Vitamin A Metabolism and Commensal Stimulationi in the Promotion of Mucosal Immunity

The gastrointestinal tract is replete with commensal microbes and dietary nutrients that provide homeostatic signals. Antigen presenting dendritic cells (DC) residing in the underlying lamina propria (Lp) respond to these signals; however, how they contribute to intestinal T cell homeostasis is unclear. In Chapter 2, LpDC are revealed to uniquely induce naïve T cell differentiation into the Foxp3+ regulatory T cell (Treg) subset. Further, the molecular mechanisms controlling this capacity both in vitro and in vivo are shown to hinge on the vitamin A metabolite, retinoic acid (RA), which LpDC are equipped to synthesize, and the cytokine, TGF-beta. T cell expression of retinoic acid receptor alpha (RARalpha) is shown to be critical for RA to induce enhanced Foxp3+ Treg induction. Chapter 3 extends upon these findings and addresses the influence of the commensal microbiota in the regulation of this pathway. A Toll like receptor (TLR) 9 ligand, commensal derived DNA, is identified as a potent adjuvant in the gut mucosa, which shapes T cell homeostasis in the GI tract. Accordingly Tlr9–⁄– mice display an intestinal site-specific increase in Foxp3+Treg concomitant with a decrease in TH cells. Dysregulation in Foxp3+ Treg/TH homeostasis results in mucosal-specific impaired immune responses in Tlr9–⁄– animals, which can be reversed upon partial depletion of Foxp3+ Treg. Chapter 4 builds upon findings from Chapter 2. The role of vitamin A metabolism in the regulation of mucosal immunity is examined. Vitamin A insufficient (VAI) mice, which lack vitamin A and metabolic derivatives, mount impaired mucosal TH-1 and TH-17 responses. These defects are reversed upon administration of RA. Moreover, Rara–⁄– mice recapitulate the homeostatic and immune defects observed in VAI mice. Strikingly, loss of basal RA/RARalpha signaling hinders early T cell activation events. Cumulatively, the data argue that steady-state cues from microbiota and nutrients shape the inflammatory tone of the Lp to prime mucosal TH responses. These data also identify a fundamental role for vitamin A metabolism in T cell activation and suggest this pathway may have evolved with the development of adaptive CD4+ T cell responses to coordinate host protection

Affinity Through Instant Messaging

This is the Author's Pre-Print.The present manuscript explores affinity seeking, testing, and signaling in initial interactions of opposite-sex strangers using instant messaging. Sixty dyads (N = 120) interacted for 20 minutes and participants identified when they showed liking and when they perceived their partner showing liking in the interaction transcript. Participants also reported overall liking for and the perception of being liked by their conversation partner on a survey instrument. The results indicated that participants who perceived more liking in the text and accurately decoded messages of liking from their partner, believed their conversational partner liked them more. Participants who perceived more disliking messages in the text liked their conversational partners less and believed their partner liked them less as well. Six dyadic analyses using structural equation modeling demonstrated that effects of affinity seeking, testing, and signaling were moderated by participant sex. For females, sending messages of disliking, perceiving messages of disliking, and accurately decoding of disliking were associated with overall liking of their male conversational partner. The implications of interpreting affinity messages in the formation of online relationships are discussed

Medial knee joint loading during stair ambulation and walking while carrying loads

Carrying loads while walking or using stairs is a common activity of daily living. Knee osteoarthritis is associated with increased external knee adduction moment (KAM) during walking, so understanding how the additional challenges of stairs and carrying loads impact these moments is of value. Sixteen healthy individuals performed three types of MOTION (walking, stair ascent, stair descent) under three LOAD conditions (no load, carrying a 13.6 kg front load, carrying 13.6 kg load in a backpack). Three-dimensional gait analysis was used to measure KAM. Results of ANOVA showed a significant main effect of both MOTION and LOAD on peak KAM (p \u3c 0.001), but no significant MOTION × LOAD interaction (p = 0.250). Peak KAM during stair ascent was about two-times those seen in stair descent (p \u3c 0.001) and was significantly higher than those seen in walking (p \u3c 0.001). Conditions with LOAD generated significantly greater KAM as compared to the no-LOAD conditions (p \u3c 0.001). These findings suggest that carrying a load of moderate magnitude while climbing stairs significantly increases the peak KAM – a risk factor associated with knee osteoarthritis

Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay.

Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3' untranslated region. Upon satellite cell activation, p38α/β MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis

Volume Fractions of the Kinematic "Near-Critical" Sets of the Quantum Ensemble Control Landscape

An estimate is derived for the volume fraction of a subset $C_{\epsilon}^{P} = \{U : ||grad J(U)|\leq {\epsilon}\}\subset\mathrm{U}(N)$ in the neighborhood of the critical set $C^{P}\simeq\mathrm{U}(\mathbf{n})P\mathrm{U}(\mathbf{m})$ of the kinematic quantum ensemble control landscape J(U) = Tr(U\rho U' O), where $U$ represents the unitary time evolution operator, {\rho} is the initial density matrix of the ensemble, and O is an observable operator. This estimate is based on the Hilbert-Schmidt geometry for the unitary group and a first-order approximation of $||grad J(U)||^2$. An upper bound on these near-critical volumes is conjectured and supported by numerical simulation, leading to an asymptotic analysis as the dimension $N$ of the quantum system rises in which the volume fractions of these "near-critical" sets decrease to zero as $N$ increases. This result helps explain the apparent lack of influence exerted by the many saddles of $J$ over the gradient flow.Comment: 27 pages, 1 figur

Ocean acidification bends the Mermaid’s Wineglass

Ocean acidification lowers the saturation state of calcium carbonate, decreasing net calcification and compromising the skeletons of organisms such as corals, molluscs and algae. These calcified structures can protect organisms from predation and improve access to light, nutrients and dispersive currents. While some species (such as urchins, corals and mussels) survive with decreased calcification, they can suffer from inferior mechanical performance. Here, we used cantilever beam theory to test the hypothesis that decreased calcification would impair the mechanical performance of the green alga Acetabularia acetabulum along a CO2 gradient created by volcanic seeps off Vulcano, Italy. Calcification and mechanical properties declined as calcium carbonate saturation fell; algae at 2283 matm CO2 were 32% less calcified, 40% less stiff and 40% droopier. Moreover, calcification was not a linear proxy for mechanical performance; stem stiffness decreased exponentially with reduced calcification. Although calcifying organisms can tolerate high CO2 conditions, even subtle changes in calcification can cause dramatic changes in skeletal performance, which may in turn affect key biotic and abiotic interactions

Time series classification with ensembles of elastic distance measures

Several alternative distance measures for comparing time series have recently been proposed and evaluated on time series classification (TSC) problems. These include variants of dynamic time warping (DTW), such as weighted and derivative DTW, and edit distance-based measures, including longest common subsequence, edit distance with real penalty, time warp with edit, and move–split–merge. These measures have the common characteristic that they operate in the time domain and compensate for potential localised misalignment through some elastic adjustment. Our aim is to experimentally test two hypotheses related to these distance measures. Firstly, we test whether there is any significant difference in accuracy for TSC problems between nearest neighbour classifiers using these distance measures. Secondly, we test whether combining these elastic distance measures through simple ensemble schemes gives significantly better accuracy. We test these hypotheses by carrying out one of the largest experimental studies ever conducted into time series classification. Our first key finding is that there is no significant difference between the elastic distance measures in terms of classification accuracy on our data sets. Our second finding, and the major contribution of this work, is to define an ensemble classifier that significantly outperforms the individual classifiers. We also demonstrate that the ensemble is more accurate than approaches not based in the time domain. Nearly all TSC papers in the data mining literature cite DTW (with warping window set through cross validation) as the benchmark for comparison. We believe that our ensemble is the first ever classifier to significantly outperform DTW and as such raises the bar for future work in this area

Mass Reduction Patterning of Silicon-on-oxide-based Micromirrors

It has long been recognized in the design of micromirror-based optical systems that balancing static flatness of the mirror surface through structural design with the system’s mechanical dynamic response is challenging. Although a variety of mass reduction approaches have been presented in the literature to address this performance trade, there has been little quantifiable comparison reported. In this work, different mass reduction approaches, some unique to the work, are quantifiably compared with solid plate thinning in both curvature and mass using commercial finite element simulation of a specific square silicon-on-insulator–based micromirror geometry. Other important considerations for micromirror surfaces, including surface profile and smoothness, are also discussed. Fabrication of one of these geometries, a two-dimensional tessellated square pattern, was performed in the presence of a 400-μm-tall central post structure using a simple single mask process. Limited experimental curvature measurements of fabricated samples are shown to correspond well with properly characterized simulation results and indicate ∼67% improvement in radius of curvature in comparison to a solid plate design of equivalent mass