The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

New Caledonian crows rapidly solve a collaborative problem without cooperative cognition

There is growing comparative evidence that the cognitive bases of cooperation are not unique to humans. However, the selective pressures that lead to the evolution of these mechanisms remain unclear. Here we show that while tool-making New Caledonian crows can produce collaborative behavior, they do not understand the causality of cooperation nor show sensitivity to inequity. Instead, the collaborative behavior produced appears to have been underpinned by the transfer of prior experience. These results suggest that a number of possible selective pressures, including tool manufacture and mobbing behaviours, have not led to the evolution of cooperative cognition in this species. They show that causal cognition can evolve in a domain specific manner-understanding the properties and flexible uses of physical tools does not necessarily enable animals to grasp that a conspecific can be used as a social tool

Biomarkers and in vitro strategies for nephrotoxicity and renal disease assessment

Acute kidney injury (AKI) is a global public health concern, impacting nearly 13.3 million patients and resulting in three million deaths per year. Chronic kidney disease has increased by 135% since 1990, representing the pathology with the fastest growth rate worldwide. The annual costs of dialysis and kidney transplants range between US$35,000 and US$100,000 per patient. Despite its great impact, kidney disease has remained mostly asymptomatic for many years. AKI continues to be a major, unmet medical condition for which there are no pharmacological treatments available, while animal models are limited to provide direction for therapeutic translation into humans. Currently, serum creatinine is the standard biomarker to identify nephrotoxicity; however, it is a late stage biomarker. Hence, there is a pressing need to study in vitro biomarkers for the assessment of nephrotoxicity in order to develop new and safer drugs. Understanding of the mechanisms by which molecules produce nephrotoxicity is vital in order to both prevent adversity and treat kidney injury. In this review, we address new technologies and models that may be used to identify earlier biomarkers and pathways involved in nephrotoxicity, such as cell culture, omics, bioinformatics platform, CRISPR/Cas9 genome-editing, in silico, organoids and 3D bioprinting, considering AOP

An assessment of upper ocean salinity content from the ocean reanalyses inter-comparison project (ORA-IP)

Many institutions worldwide have developed ocean reanalyses systems (ORAs) utilizing a variety of ocean models and assimilation techniques. However, the quality of salinity reanalyses arising from the various ORAs has not yet been comprehensively assessed. In this study, we assess the upper ocean salinity content (depth-averaged over 0–700 m) from 14 ORAs and 3 objective ocean analysis systems (OOAs) as part of the Ocean Reanalyses Intercomparison Project. Our results show that the best agreement between estimates of salinity from different ORAs is obtained in the tropical Pacific, likely due to relatively abundant atmospheric and oceanic observations in this region. The largest disagreement in salinity reanalyses is in the Southern Ocean along the Antarctic circumpolar current as a consequence of the sparseness of both atmospheric and oceanic observations in this region. The West Pacific warm pool is the largest region where the signal to noise ratio of reanalysed salinity anomalies is >1. Therefore, the current salinity reanalyses in the tropical Pacific Ocean may be more reliable than those in the Southern Ocean and regions along the western boundary currents. Moreover, we found that the assimilation of salinity in ocean regions with relatively strong ocean fronts is still a common problem as seen in most ORAs. The impact of the Argo data on the salinity reanalyses is visible, especially within the upper 500m, where the interannual variability is large. The increasing trend in global-averaged salinity anomalies can only be found within the top 0–300m layer, but with quite large diversity among different ORAs. Beneath the 300m depth, the global-averaged salinity anomalies from most ORAs switch their trends from a slightly growing trend before 2002 to a decreasing trend after 2002. The rapid switch in the trend is most likely an artefact of the dramatic change in the observing system due to the implementation of Argo

Exploring perceptions of advertising ethics: an informant-derived approach

Whilst considerable research exists on determining consumer responses to pre-determined statements within numerous ad ethics contexts, our understanding of consumer thoughts regarding ad ethics in general remains lacking. The purpose of our study therefore is to provide a first illustration of an emic and informant-based derivation of perceived ad ethics. The authors use multi-dimensional scaling as an approach enabling the emic, or locally derived deconstruction of perceived ad ethics. Given recent calls to develop our understanding of ad ethics in different cultural contexts, and in particular within the Middle East and North Africa (MENA) region, we use Lebanon—the most ethically charged advertising environment within MENA—as an illustrative context for our study. Results confirm the multi-faceted and pluralistic nature of ad ethics as comprising a number of dimensional themes already salient in the existing literature but in addition, we also find evidence for a bipolar relationship between individual themes. The specific pattern of inductively derived relationships is culturally bound. Implications of the findings are discussed, followed by limitations of the study and recommendations for further research

Determination of the number of J/ψ events with J/ψ → inclusive decays

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Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

D1 Dopamine Receptor Signaling Is Modulated by the R7 RGS Protein EAT-16 and the R7 Binding Protein RSBP-1 in Caenoerhabditis elegans Motor Neurons

Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1) required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior

Substantiating chemical groups for read-across using molecular response profiles

By grouping structurally similar chemicals, toxicity endpoints from data-rich substances can be read across to data-poor substances, supporting environmental and human health risk assessment without animal testing. However, structural similarity alone is insufficient, and additional supporting data can strengthen a grouping justification. This study aimed to demonstrate how multi-omics bioactivity data can increase confidence in a grouping hypothesis, where the bioactivity profiles can reflect a chemical’s mode(s) of action. We investigated three structurally similar phthalates and three uncouplers of oxidative phosphorylation, applying structure-based grouping approaches and short-term exposures of the ecotoxicological test species Daphnia magna to generate multi-omics data. Bioactivity similarities between the ‘omics responses to chemical exposure were assessed using t-statistics comparing treated samples to controls and visualised using hierarchical cluster analysis. Conventional structure-based grouping did not assign the phthalates and uncouplers into two anticipated categories, with the structurally more diverse uncouplers often assigned into multiple groups. Following bioactivity thresholding, which removed one uncoupler as it induced minimal molecular responses, bioactivity profile-based grouping of the remaining five substances correctly separated them into two chemical classes with high replicability confidence. However, a plausible toxicological interpretation of the reduced set of functionally annotated molecular features driving the grouping was attempted, although of limited success. This study demonstrates how multi-omics bioactivity profiles can increase confidence in chemical grouping and investigates a potential strategy for plausibly interpreting ‘omics data

Host Responses to Intestinal Microbial Antigens in Gluten-Sensitive Mice

BACKGROUND AND AIMS: Excessive uptake of commensal bacterial antigens through a permeable intestinal barrier may influence host responses to specific antigen in a genetically predisposed host. The aim of this study was to investigate whether intestinal barrier dysfunction induced by indomethacin treatment affects the host response to intestinal microbiota in gluten-sensitized HLA-DQ8/HCD4 mice. METHODOLOGY/PRINCIPAL FINDINGS: HLA-DQ8/HCD4 mice were sensitized with gluten, and gavaged with indomethacin plus gluten. Intestinal permeability was assessed by Ussing chamber; epithelial cell (EC) ultra-structure by electron microscopy; RNA expression of genes coding for junctional proteins by Q-real-time PCR; immune response by in-vitro antigen-specific T-cell proliferation and cytokine analysis by cytometric bead array; intestinal microbiota by fluorescence in situ hybridization and analysis of systemic antibodies against intestinal microbiota by surface staining of live bacteria with serum followed by FACS analysis. Indomethacin led to a more pronounced increase in intestinal permeability in gluten-sensitized mice. These changes were accompanied by severe EC damage, decreased E-cadherin RNA level, elevated IFN-gamma in splenocyte culture supernatant, and production of significant IgM antibody against intestinal microbiota. CONCLUSION: Indomethacin potentiates barrier dysfunction and EC injury induced by gluten, affects systemic IFN-gamma production and the host response to intestinal microbiota antigens in HLA-DQ8/HCD4 mice. The results suggest that environmental factors that alter the intestinal barrier may predispose individuals to an increased susceptibility to gluten through a bystander immune activation to intestinal microbiota