracellular lipid concentrations were assessed to investigate possible mechanisms behind metal-mixture interactions. Both microalgae had similar responses to the equitoxic mixture: non-interactive by IA and antagonistic by CA. Toxicity from the environmental mixture was antagonistic by IA to P. antarctica; however, to C. armigera it was concentration-dependent with antagonism at low toxicities and synergism at high toxicities by both IA and CA. Differences in dissolved organic carbon production and detoxification mechanisms may be responsible for these responses and warrants further investigation. This study shows that mixture toxicity interactions can be ratio, species, and concentration dependent. The responses of the microalgae to different mixture ratios highlight the need to assess toxicity at environmentally realistic metal ratios. Parameterising IA and CA reference models to use EC10s allowed for the inclusion of metals at low effect concentrations, which may otherwise be ignored. Reference mixture models are generally suitable for predicting chronic toxicity of metals to these marine microalgae at environmentally realistic ratios and concentrations. Toxic metal-mixture interactions were found to be concentration, ratio, and species dependent in exposures to two Antarctic marine microalgae

Assessing the Risk of Metals and Their Mixtures in the Antarctic Nearshore Marine Environment with Diffusive Gradients in Thin-Films

© 2019 American Chemical Society. Robust environmental assessments and contaminant monitoring in Antarctic near-shore marine environments need new techniques to overcome challenges presented by a highly dynamic environment. This study outlines an approach for contaminant monitoring and risk assessment in Antarctic marine conditions using diffusive gradients in thin-films (DGT) coupled to regionally specific ecotoxicology data and environmental quality standards. This is demonstrated in a field study where DGT samplers were deployed in the near-shore marine environment of East Antarctica around the operational Casey station and the abandoned Wilkes station to measure the time-averaged biologically available fraction of metal contaminants. The incorporation of DGT-labile concentrations to reference toxicity mixture models for three Antarctic organisms predicted low toxic effects (<5% effect to the growth or development of each organism). The comparison of metal concentrations to the Australian and New Zealand default water quality guideline values (WQGVs) showed no marine site exceeding the WQGVs for 95% species protection. However, all sites exceeded the 99% WQGVs due to copper concentrations that are likely of geogenic origin (i.e., not from anthropogenic sources). This study provides evidence supporting the use of the DGT technique to monitor contaminants and assess their environmental risk in the near-shore marine environment of Antarctica

Intra-epithelial neutrophils in paediatric severe asthma are associated with better lung function

BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in paediatric asthma is unknown. OBJECTIVES: To investigate the role of neutrophils and the IL-17A pathway in mediating paediatric severe therapy resistant asthma (STRA). METHODS: Children with STRA (n=51, age 12.6 (6 -16.3) years) and non-asthmatic controls (n=15, age 4.75 (1.6-16) years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings and biopsy. Neutrophils, IL-17A and IL-17RA expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells (PBECs) were stimulated with IL-17A and/or IL-22, with and without Budesonide. RESULTS: Children with STRA had increased intra-epithelial neutrophils, which positively correlated with FEV1 %predicted (r=0.43, p=0.008). Neutrophil-high patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in STRA. Submucosal and epithelial IL-17A positive cells and BAL IL-17A and IL-22 levels were similar in STRA and controls. However, there were significantly more IL-17RA positive cells in the submucosa and epithelium in children with STRA compared to controls (p=0.001). Stimulation of PBECs with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of Budesonide. CONCLUSIONS: A proportion of children with STRA exhibit increased intra-epithelial airway neutrophilia that correlated with better lung function. STRA was additionally characterised by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in paediatric severe asthma pathophysiology

Protocol for The International Cohort on Lifestyle Determinants of Health Study: A Longitudinal Investigation of Complementary and Integrative Health Utilization in Postsecondary Education Students.

Objectives: The specific aims are: 1) To characterize the health, wellness, and lifestyle of graduate and undergraduate students, and how these characteristics change over time; 2) To evaluate associations between lifestyle factors and gut microbiota populations and diversity; and 3) To evaluate associations between stress and stress management practices with sleep habits, quality of life, and overall health. Design: The International Cohort on Lifestyle Determinants of Health (INCLD Health) longitudinal cohort study is designed to assess health behaviors and lifestyle practices amongst adults studying complementary and integrative health (CIH) and higher-education students more generally after at least one to six years of exposure to CIH education. INCLD Health will adhere to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines. Settings/Location: Colleges and universities with a CIH focus or interest with the flagship site being the National University of Natural Medicine. Participants: Adults currently enrolled in a college or university with a CIH focus or interest. Outcome Measures: Study visits will be conducted at baseline, 6 months, then every 12 months until the end of each participants' degree program. Measures include anthropometrics; serum and salivary biomarkers of cardiovascular risk, reproductive hormones, and cortisol; nutritional intake measured by a digital food frequency questionnaire; sequencing of fecal microbiota; plus validated questionnaires investigating mood, perceived stress, stress management practices, physical activity, sleep, and wellness. Conclusions: The INCLD Health Study, approved by the NUNM IRB in late 2018, will enroll a unique cohort of adults to characterize the use of CIH practices in relation to short- and long-term health. Our study design provides a breadth of information that could be implemented at multiple sites internationally allowing for comparisons across diverse student cohorts with relatively low cost and personnel

Retrospective model-based inference guides model-free credit assignment

An extensive reinforcement learning literature shows that organisms assign credit efficiently, even under conditions of state uncertainty. However, little is known about credit-assignment when state uncertainty is subsequently resolved. Here, we address this problem within the framework of an interaction between model-free (MF) and model-based (MB) control systems. We present and support experimentally a theory of MB retrospective-inference. Within this framework, a MB system resolves uncertainty that prevailed when actions were taken thus guiding an MF credit-assignment. Using a task in which there was initial uncertainty about the lotteries that were chosen, we found that when participants’ momentary uncertainty about which lottery had generated an outcome was resolved by provision of subsequent information, participants preferentially assigned credit within a MF system to the lottery they retrospectively inferred was responsible for this outcome. These findings extend our knowledge about the range of MB functions and the scope of system interactions

New Sum Rules from Low Energy Compton Scattering on Arbitrary Spin Target

We derive two sum rules by studying the low energy Compton scattering on a target of arbitrary (nonzero) spin j. In the first sum rule, we consider the possibility that the intermediate state in the scattering can have spin |j \pm 1| and the same mass as the target. The second sum rule applies if the theory at hand possesses intermediate narrow resonances with masses different from the mass of the scatterer. These sum rules are generalizations of the Gerasimov-Drell-Hearn-Weinberg sum rule. Along with the requirement of tree level unitarity, they relate different low energy couplings in the theory. Using these sum rules, we show that in certain cases the gyromagnetic ratio can differ from the "natural" value g=2, even at tree level, without spoiling perturbative unitarity. These sum rules can be used as constraints applicable to all supergravity and higher-spin theories that contain particles charged under some U(1) gauge field. In particular, applied to four dimensional N=8 supergravity in a spontaneously broken phase, these sum rules suggest that for the theory to have a good ultraviolet behavior, additional massive states need to be present, such as those coming from the embedding of the N=8 supergravity in type II superstring theory. We also discuss the possible implications of the sum rules for QCD in the large-N_c limit.Comment: 18 pages, v2: discussion on black hole contribution is included, references added; v3: extended discussion in introduction, version to appear in JHE

The C-Terminal Domain of the Arabinosyltransferase Mycobacterium tuberculosis EmbC Is a Lectin-Like Carbohydrate Binding Module

The D-arabinan-containing polymers arabinogalactan (AG) and lipoarabinomannan (LAM) are essential components of the unique cell envelope of the pathogen Mycobacterium tuberculosis. Biosynthesis of AG and LAM involves a series of membrane-embedded arabinofuranosyl (Araf) transferases whose structures are largely uncharacterised, despite the fact that several of them are pharmacological targets of ethambutol, a frontline drug in tuberculosis therapy. Herein, we present the crystal structure of the C-terminal hydrophilic domain of the ethambutol-sensitive Araf transferase M. tuberculosis EmbC, which is essential for LAM synthesis. The structure of the C-terminal domain of EmbC (EmbCCT) encompasses two sub-domains of different folds, of which subdomain II shows distinct similarity to lectin-like carbohydrate-binding modules (CBM). Co-crystallisation with a cell wall-derived di-arabinoside acceptor analogue and structural comparison with ligand-bound CBMs suggest that EmbCCT contains two separate carbohydrate binding sites, associated with subdomains I and II, respectively. Single-residue substitution of conserved tryptophan residues (Trp868, Trp985) at these respective sites inhibited EmbC-catalysed extension of LAM. The same substitutions differentially abrogated binding of di- and penta-arabinofuranoside acceptor analogues to EmbCCT, linking the loss of activity to compromised acceptor substrate binding, indicating the presence of two separate carbohydrate binding sites, and demonstrating that subdomain II indeed functions as a carbohydrate-binding module. This work provides the first step towards unravelling the structure and function of a GT-C-type glycosyltransferase that is essential in M. tuberculosis. Author Summary Top Tuberculosis (TB), an infectious disease caused by the bacillus Mycobacterium tuberculosis, burdens large swaths of the world population. Treatment of active TB typically requires administration of an antibiotic cocktail over several months that includes the drug ethambutol. This front line compound inhibits a set of arabinosyltransferase enzymes, called EmbA, EmbB and EmbC, which are critical for the synthesis of arabinan, a vital polysaccharide in the pathogen's unique cell envelope. How precisely ethambutol inhibits arabinosyltransferase activity is not clear, in part because structural information of its pharmacological targets has been elusive. Here, we report the high-resolution structure of the C-terminal domain of the ethambutol-target EmbC, a 390-amino acid fragment responsible for acceptor substrate recognition. Combining the X-ray crystallographic analysis with structural comparisons, site-directed mutagenesis, activity and ligand binding assays, we identified two regions in the C-terminal domain of EmbC that are capable of binding acceptor substrate mimics and are critical for activity of the full-length enzyme. Our results begin to define structure-function relationships in a family of structurally uncharacterised membrane-embedded glycosyltransferases, which are an important target for tuberculosis therapy

“Am I my genes?”: Questions of identity among individuals confronting genetic disease

Purpose: To explore many questions raised by genetics concerning personal identities that have not been fully investigated. Methods: We interviewed in depth, for 2 hours each, 64 individuals who had or were at risk for Huntington disease, breast cancer, or alpha-1 antitrypsin deficiency. Results: These individuals struggled with several difficult issues of identity. They drew on a range of genotypes and phenotypes (e.g., family history alone; mutations, but no symptoms; or symptoms). They often felt that their predicament did not fit preexisting categories well (e.g., “sick,” “healthy,” “disabled,” “predisposed”), due in part to uncertainties involved (e.g., unclear prognoses, since mutations may not produce symptoms). Hence, individuals varied in how much genetics affected their identity, in what ways, and how negatively. Factors emerged related to disease, family history, and other sources of identity. These identities may, in turn, shape disclosure, coping, and other health decisions. Conclusions: Individuals struggle to construct a genetic identity. They view genetic information in highly subjective ways, varying widely in what aspects of genetic information they focus on and how. These data have important implications for education of providers (to assist patients with these issues), patients, and family members; and for research, to understand these issues more fully

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation