Peril and Possibility: Wilderness as a Space of Becoming in Tolkien\u27s The Children of Húrin and Whedon\u27s Firefly and Serenity

A tension between wilderness as place of peril and as a place of purity has existed throughout the history of Western civilization. While the Puritan minister Cotton Mather described the wilderness as a habitation of “Dragons,” “Droves of Devils,” and “Fiery Flying Serpents,” Henry David Thoreau maintained that in order to draw near to God, one must draw near to nature. A spectrum of perspectives about wilderness exists within the tension between these two opposing ideas. As a refugee from civilization who makes his home in the wilderness on the borders of society, the Wild Man archetype, famously expressed in the monster Grendel and the noble outlaw Robin Hood, inhabits this spectrum. Both Tolkien’s The Children of Húrin and Whedon’s Firefly and Serenity unfold in settings characterized by being on the border. Furthermore, their heroes are noble outlaws, who choose to live outside of the boundaries of civilization. With these settings and heroes, Tolkien and Whedon make similar contributions to the nuances found in Western traditions of wilderness by emphasizing wilderness as a place of becoming, rich with possibility yet fraught with peril

Wizards and Woods: The Environmental Ethics of Tolkien’s Istari

Tolkien’s wizards are some of the most interesting and impactful characters in The Lord of the Rings, sent to Middle-earth to inspire the free peoples to resist Sauron. Principal among the Istari are Gandalf and Saruman, both of whom feature prominently in the events of The Lord of the Rings. A much more minor role, however, is played by Radagast the Brown, who appears only in passing mentions in The Hobbit and serves almost as a messenger in The Lord of the Rings. These three Istari enable an interesting discussion of environmental relationships, with Radagast and Saruman portrayed as failures and Gandalf alone successful. Radagast is said to have forsaken Men and Elves for the birds and beasts and thus fails in his mission. Saruman also fails, but because of his lust for power and consequent subjugation of people and landscapes, especially Isengard, the Shire, and Fangorn. Gandalf alone succeeds, caring both for the landscapes of Middle-earth and for its peoples. In an environmental ethical framework, Saruman aligns in an extreme anthropocentric position, prioritizing his own preferences over the health of others and their ecosystems. Conversely, Radagast seems to align more with the ecocentric side of the spectrum, considering the Free Peoples relatively unimportant and giving himself instead to the birds and the beasts. In contrast to both, Gandalf understands himself as accountable to the Valar for the accomplishment of his mission to stir up the Free Peoples in opposition to Sauron, alongside care of nonhuman organisms and their environment. Tolkien’s framing of Gandalf as the only successful wizard underscores this theocentric approach as his preferred resolution of the tension between humans and the nonhuman—rightly relating all of them to one another in the service of their Creator

Spontaneous Emission Spectra and Quantum Light-Matter Interactions from a Strongly-Coupled Quantum Dot Metal-Nanoparticle System

We investigate the quantum optical properties of a single photon emitter coupled to a finite-size metal nanoparticle using a photon Green function technique that rigorously quantizes the electromagnetic fields. We first obtain pronounced Purcell factors and photonic Lamb shifts for both a 7-nm and 20-nm radius metal nanoparticle, without adopting a dipole approximation. We then consider a quantum-dot photon emitter positioned sufficiently near to the metal nanoparticle so that the strong coupling regime is possible. Accounting for non-dipole interactions, quenching, and photon transport from the dot to the detector, we demonstrate that the strong coupling regime should be observable in the far-field spontaneous emission spectrum, even at room temperature. The emission spectra show that the usual vacuum Rabi doublet becomes a rich spectral triplet or quartet with two of the four peaks anticrossing, which survives in spite of significant non-radiative decays. We discuss the emitted light spectrum and the effects of quenching for two different dipole polarizations.Comment: 5 figure

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression

<p>Abstract</p> <p>Background</p> <p>The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called 'intestinal barrier proteins'. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARα), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARα on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPARα-null mice. Treatment with the synthetic PPARα agonist WY14643 served as reference.</p> <p>Results</p> <p>We identified 74 barrier genes that were PPARα-dependently regulated 6 hours after activation with WY14643. For eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46, 41, and 19, respectively. The overlap between EPA-, DHA-, and WY14643-regulated genes was considerable, whereas OA treatment showed limited overlap. Functional implications inferred form our data suggested that nutrient-activated PPARα regulated transporters and phase I/II metabolic enzymes were involved in a) fatty acid oxidation, b) cholesterol, glucose, and amino acid transport and metabolism, c) intestinal motility, and d) oxidative stress defense.</p> <p>Conclusion</p> <p>We identified intestinal barrier genes that were PPARα-dependently regulated after acute activation by fatty acids. This knowledge provides a better understanding of the impact dietary fat has on the barrier function of the gut, identifies PPARα as an important factor controlling this key function, and underscores the importance of PPARα for nutrient-mediated gene regulation in intestine.</p

Retinal orientation and interactions in rhodopsin reveal a two-stage trigger mechanism for activation

The 11-cis retinal chromophore is tightly packed within the interior of the visual receptor rhodopsin and isomerizes to the all-trans configuration following absorption of light. The mechanism by which this isomerization event drives the outward rotation of transmembrane helix H6, a hallmark of activated G protein-coupled receptors, is not well established. To address this question, we use solid-state NMR and FTIR spectroscopy to define the orientation and interactions of the retinal chromophore in the active metarhodopsin II intermediate. Here we show that isomerization of the 11-cis retinal chromophore generates strong steric interactions between its β-ionone ring and transmembrane helices H5 and H6, while deprotonation of its protonated Schiff’s base triggers the rearrangement of the hydrogen-bonding network involving residues on H6 and within the second extracellular loop. We integrate these observations with previous structural and functional studies to propose a two-stage mechanism for rhodopsin activation

Trends in absolute socioeconomic inequalities in mortality in Sweden and New Zealand. A 20-year gender perspective

BACKGROUND: Both trends in socioeconomic inequalities in mortality, and cross-country comparisons, may give more information about the causes of health inequalities. We analysed trends in socioeconomic differentials by mortality from early 1980s to late 1990s, comparing Sweden with New Zealand. METHODS: The New Zealand Census Mortality Study (NZCMS) consisting of over 2 million individuals and the Swedish Survey of Living Conditions (ULF) comprising over 100, 000 individuals were used for analyses. Education and household income were used as measures of socioeconomic position (SEP). The slope index of inequality (SII) was calculated to estimate absolute inequalities in mortality. Analyses were based on 3–5 year follow-up and limited to individuals aged 25–77 years. Age standardised mortality rates were calculated using the European population standard. RESULTS: Absolute inequalities in mortality on average over the 1980s and 1990s for both men and women by education were similar in Sweden and New Zealand, but by income were greater in Sweden. Comparing trends in absolute inequalities over the 1980s and 1990s, men's absolute inequalities by education decreased by 66% in Sweden and by 17% in New Zealand (p for trend <0.01 in both countries). Women's absolute inequalities by education decreased by 19% in Sweden (p = 0.03) and by 8% in New Zealand (p = 0.53). Men's absolute inequalities by income decreased by 51% in Sweden (p for trend = 0.06), but increased by 16% in New Zealand (p = 0.13). Women's absolute inequalities by income increased in both countries: 12% in Sweden (p = 0.03) and 21% in New Zealand (p = 0.04). CONCLUSION: Trends in socioeconomic inequalities in mortality were clearly most favourable for men in Sweden. Trends also seemed to be more favourable for men than women in New Zealand. Assuming the trends in male inequalities in Sweden were not a statistical chance finding, it is not clear what the substantive reason(s) was for the pronounced decrease. Further gender comparisons are required

The Molecular Switching Mechanism at the Conserved D(E)RY Motif in Class-A GPCRs

The disruption of ionic and H-bond interactions between the cytosolic ends of transmembrane helices TM3 and TM6 of class-A (rhodopsin-like) G protein-coupled receptors (GPCRs) is a hallmark for their activation by chemical or physical stimuli. In the bovine photoreceptor rhodopsin, this is accompanied by proton uptake at Glu134 in the class-conserved D(E)RY motif. Studies on TM3 model peptides proposed a crucial role of the lipid bilayer in linking protonation to stabilization of an active state-like conformation. However, the molecular details of this linkage could not be resolved and have been addressed in this study by molecular dynamics (MD) simulations on TM3 model peptides in a bilayer of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). We show that protonation of the conserved glutamic acid alters the peptide insertion depth in the membrane, its side-chain rotamer preferences, and stabilizes the C-terminal helical structure. These factors contribute to the rise of the side-chain pKa (> 6) and to reduced polarity around the TM3 C terminus as confirmed by fluorescence spectroscopy. Helix stabilization requires the protonated carboxyl group; unexpectedly, this stabilization could not be evoked with an amide in MD simulations. Additionally, time-resolved Fourier transform infrared (FTIR) spectroscopy of TM3 model peptides revealed a different kinetics for lipid ester carbonyl hydration, suggesting that the carboxyl is linked to more extended H-bond clusters than an amide. Remarkably, this was seen as well in DOPC-reconstituted Glu134- and Gln134-containing bovine opsin mutants and demonstrates that the D(E)RY motif is a hydrated microdomain. The function of the D(E)RY motif as a proton switch is suggested to be based on the reorganization of the H-bond network at the membrane interface

Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema

Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies

Biomarker-based staging of Alzheimer disease: rationale and clinical applications

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications