Corrigendum: Solar cycles or random processes? Evaluating solar variability in Holocene climate records

This is the final version of the article. Available from Springer Nature via the DOI in this record.The article to which this is the corrigendum is in ORE at http://hdl.handle.net/10871/21766A coding error in the Monte Carlo procedure for the determination of critical values in running correlation analysis (presented in Supplementary Data S8) has been brought to the attention of the authors.[...

A transient helix in the disordered region of dynein light intermediate chain links the motor to structurally diverse adaptors for cargo transport

All animal cells use the motor cytoplasmic dynein 1 (dynein) to transport diverse cargo toward microtubule minus ends and to organize and position microtubule arrays such as the mitotic spindle. Cargo-specific adaptors engage with dynein to recruit and activate the motor, but the molecular mechanisms remain incompletely understood. Here, we use structural and dynamic nuclear magnetic resonance (NMR) analysis to demonstrate that the C-terminal region of human dynein light intermediate chain 1 (LIC1) is intrinsically disordered and contains two short conserved segments with helical propensity. NMR titration experiments reveal that the first helical segment (helix 1) constitutes the main interaction site for the adaptors Spindly (SPDL1), bicaudal D homolog 2 (BICD2), and Hook homolog 3 (HOOK3). In vitro binding assays show that helix 1, but not helix 2, is essential in both LIC1 and LIC2 for binding to SPDL1, BICD2, HOOK3, RAB-interacting lysosomal protein (RILP), RAB11 family-interacting protein 3 (RAB11FIP3), ninein (NIN), and trafficking kinesin-bind-ing protein 1 (TRAK1). Helix 1 is sufficient to bind RILP, whereas other adaptors require additional segments preceding helix 1 for efficient binding. Point mutations in the C-terminal helix 1 of Caenorhabditis elegans LIC, introduced by genome editing, severely affect development, locomotion, and life span of the animal and disrupt the distribution and transport kinetics of membrane cargo in axons of mechanosensory neurons, identical to what is observed when the entire LIC C-terminal region is deleted. Deletion of the C-terminal helix 2 delays dynein-dependent spindle positioning in the one-cell embryo but overall does not significantly perturb dynein function. We conclude that helix 1 in the intrinsically disordered region of LIC provides a conserved link between dynein and structurally diverse cargo adaptor families that is critical for dynein function in vivo.This work was financed by the Fundo Europeu de Desenvolvimento Regional (FEDER) through the Norte Portugal Regional Operational Programme (NORTE 2020), Portugal 2020 (RG); by the Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project NORTE-01-0145-FEDER-030507 (RG); by FCT fellowships IF/01015/2013/CP1157/CT0006 (RG) and SFRH/ BPD/101898/2014 (DJB); by the European Research Council under the European Union’s Seventh Framework Programme, ERC grant agreement no. ERC-2013-StG-338410-DYNEINOME (RG), and by a start-up package of the University of Colorado (BV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Assessing Internet addiction using the parsimonious Internet addiction components model - a preliminary study [forthcoming]

Internet usage has grown exponentially over the last decade. Research indicates that excessive Internet use can lead to symptoms associated with addiction. To date, assessment of potential Internet addiction has varied regarding populations studied and instruments used, making reliable prevalence estimations difficult. To overcome the present problems a preliminary study was conducted testing a parsimonious Internet addiction components model based on Griffiths’ addiction components (2005), including salience, mood modification, tolerance, withdrawal, conflict, and relapse. Two validated measures of Internet addiction were used (Compulsive Internet Use Scale [CIUS], Meerkerk et al., 2009, and Assessment for Internet and Computer Game Addiction Scale [AICA-S], Beutel et al., 2010) in two independent samples (ns = 3,105 and 2,257). The fit of the model was analysed using Confirmatory Factor Analysis. Results indicate that the Internet addiction components model fits the data in both samples well. The two sample/two instrument approach provides converging evidence concerning the degree to which the components model can organize the self-reported behavioural components of Internet addiction. Recommendations for future research include a more detailed assessment of tolerance as addiction component

"Of Mice and Measures": A Project to Improve How We Advance Duchenne Muscular Dystrophy Therapies to the Clinic

A new line of dystrophic mdx mice on the DBA/2J (D2) background has emerged as a candidate to study the efficacy of therapeutic approaches for Duchenne muscular dystrophy (DMD). These mice harbor genetic polymorphisms that appear to increase the severity of the dystropathology, with disease modifiers that also occur in DMD patients, making them attractive for efficacy studies and drug development. This workshop aimed at collecting and consolidating available data on the pathological features and the natural history of these new D2/mdx mice, for comparison with classic mdx mice and controls, and to identify gaps in information and their potential value. The overall aim is to establish guidance on how to best use the D2/mdx mouse model in preclinical studies

Phosphorylated Dihydroceramides from Common Human Bacteria Are Recovered in Human Tissues

Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle

A New Saurolophine Dinosaur from the Latest Cretaceous of Far Eastern Russia

Background: Four main dinosaur sites have been investigated in latest Cretaceous deposits from the Amur/Heilongjiang Region: Jiayin and Wulaga in China (Yuliangze Formation), Blagoveschensk and Kundur in Russia (Udurchukan Formation). More than 90% of the bones discovered in these localities belong to hollow-crested lambeosaurine saurolophids, but flat-headed saurolophines are also represented: Kerberosaurus manakini at Blagoveschensk and Wulagasaurus dongi at Wulaga. Methodology/Principal Findings: Herein we describe a new saurolophine dinosaur, Kundurosaurus nagornyi gen. et sp. nov. from the Udurchukan Formation (Maastrichtian) of Kundur, represented by disarticulated cranial and postcranial material. This new taxon is diagnosed by four autapomorphies. Conclusions/Significance: A phylogenetic analysis of saurolophines indicates that Kundurosaurus nagornyi is nested within a rather robust clade including Edmontosaurus spp. Saurolophus spp. and Prosaurolophus maximus, possibly as a sister-taxon for Kerberosaurus manakini also from the Udurchukan Formation of Far Eastern Russia. The high diversity and mosaic distribution of Maastrichtian hadrosaurid faunas in the Amur-Heilongjiang region are the result of a complex palaeogeographical history and imply that many independent hadrosaurid lineages dispersed without any problem between western America and eastern Asia at the end of the Cretaceous. © 2012 Godefroit et al.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Liver disease is a significant risk factor for cardiovascular outcomes – A UK Biobank study

Background & Aims: Chronic liver disease (CLD) is associated with increased cardiovascular disease (CVD) risk. We investigated whether early signs of liver disease (measured by iron-corrected T1-mapping [cT1]) were associated with an increased risk of major CVD events. Methods: Liver disease activity (cT1) and fat (proton density fat fraction [PDFF]) were measured using LiverMultiScan® between January 2016 and February 2020 in the UK Biobank imaging sub-study. Using multivariable Cox regression, we explored associations between liver cT1 (MRI) and primary CVD (coronary artery disease, atrial fibrillation [AF], embolism/vascular events, heart failure [HF] and stroke), and CVD hospitalisation and all-cause mortality. Liver blood biomarkers, general metabolism biomarkers, and demographics were also included. Subgroup analysis was conducted in those without metabolic syndrome (defined as at least three of: a large waist, high triglycerides, low high-density lipoprotein cholesterol, increased systolic blood pressure, or elevated haemoglobin A1c). Results: A total of 33,616 participants (mean age 65 years, mean BMI 26 kg/m2, mean haemoglobin A1c 35 mmol/mol) had complete MRI liver data with linked clinical outcomes (median time to major CVD event onset: 1.4 years [range: 0.002-5.1]; follow-up: 2.5 years [range:1.1-5.2]). Liver disease activity (cT1), but not liver fat (PDFF), was associated with higher risk of any major CVD event (hazard ratio 1.14; 95% CI 1.03–1.26; p = 0.008), AF (1.30; 1.12–1.51; p <0.001); HF (1.30; 1.09–1.56; p = 0.004); CVD hospitalisation (1.27; 1.18-1.37; p <0.001) and all-cause mortality (1.19; 1.02–1.38; p = 0.026). FIB-4 index was associated with HF (1.06; 1.01–1.10; p = 0.007). Risk of CVD hospitalisation was independently associated with cT1 in individuals without metabolic syndrome (1.26; 1.13-1.4; p <0.001). Conclusion: Liver disease activity, by cT1, was independently associated with a higher risk of incident CVD and all-cause mortality, independent of pre-existing metabolic syndrome, liver fibrosis or fat. Impact and implications: Chronic liver disease (CLD) is associated with a twofold greater incidence of cardiovascular disease. Our work shows that early liver disease on iron-corrected T1 mapping was associated with a higher risk of major cardiovascular disease (14%), cardiovascular disease hospitalisation (27%) and all-cause mortality (19%). These findings highlight the prognostic relevance of a comprehensive evaluation of liver health in populations at risk of CVD and/or CLD, even in the absence of clinical manifestations or metabolic syndrome, when there is an opportunity to modify/address risk factors and prevent disease progression. As such, they are relevant to patients, carers, clinicians, and policymakers

Elucidating the aetiology of human Campylobacter coli infections

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WiseEye: next generation expandable and programmable camera trap platform for wildlife research

Funding: The work was supported by the RCUK Digital Economy programme to the dot.rural Digital Economy Hub; award reference: EP/G066051/1. The work of S. Newey and RJI was part funded by the Scottish Government's Rural and Environment Science and Analytical Services (RESAS). Details published as an Open Source Toolkit, PLOS Journals at: http://dx.doi.org/10.1371/journal.pone.0169758Peer reviewedPublisher PD