From Continent to Ocean: Investigating the Multi-Element and Precious Metal Geochemistry of the Paraná-Etendeka Large Igneous Province Using Machine Learning Tools

This is the final version. Available on open access from the Geological Society of London via the DOI in this recordData Availability Statement: The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.Large Igneous Provinces, and by extension the mantle plumes that generate them, are frequently associated with platinum-group element (PGE) ore deposits, yet the processes controlling the metal budget in plume-derived magmas remains debated. In this paper, we present a new whole-rock geochemical data set from the 135 Ma Paraná-Etendeka Large Igneous Province (PELIP) in the South Atlantic, which includes major and trace elements, PGE, and Au concentrations for onshore and offshore lavas from different developmental stages in the province, which underwent significant syn-magmatic continental rifting from 134 Ma onwards. The PELIP presents an opportunity to observe magma geochemistry as the continent and sub-continental lithospheric mantle (SCLM) are progressively removed from a melting environment. Here, we use an unsupervised machine learning approach (featuring the PCA, t-SNE and k-means clustering algorithms) to investigate the geochemistry of a set of (primarily basaltic) onshore and offshore PELIP lavas. We test the hypothesis that plume-derived magmas can scavenge precious metals including PGE from the SCLM and explore how metal concentrations might change the metal content in intraplate magmas throughout rifting. Onshore lavas on the Etendeka side of the PELIP are classified as the products of deep partial melts of the mantle below the African craton but without significant PGE enrichment. Offshore lavas on both continents exhibit similarities through the multi-element space to their onshore equivalents, but they again lack PGE enrichment. Of the four onshore lava types on the Paraná side of the PELIP, the Type 1 (Southern) and Type 1 (Central-Northern) localities exhibit separate PGE-enriched assemblages (Ir-Ru-Rh and Pd-Au-Cu, respectively). It follows that there is a significant asymmetry to the metallogenic character of the PELIP, with enrichment focused specifically on lavas from the South American continent edge in Paraná. This asymmetry contrasts with the North Atlantic Igneous Province (NAIP), a similar geodynamic environment in which continent-edge lavas are also PGE-enriched, albeit on both sides of the plume-rift system. We conclude that, given the similarities in PGE studies of plume-rift environments, SCLM incorporation under progressively shallowing (i.e., rifting) asthenospheric conditions promotes the acquisition of metasomatic and residual PGE-bearing minerals, boosting the magma metal budget.University of Exete

A machine learning approach for regional geochemical data: Platinum-group element geochemistry vs geodynamic settings of the North Atlantic Igneous Province

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordWhilst traditional approaches to geochemistry provide valuable insights into magmatic processes such as melting and element fractionation, by considering entire regional data sets on an objective basis using machine learning algorithms (MLA), we can highlight new facets within the broader data structure and significantly enhance previous geochemical interpretations. The platinum-group element (PGE) budget of lavas in the North Atlantic Igneous Province (NAIP) have been shown to vary systematically according to age, geographic location and geodynamic environment. Given the large multi-element geochemical data set available for the region, MLA was employed to explore the magmatic controls on these shifting concentrations. The key advantage of using machine learning in analysis is its ability to cluster samples across multi-dimensional (i.e., multi-element) space. The NAIP data set is manipulated using Principal Component Analysis (PCA) and t-Distributed Stochastic Neighbour Embedding (t-SNE) techniques to increase separability in the data alongside clustering using the k-means MLA. The new multi-element classification is compared to the original geographic classification to assess the performance of both approaches. The workflow provides a means for creating an objective high-dimensional investigation on a geochemical data set and particularly enhances the identification of metallogenic anomalies across the region. The techniques used highlight three distinct multi-element end-members which successfully capture the variability of the majority of elements included as input variables. These end-members are seen to fluctuate in prominence throughout the NAIP, which we propose reflects the changing geodynamic environment and melting source. Crucially, the variability of Pt and Pd are not reflected in MLA-based clustering trends, suggesting that they vary independently through controls not readily demonstrated by the NAIP major or trace element data structure (i.e., other proxies for magmatic differentiation). This data science approach thus highlights that PGE (here signalled by Pt/Pd ratio) may be used to identify otherwise localised or cryptic geochemical inputs from the subcontinental lithospheric mantle (SCLM) during the ascent of plume-derived magma, and thereby impact upon the resulting metallogenic basket.University of Exete

Phage-mediated horizontal transfer of a Staphylococcus aureus virulence-associated genomic island

Staphylococcus aureus is a major pathogen of humans and animals. The capacity of S. aureus to adapt to different host species and tissue types is strongly influenced by the acquisition of mobile genetic elements encoding determinants involved in niche adaptation. The genomic islands νSaα and νSaβ are found in almost all S. aureus strains and are characterized by extensive variation in virulence gene content. However the basis for the diversity and the mechanism underlying mobilization of the genomic islands between strains are unexplained. Here, we demonstrated that the genomic island, νSaβ, encoding an array of virulence factors including staphylococcal superantigens, proteases, and leukotoxins, in addition to bacteriocins, was transferrable in vitro to human and animal strains of multiple S. aureus clones via a resident prophage. The transfer of the νSaβ appears to have been accomplished by multiple conversions of transducing phage particles carrying overlapping segments of the νSaβ. Our findings solve a long-standing mystery regarding the diversification and spread of the genomic island νSaβ, highlighting the central role of bacteriophages in the pathogenic evolution of S. aureus

Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface.

Targeted hybridization enrichment prior to next-generation sequencing is a widespread method for characterizing sequence variation in a research setting, and is being adopted by diagnostic laboratories. However, the number of variants identified can overwhelm clinical laboratories with strict time constraints, the final interpretation of likely pathogenicity being a particular bottleneck. To address this, we have developed an approach in which, after automatic variant calling on a standard unix pipeline, subsequent variant filtering is performed interactively, using AgileExomeFilter and AgilePindelFilter (http://dna.leeds.ac.uk/agile), tools designed for clinical scientists with standard desktop computers. To demonstrate the method's diagnostic efficacy, we tested 128 patients using (1) a targeted capture of 36 cancer-predisposing genes or (2) whole-exome capture for diagnosis of the genetically heterogeneous disorder primary ciliary dyskinesia (PCD). In the cancer cohort, complete concordance with previous diagnostic data was achieved across 793 variant genotypes. A high yield (42%) was also achieved for exome-based PCD diagnosis, underscoring the scalability of our method. Simple adjustments to the variant filtering parameters further allowed the identification of a homozygous truncating mutation in a presumptive new PCD gene, DNAH8. These tools should allow diagnostic laboratories to expand their testing portfolios flexibly, using a standard set of reagents and techniques

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits

Football fans in training: the development and optimization of an intervention delivered through professional sports clubs to help men lose weight, become more active and adopt healthier eating habits

&lt;p&gt;Background: The prevalence of obesity in men is rising, but they are less likely than women to engage in existing weight management programmes. The potential of professional sports club settings to engage men in health promotion activities is being increasingly recognised. This paper describes the development and optimization of the Football Fans in Training (FFIT) programme, which aims to help overweight men (many of them football supporters) lose weight through becoming more active and adopting healthier eating habits.&lt;/p&gt; &lt;p&gt;Methods: The MRC Framework for the design and evaluation of complex interventions was used to guide programme development in two phases. In Phase 1, a multidisciplinary working group developed the pilot programme (p-FFIT) and used a scoping review to summarize previous research and identify the target population. Phase 2 involved a process evaluation of p-FFIT in 11 Scottish Premier League (SPL) clubs. Participant and coach feedback, focus group discussions and interviews explored the utility/acceptability of programme components and suggestions for changes. Programme session observations identified examples of good practice and problems/issues with delivery. Together, these findings informed redevelopment of the optimized programme (FFIT), whose components were mapped onto specific behaviour change techniques using an evidence-based taxonomy.&lt;/p&gt; &lt;p&gt;Results: p-FFIT comprised 12, weekly, gender-sensitised, group-based weight management classroom and ‘pitch-side’ physical activity sessions. These in-stadia sessions were complemented by an incremental, pedometer-based walking programme. p-FFIT was targeted at men aged 35-65 years with body mass index ≥ 27 kg/m2. Phase 2 demonstrated that participants in p-FFIT were enthusiastic about both the classroom and physical activity components, and valued the camaraderie and peer-support offered by the programme. Coaches appreciated the simplicity of the key healthy eating and physical activity messages. Suggestions for improvements that were incorporated into the optimized FFIT programme included: more varied in-stadia physical activity with football-related components; post-programme weight management support (emails and a reunion session); and additional training for coaches in SMART goal setting and the pedometer-based walking programme.&lt;/p&gt; &lt;p&gt;Conclusions: The Football Fans in Training programme is highly acceptable to participants and SPL coaches, and is appropriate for evaluation in a randomised controlled trial.&lt;/p&gt

Ethnic differences in Glycaemic control in people with type 2 diabetes mellitus living in Scotland

Background and Aims: Previous studies have investigated the association between ethnicity and processes of care and intermediate outcomes of diabetes, but there are limited population-based studies available. The aim of this study was to use population-based data to investigate the relationships between ethnicity and glycaemic control in men and women with diabetes mellitus living in Scotland.&lt;p&gt;&lt;/p&gt; Methods: We used a 2008 extract from the population-based national electronic diabetes database of Scotland. The association between ethnicity with mean glycaemic control in type 2 diabetes mellitus was examined in a retrospective cohort study, including adjustment for a number of variables including age, sex, socioeconomic status, body mass index (BMI), prescribed treatment and duration of diabetes.&lt;p&gt;&lt;/p&gt; Results: Complete data for analyses were available for 56,333 White Scottish adults, 2,535 Pakistanis, 857 Indians, 427 Chinese and 223 African-Caribbeans. All other ethnic groups had significantly (p&#60;0.05) greater proportions of people with suboptimal glycaemic control (HbA1c &#62;58 mmol/mol, 7.5%) compared to the White Scottish group, despite generally younger mean age and lower BMI. Fully adjusted odds ratios for suboptimal glycaemic control were significantly higher among Pakistanis and Indians (1.85, 95% CI: 1.68–2.04, and 1.62,95% CI: 1.38–1.89) respectively.&lt;p&gt;&lt;/p&gt; Conclusions: Pakistanis and Indians with type 2 diabetes mellitus were more likely to have suboptimal glycaemic control than the white Scottish population. Further research on health services and self-management are needed to understand the association between ethnicity and glycaemic control to address ethnic disparities in glycaemic control.&lt;p&gt;&lt;/p&gt

Enhanced cosmic-ray flux toward zeta Persei inferred from laboratory study of H3+ - e- recombination rate

The H3+ molecular ion plays a fundamental role in interstellar chemistry, as it initiates a network of chemical reactions that produce many interstellar molecules. In dense clouds, the H3+ abundance is understood using a simple chemical model, from which observations of H3+ yield valuable estimates of cloud path length, density, and temperature. On the other hand, observations of diffuse clouds have suggested that H3+ is considerably more abundant than expected from the chemical models. However, diffuse cloud models have been hampered by the uncertain values of three key parameters: the rate of H3+ destruction by electrons, the electron fraction, and the cosmic-ray ionisation rate. Here we report a direct experimental measurement of the H3+ destruction rate under nearly interstellar conditions. We also report the observation of H3+ in a diffuse cloud (towards zeta Persei) where the electron fraction is already known. Taken together, these results allow us to derive the value of the third uncertain model parameter: we find that the cosmic-ray ionisation rate in this sightline is forty times faster than previously assumed. If such a high cosmic-ray flux is indeed ubiquitous in diffuse clouds, the discrepancy between chemical models and the previous observations of H3+ can be resolved.Comment: 6 pages, Nature, in pres

The Sec1/Munc18 protein Vps45 regulates cellular levels of its SNARE binding partners Tlg2 and Snc2 in Saccharomyces cerevisiae

Intracellular membrane trafficking pathways must be tightly regulated to ensure proper functioning of all eukaryotic cells. Central to membrane trafficking is the formation of specific SNARE (soluble N-ethylmeleimide-sensitive factor attachment protein receptor) complexes between proteins on opposing lipid bilayers. The Sec1/Munc18 (SM) family of proteins play an essential role in SNARE-mediated membrane fusion, and like the SNAREs are conserved through evolution from yeast to humans. The SM protein Vps45 is required for the formation of yeast endosomal SNARE complexes and is thus essential for traffic through the endosomal system. Here we report that, in addition to its role in regulating SNARE complex assembly, Vps45 regulates cellular levels of its SNARE binding partners: the syntaxin Tlg2 and the v-SNARE Snc2: Cells lacking Vps45 have reduced cellular levels of Tlg2 and Snc2; and elevation of Vps45 levels results in concomitant increases in the levels of both Tlg2 and Snc2. As well as regulating traffic through the endosomal system, the Snc v-SNAREs are also required for exocytosis. Unlike most vps mutants, cells lacking Vps45 display multiple growth phenotypes. Here we report that these can be reversed by selectively restoring Snc2 levels in vps45 mutant cells. Our data indicate that as well as functioning as part of the machinery that controls SNARE complex assembly, Vps45 also plays a key role in determining the levels of its cognate SNARE proteins; another key factor in regulation of membrane traffic

Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE Study

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID) use may protect against Alzheimer's disease (AD) risk. We sought examine the association between NSAID use and risk of AD, and potential effect modification by APOE-ε4 carrier status and ethnicity. METHODS: The MIRAGE Study is a multi-center family study of genetic and environmental risk factors for AD. Subjects comprised 691 AD patients (probands) and 973 family members enrolled at 15 research centers between 1996 and 2002. The primary independent and dependent variables were prior NSAID use and AD case status, respectively. We stratified the dataset in order to evaluate whether the association between NSAID use and AD was similar in APOE-ε4 carriers and non-carriers. Ethnicity was similarly examined as an effect modifier. RESULTS: NSAID use was less frequent in cases compared to controls in the overall sample (adjusted OR = 0.64; 95% CI = 0.38–1.05). The benefit of NSAID use appeared more pronounced among APOE-ε4 carriers (adjusted OR = 0.49; 95% CI = 0.24–0.98) compared to non-carriers, although this association was not statistically significant. The pattern of association was similar in Caucasian and African Americans. CONCLUSIONS: NSAID use is inversely associated with AD and may be modified by APOE genotype. Prospective studies and clinical trials of sufficient power to detect effect modification by APOE-ε4 carrier status are needed