Education and Polar Research: Bringing Polar Science into the Classroom

The Polar Regions play an important role in the global processes of our planet, from climate change to sea level rise, protection from UV (ultraviolet) radiation to uptake of carbon dioxide. In addition, their scientific importance, extraordinary beauty and adventurous history provide perfect ingredients for both education and public outreach.Polar examples provide an excellent way to transmit basic concepts about a wide range of STEM (science, technology, engineering and mathematics) disciplines. The IPY (International Polar Year) brought educators and scientists together and provided the incentive for the formation of the PEI (Polar Educators International), an organization encouraging the exchange of ideas between educators and researchers and enhancement of the profile of polar education on the international scene. Educators must be adequately informed about current scientific polar research and have the confidenceto teach it to students. Scientists have the knowledge and data to explain these complexities, but may lack the communication skills to make the subject accessible to non-technical audiences. The development of this new network between polar educators and scientists has the potential to break down walls that restrict international collaboration and understanding, provide educators with topical and reliable information and share best practices internationally in an effective way

The role of charge in solvation at liquid/liquid interfaces

This dissertation describes the development and characterization of new surfactants, dubbed "molecular rulers," that provide an upper limit to the dipolar width in aqueous/organic systems. Here, dipolar width describes the distance required for the dielectric properties of one phase to converge to those of the adjacent phase. Molecular rulers consist of a hydrophobic, solvatochromic chromophore and a charged headgroup connected via a variable length methylene chain. These surfactants are anchored to the aqueous phase by the ionic headgroup while the solvatochromic probe "floats" into the organic phase. The length of the alkyl chain controls the position of the chromophore within the interfacial region. Resonance-enhanced second harmonic generation (SHG) is used to profile the electronic excitation energy of the chromophore as a function of alkyl chain length. Since the solute's excitation energy depends on solvent polarity, we can infer interfacial dipolar width. In previous work anionic molecular rulers were used to characterize the water/cyclohexane interface. Anionic rulers having two carbon alkyl chains sample a polarity between that of bulk water and bulk cyclohexane. Analogous cationic rulers described in this dissertation sample an environment equivalent to that of bulk cyclohexane. These results suggest that interfacial polarity may depend on surface charges having a close proximity to the adsorbed solute. This idea was tested using cationic rulers adsorbed to the water/vapor surface of an electrolyte solution saturated with 1-octanol (a mimic of the water/alkane interface). As ionic strength increases, cationic ruler SHG behavior approaches that of the anionic species, suggesting that the ions in solution shield the cationic charge from a probe-headgroup interaction that was observed with NMR experiments for bulk aqueous solution samples. A neutral organic molecule at the electrolyte solution/cyclohexane interface was employed to elucidate the role of charge in interfacial solvation. Observed shifts in SHG spectra from salt-free limits are similar to those of absorbance spectra for the solute in bulk electrolyte solutions. We conclude that, in the absence of direct charge-probe correlation, charges have a similar influence on interfacial solvation of neutral species as they do in bulk solution

Education and polar research: bringing polar science into the classroom

The Polar Regions play an important role in the global processes of our planet, from climate change to sea level rise, protection from UV (ultraviolet) radiation to uptake of carbon dioxide. In addition, their scientific importance, extraordinary beauty and adventurous history provide perfect ingredients for both education and public outreach.Polar examples provide an excellent way to transmit basic concepts about a wide range of STEM (science, technology, engineering and mathematics) disciplines. The IPY (International Polar Year) brought educators and scientists together and provided the incentive for the formation of the PEI (Polar Educators International), an organization encouraging the exchange of ideas between educators and researchers and enhancement of the profile of polar education on the international scene. Educators must be adequately informed about current scientific polar research and have the confidenceto teach it to students. Scientists have the knowledge and data to explain these complexities, but may lack the communication skills to make the subject accessible to non-technical audiences. The development of this new network between polar educators and scientists has the potential to break down walls that restrict international collaboration and understanding, provide educators with topical and reliable information and share best practices internationally in an effective way

Multiscale Exploration of Mouse Brain Microstructures Using the Knife-Edge Scanning Microscope Brain Atlas

Connectomics is the study of the full connection matrix of the brain. Recent advances in high-throughput, high-resolution 3D microscopy methods have enabled the imaging of whole small animal brains at a sub-micrometer resolution, potentially opening the road to full-blown connectomics research. One of the first such instruments to achieve whole-brain-scale imaging at sub-micrometer resolution is the Knife-Edge Scanning Microscope (KESM). KESM whole-brain data sets now include Golgi (neuronal circuits), Nissl (soma distribution), and India ink (vascular networks). KESM data can contribute greatly to connectomics research, since they fill the gap between lower resolution, large volume imaging methods (such as diffusion MRI) and higher resolution, small volume methods (e.g., serial sectioning electron microscopy). Furthermore, KESM data are by their nature multiscale, ranging from the subcellular to the whole organ scale. Due to this, visualization alone is a huge challenge, before we even start worrying about quantitative connectivity analysis. To solve this issue, we developed a web-based neuroinformatics framework for efficient visualization and analysis of the multiscale KESM data sets. In this paper, we will first provide an overview of KESM, then discuss in detail the KESM data sets and the web-based neuroinformatics framework, which is called the KESM brain atlas (KESMBA). Finally, we will discuss the relevance of the KESMBA to connectomics research, and identify challenges and future directions

Specimen Preparation, Imaging, and Analysis Protocols for Knife-edge Scanning Microscopy

Major advances in high-throughput, high-resolution, 3D microscopy techniques have enabled the acquisition of large volumes of neuroanatomical data at submicrometer resolution. One of the first such instruments producing whole-brain-scale data is the Knife-Edge Scanning Microscope (KESM)7, 5, 9, developed and hosted in the authors' lab. KESM has been used to section and image whole mouse brains at submicrometer resolution, revealing the intricate details of the neuronal networks (Golgi)1, 4, 8, vascular networks (India ink)1, 4, and cell body distribution (Nissl)3. The use of KESM is not restricted to the mouse nor the brain. We have successfully imaged the octopus brain6, mouse lung, and rat brain. We are currently working on whole zebra fish embryos. Data like these can greatly contribute to connectomics research10; to microcirculation and hemodynamic research; and to stereology research by providing an exact ground-truth

Methionine restriction improves renal insulin signalling in aged kidneys.

Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer therapeutic potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression

Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 1; peer review:1 approved, 1 approved with reservations]

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P&lt;2•8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.</p

Integrative pathway genomics of lung function and airflow obstruction

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung diseas

Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction (beta(int) = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.Peer reviewe