A Novel Antibody-Based Biomarker for Chronic Algal Toxin Exposure and Sub-Acute Neurotoxicity

The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins

Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity

Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins

The TIGGE project and its achievements

TIGGE was a major component of the THORPEX (The Observing System Research and Predictability Experiment) research program, whose aim is to accelerate improvements in forecasting high-impact weather. By providing ensemble prediction data from leading operational forecast centers, TIGGE has enhanced collaboration between the research and operational meteorological communities and enabled research studies on a wide range of topics. The paper covers the objective evaluation of the TIGGE data. For a range of forecast parameters, it is shown to be beneficial to combine ensembles from several data providers in a Multi-model Grand Ensemble. Alternative methods to correct systematic errors, including the use of reforecast data, are also discussed. TIGGE data have been used for a range of research studies on predictability and dynamical processes. Tropical cyclones are the most destructive weather systems in the world, and are a focus of multi-model ensemble research. Their extra-tropical transition also has a major impact on skill of mid-latitude forecasts. We also review how TIGGE has added to our understanding of the dynamics of extra-tropical cyclones and storm tracks. Although TIGGE is a research project, it has proved invaluable for the development of products for future operational forecasting. Examples include the forecasting of tropical cyclone tracks, heavy rainfall, strong winds, and flood prediction through coupling hydrological models to ensembles. Finally the paper considers the legacy of TIGGE. We discuss the priorities and key issues in predictability and ensemble forecasting, including the new opportunities of convective-scale ensembles, links with ensemble data assimilation methods, and extension of the range of useful forecast skill

Structure Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.</p

Using European travellers as an early alert to detect emerging pathogens in countries with limited laboratory resources

BACKGROUND: The volume, extent and speed of travel have dramatically increased in the past decades, providing the potential for an infectious disease to spread through the transportation network. By collecting information on the suspected place of infection, existing surveillance systems in industrialized countries may provide timely information for areas of the world without adequate surveillance currently in place. We present the results of a case study using reported cases of Shigella dysenteriae serotype 1 (Sd1) in European travellers to detect "events" of Sd1, related to either epidemic cases or endemic cases in developing countries. METHODS: We identified papers from a Medline search for reported events of Sd1 from 1940 to 2002. We requested data on shigella infections reported to the responsible surveillance entities in 17 European countries. Reports of Sd1 from the published literature were then compared with Sd1 notified cases among European travellers from 1990 to 2002. RESULTS: Prior to a large epidemic in 1999–2000, no cases of Sd1 had been identified in West Africa. However, if travellers had been used as an early warning, Sd1 could have been identified in this region as earlier as 1992. CONCLUSION: This project demonstrates that tracking diseases in European travellers could be used to detect emerging disease in developing countries. This approach should be further tested with a view to the continuous improvement of national health surveillance systems and existing European networks, and may play a significant role in aiding the international public health community to improve infectious disease control

Attribution: how is it relevant for loss and damage policy and practice?

Attribution has become a recurring issue in discussions about Loss and Damage (L&D). In this highly-politicised context, attribution is often associated with responsibility and blame; and linked to debates about liability and compensation. The aim of attribution science, however, is not to establish responsibility, but to further scientific understanding of causal links between elements of the Earth System and society. This research into causality could inform the management of climate-related risks through improved understanding of drivers of relevant hazards, or, more widely, vulnerability and exposure; with potential benefits regardless of political positions on L&D. Experience shows that it is nevertheless difficult to have open discussions about the science in the policy sphere. This is not only a missed opportunity, but also problematic in that it could inhibit understanding of scientific results and uncertainties, potentially leading to policy planning which does not have sufficient scientific evidence to support it. In this chapter, we first explore this dilemma for science-policy dialogue, summarising several years of research into stakeholder perspectives of attribution in the context of L&D. We then aim to provide clarity about the scientific research available, through an overview of research which might contribute evidence about the causal connections between anthropogenic climate change and losses and damages, including climate science, but also other fields which examine other drivers of hazard, exposure, and vulnerability. Finally, we explore potential applications of attribution research, suggesting that an integrated and nuanced approach has potential to inform planning to avert, minimise and address losses and damages. The key messages are In the political context of climate negotiations, questions about whether losses and damages can be attributed to anthropogenic climate change are often linked to issues of responsibility, blame, and liability. Attribution science does not aim to establish responsibility or blame, but rather to investigate drivers of change. Attribution science is advancing rapidly, and has potential to increase understanding of how climate variability and change is influencing slow onset and extreme weather events, and how this interacts with other drivers of risk, including socio-economic drivers, to influence losses and damages. Over time, some uncertainties in the science will be reduced, as the anthropogenic climate change signal becomes stronger, and understanding of climate variability and change develops. However, some uncertainties will not be eliminated. Uncertainty is common in science, and does not prevent useful applications in policy, but might determine which applications are appropriate. It is important to highlight that in attribution studies, the strength of evidence varies substantially between different kinds of slow onset and extreme weather events, and between regions. Policy-makers should not expect the later emergence of conclusive evidence about the influence of climate variability and change on specific incidences of losses and damages; and, in particular, should not expect the strength of evidence to be equal between events, and between countries. Rather than waiting for further confidence in attribution studies, there is potential to start working now to integrate science into policy and practice, to help understand and tackle drivers of losses and damages, informing prevention, recovery, rehabilitation, and transformation

Pleiotropy of Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Self-Renewal of Embryonic Stem Cells from Refractory Mouse Strains

Background: Inhibition of glycogen synthase kinase-3 (GSK-3) improves the efficiency of embryonic stem (ES) cell derivation from various strains of mice and rats, as well as dramatically promotes ES cell self-renewal potential. b-catenin has been reported to be involved in the maintenance of self-renewal of ES cells through TCF dependent and independent pathway. But the intrinsic difference between ES cell lines from different species and strains has not been characterized. Here, we dissect the mechanism of GSK-3 inhibition by CHIR99021 in mouse ES cells from refractory mouse strains. Methodology/Principal Findings: We found that CHIR99021, a GSK-3 specific inhibitor, promotes self-renewal of ES cells from recalcitrant C57BL/6 (B6) and BALB/c mouse strains through stabilization of b-catenin and c-Myc protein levels. Stabilized b-catenin promoted ES self-renewal through two mechanisms. First, b-catenin translocated into the nucleus to maintain stem cell pluripotency in a lymphoid-enhancing factor/T-cell factor–independent manner. Second, b-catenin binds plasma membrane-localized E-cadherin, which ensures a compact, spherical morphology, a hallmark of ES cells. Further, elevated c-Myc protein levels did not contribute significantly to CH-mediated ES cell self-renewal. Instead, the role of c-Myc is dependent on its transformation activity and can be replaced by N-Myc but not L-Myc. b-catenin and c-Myc have similar effects on ES cells derived from both B6 and BALB/c mice. Conclusions/Significance: Our data demonstrated that GSK-3 inhibition by CH promotes self-renewal of mouse ES cell