Random lasing in a solution of reflective colloidal particles: the effect of interfaces and inter-particle correlations

The propagation of light across 2D and 3D slabs of reflective colloidal particles in a fluid-like state has been investigated by simulation. The colloids are represented as hard spheres with and without an attractive square-well tail. Representative configurations of particles have been generated by Monte Carlo. The path of rays entering the slab normal to its planar surface has been determined by exact geometric scattering conditions, assuming that particles are macroscopic spheres fully reflective at the surface of their hard-core potential. The analysis of light paths provides the transmission and reflection coefficients, the mean-free path, the average length of transmitted and reflected paths, the distribution of scattering events across the slab, and the angular spread of the outcoming rays as a function of dimensionality and thermodynamic state. The results highlight the presence of a sizeable population of very long paths, which play an important role in random lasing from solutions of metal particles in an optically active fluid. The output power spectrum resulting from the stimulated emission amplification decays asymptotically as an inverse power law. The present study goes beyond the standard approach based on a random walk confined between two planar interfaces and parametrised in terms of the mean-free path and scattering matrix. Here, instead, the mean free path, the correlation among scattering events, and memory effects are not assumed a priori but emerge from the underlying statistical mechanics model of interacting particles. Moreover, the approach joins smoothly the ballistic regime of light propagation at low density with the diffusive regime at high density of scattering centres. These properties are exploited to investigate the effect of weak polydispersivity and of large density fluctuations at the critical point of the model with the attractive potential tail

Aha! Vivat Homo Sapiens

Program for the twelfth and final annual RISD Cabaret held in the Cellar at the top of the Waterman Building.https://digitalcommons.risd.edu/liberalarts_cabaret_programs/1011/thumbnail.jp

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1 beta (IL-1 beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease

Stress Hyperglycaemia in Hospitalised Patients and Their 3-Year Risk of Diabetes: A Scottish Retrospective Cohort Study

Background<p></p> Hyperglycaemia during hospital admission is common in patients who are not known to have diabetes and is associated with adverse outcomes. The risk of subsequently developing type 2 diabetes, however, is not known.<p></p> We linked a national database of hospital admissions with a national register of diabetes to describe the association between admission glucose and the risk of subsequently developing type 2 diabetes.<p></p> Methods and Findings<p></p> In a retrospective cohort study, patients aged 30 years or older with an emergency admission to hospital between 2004 and 2008 were included. Prevalent and incident diabetes were identified through the Scottish Care Information (SCI)-Diabetes Collaboration national registry. Patients diagnosed prior to or up to 30 days after hospitalisation were defined as prevalent diabetes and were excluded.<p></p> The predicted risk of developing incident type 2 diabetes during the 3 years following hospital discharge by admission glucose, age, and sex was obtained from logistic regression models. We performed separate analyses for patients aged 40 and older, and patients aged 30 to 39 years.<p></p> Glucose was measured in 86,634 (71.0%) patients aged 40 and older on admission to hospital. The 3-year risk of developing type 2 diabetes was 2.3% (1,952/86,512) overall, was <1% for a glucose ≤5 mmol/l, and increased to approximately 15% at 15 mmol/l. The risks at 7 mmol/l and 11.1 mmol/l were 2.6% (95% CI 2.5–2.7) and 9.9% (95% CI 9.2–10.6), respectively, with one in four (21,828/86,512) and one in 40 (1,798/86,512) patients having glucose levels above each of these cut-points. For patients aged 30–39, the risks at 7 mmol/l and 11.1 mmol/l were 1.0% (95% CI 0.8–1.3) and 7.8% (95% CI 5.7–10.7), respectively, with one in eight (1,588/11,875) and one in 100 (120/11,875) having glucose levels above each of these cut-points.<p></p> The risk of diabetes was also associated with age, sex, and socio-economic deprivation, but not with specialty (medical versus surgical), raised white cell count, or co-morbidity. Similar results were obtained for pre-specified sub-groups admitted with myocardial infarction, chronic obstructive pulmonary disease, and stroke.<p></p> There were 25,193 deaths (85.8 per 1,000 person-years) over 297,122 person-years, of which 2,406 (8.1 per 1,000 person-years) were attributed to vascular disease. Patients with glucose levels of 11.1 to 15 mmol/l and >15 mmol/l had higher mortality than patients with a glucose of <6.1 mmol/l (hazard ratio 1.54; 95% CI 1.42–1.68 and 2.50; 95% CI 2.14–2.95, respectively) in models adjusting for age and sex.<p></p> Limitations of our study include that we did not have data on ethnicity or body mass index, which may have improved prediction and the results have not been validated in non-white populations or populations outside of Scotland.<p></p> Conclusion<p></p> Plasma glucose measured during an emergency hospital admission predicts subsequent risk of developing type 2 diabetes. Mortality was also 1.5-fold higher in patients with elevated glucose levels. Our findings can be used to inform patients of their long-term risk of type 2 diabetes, and to target lifestyle advice to those patients at highest risk

The Molecular Evolution of Cetacean Dim-Light Vision: In Vitro Studies of Rhodopsin Over a Macroevolutionary Transition

Cetaceans (whales and dolphins) are fully aquatic mammals that have captured the imagination of biologists due to their iconic evolutionary transformation from terrestrial ancestors. Nevertheless, much about how this extreme macroevolutionary transition occurred at the molecular level remains unknown. The vertebrate visual system is ideal for studying molecular adaptation due to the reliance organisms place on it for fitness-related behaviours, and because key molecular components of the visual transduction cascade in photoreceptors are relatively well understood. Light activation of the dim-light pigment, rhodopsin, is the first step of the visual transduction cascade, and is thought to have been the target of selection across a wide variety of vertebrate lineages. Cetaceans, due to their rich evolutionary history, are model organisms for understanding how changing environments put selective pressure on sensory processes. In this dissertation, I investigate the molecular basis for adaptive evolution in cetacean rhodopsin using a combination of in vitro expression experiments and computational analyses. First, I evaluate evidence for adaptation in cetacean rhodopsin through characterization of its spectral properties in the killer whale (Orcinus orca), and a statistical assessment of selection patterns in a representative dataset of cetacean rhodopsin genes. Next, I focus on the evolutionary significance of key amino acid substitutions in killer whale rhodopsin that confer both spectral and non-spectral (kinetic) functional shifts, specifically through comparison with rhodopsin pigments from two outgroup species (bovine and hippopotamus). Finally, I use an ancestral sequence reconstruction and protein resurrection approach to establish functional and corresponding molecular shifts across the terrestrial-aquatic transition at the root of Cetacea. Together, these projects provide a more complete investigation of cetacean rhodopsin, not only addressing questions regarding dim-light (aquatic) adaptation in cetaceans, but also generating new hypotheses about how the ecology of living and ancient cetaceans has shaped the visual system.Ph.D

Data for Dungan & Chang 2017, Proceedings B

The .zip archive contains two files: 1) A fasta alignment of the rhodopsin coding sequences used for ancestral sequence reconstruction and 2) an excel file with fluorescence and absorbance data serie

Data from: Epistatic interactions influence terrestrial-marine functional shifts in cetacean rhodopsin

Like many aquatic vertebrates, whales have blue-shifting spectral tuning substitutions in the dim-light visual pigment, rhodopsin, that are thought to increase photosensitivity in underwater environments. We have discovered that known spectral tuning substitutions also have surprising epistatic effects on another function of rhodopsin, the kinetic rates associated with light-activated intermediates. By using absorbance spectroscopy and fluorescence-based retinal release assays on heterologously expressed rhodopsin, we assessed both spectral and kinetic differences between cetaceans (killer whale) and terrestrial outgroups (hippo, bovine). Mutation experiments revealed that killer whale rhodopsin is unusually resilient to pleiotropic effects on retinal release from key blue-shifting substitutions (D83N and A292S), largely due to a surprisingly specific epistatic interaction between D83N and the background residue, S299. Ancestral sequence reconstruction indicated that S299 is an ancestral residue that predates the evolution of blue-shifting substitutions at the origins of Cetacea. Based on these results, we hypothesize that intramolecular epistasis helped to conserve rhodopsin's kinetic properties while enabling blue-shifting spectral tuning substitutions as cetaceans adapted to aquatic environments. Trade-offs between different aspects of molecular function are rarely considered in protein evolution, but in cetacean and other vertebrate rhodopsins, may underlie multiple evolutionary scenarios for the selection of specific amino acid substitutions

Selection on synonymous codons in mammalian rhodopsins: a possible role in optimizing translational processes

Abstract Background Synonymous codon usage can affect many cellular processes, particularly those associated with translation such as polypeptide elongation and folding, mRNA degradation/stability, and splicing. Highly expressed genes are thought to experience stronger selection pressures on synonymous codons. This should result in codon usage bias even in species with relatively low effective population sizes, like mammals, where synonymous site selection is thought to be weak. Here we use phylogenetic codon-based likelihood models to explore patterns of codon usage bias in a dataset of 18 mammalian rhodopsin sequences, the protein mediating the first step in vision in the eye, and one of the most highly expressed genes in vertebrates. We use these patterns to infer selection pressures on key translational mechanisms including polypeptide elongation, protein folding, mRNA stability, and splicing. Results Overall, patterns of selection in mammalian rhodopsin appear to be correlated with post-transcriptional and translational processes. We found significant evidence for selection at synonymous sites using phylogenetic mutation-selection likelihood models, with C-ending codons found to have the highest relative fitness, and to be significantly more abundant at conserved sites. In general, these codons corresponded with the most abundant tRNAs in mammals. We found significant differences in codon usage bias between rhodopsin loops versus helices, though there was no significant difference in mean synonymous substitution rate between these motifs. We also found a significantly higher proportion of GC-ending codons at paired sites in rhodopsin mRNA secondary structure, and significantly lower synonymous mutation rates in putative exonic splicing enhancer (ESE) regions than in non-ESE regions. Conclusions By focusing on a single highly expressed gene we both distinguish synonymous codon selection from mutational effects and analytically explore underlying functional mechanisms. Our results suggest that codon bias in mammalian rhodopsin arises from selection to optimally balance high overall translational speed, accuracy, and proper protein folding, especially in structurally complicated regions. Selection at synonymous sites may also be contributing to mRNA stability and splicing efficiency at exonic-splicing-enhancer (ESE) regions. Our results highlight the importance of investigating highly expressed genes in a broader phylogenetic context in order to better understand the evolution of synonymous substitutions

Supplemental Data from Epistatic interactions influence terrestrial-marine functional shifts in cetacean rhodopsin

Supplemental Tables 1-

l-Proline-derived ligands to mimic the ‘2-His-1-carboxylate’ triad of the non-haem iron oxidase active site

Non-haem iron(II) oxidases (NHIOs) catalyse a variety of oxidative transformations in biology. The iron-binding environment of the NHIO active site typically incorporates a ‘2-His-1-carboxylate’ facial triad of amino acid side-chains, a motif that has emerged as a defining feature of the enzyme family. Towards the goal of biomimetic, iron-mediated C–H activation we have synthesized a series of peptidomimetic ligands from l-proline. By coupling l-proline to 2,6-bis(bromomethyl)pyridine, 2-(bromomethyl)-6-((tert-butyldimethylsilyloxy)methyl)pyridine and picolinic acid, we have generated several new ligand architectures designed to complex with iron(II) and mimic the NHIO active site. The resulting iron complexes promote modest levels of alkene dihydroxylation and allylic oxidation using hydrogen peroxide as oxidant