One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.

Continuous eclogite melting and variable refertilisation in upwelling heterogeneous mantle

Large-scale tectonic processes introduce a range of crustal lithologies into the Earth's mantle. These lithologies have been implicated as sources of compositional heterogeneity in mantle-derived magmas. The model being explored here assumes the presence of widely dispersed fragments of residual eclogite (derived from recycled oceanic crust), stretched and stirred by convection in the mantle. Here we show with an experimental study that these residual eclogites continuously melt during upwelling of such heterogeneous mantle and we characterize the melting reactions and compositional changes in the residue minerals. The chemical exchange between these partial melts and more refractory peridotite leads to a variably metasomatised mantle. Re-melting of these metasomatised peridotite lithologies at given pressures and temperatures results in diverse melt compositions, which may contribute to the observed heterogeneity of oceanic basalt suites. We also show that heterogeneous upwelling mantle is subject to diverse local freezing, hybridization and carbonate-carbon-silicate redox reactions along a mantle adiabat.

The impacts of volcanic aerosol on stratospheric ozone and the Northern Hemisphere polar vortex: separating radiative-dynamical changes from direct effects due to enhanced aerosol heterogeneous chemistry

After major volcanic eruptions the enhanced aerosol causes ozone changes due to greater heterogeneous chemistry on the particle surfaces (HET-AER) and from dynamical effects related to the radiative heating of the lower stratosphere (RAD-DYN). We carry out a series of experiments with an atmosphere–ocean–chemistry–climate model to assess how these two processes change stratospheric ozone and Northern Hemispheric (NH) polar vortex dynamics. Ensemble simulations are performed under present day and preindustrial conditions, and with aerosol forcings representative of different eruption strength, to investigate changes in the response behaviour. We show that the halogen component of the HET-AER effect dominates under present-day conditions with a global reduction of ozone (−21 DU for the strongest eruption) particularly at high latitudes, whereas the HET-AER effect increases stratospheric ozone due to N2O5 hydrolysis in a preindustrial atmosphere (maximum anomalies +4 DU). The halogen-induced ozone changes in the present-day atmosphere offset part of the strengthening of the NH polar vortex during mid-winter (reduction of up to −16 m s-1 in January) and slightly amplify the dynamical changes in the polar stratosphere in late winter (+11 m s-1 in March). The RAD-DYN mechanism leads to positive column ozone anomalies which are reduced in a present-day atmosphere by amplified polar ozone depletion (maximum anomalies +12 and +18 DU for present day and preindustrial, respectively). For preindustrial conditions, the ozone response is consequently dominated by RAD-DYN processes, while under present-day conditions, HET-AER effects dominate. The dynamical response of the stratosphere is dominated by the RAD-DYN mechanism showing an intensification of the NH polar vortex in winter (up to +10 m s-1 in January). Ozone changes due to the RAD-DYN mechanism slightly reduce the response of the polar vortex after the eruption under present-day conditions.

Living in Heterogeneous Woodlands – Are Habitat Continuity or Quality Drivers of Genetic Variability in a Flightless Ground Beetle?

Although genetic diversity is one of the key components of biodiversity, its drivers are still not fully understood. While it is known that genetic diversity is affected both by environmental parameters as well as habitat history, these factors are not often tested together. Therefore, we analyzed 14 microsatellite loci in Abax parallelepipedus, a flightless, forest dwelling ground beetle, from 88 plots in two study regions in Germany. We modeled the effects of historical and environmental variables on allelic richness, and found for one of the regions, the Schorfheide-Chorin, a significant effect of the depth of the litter layer, which is a main component of habitat quality, and of the sampling effort, which serves as an inverse proxy for local population size. For the other region, the Schwäbische Alb, none of the potential drivers showed a significant effect on allelic richness. We conclude that the genetic diversity in our study species is being driven by current local population sizes via environmental variables and not by historical processes in the studied regions. This is also supported by lack of genetic differentiation between local populations sampled from ancient and from recent woodlands. We suggest that the potential effects of former fragmentation and recolonization processes have been mitigated by the large and stable local populations of Abax parallelepipedus in combination with the proximity of the ancient and recent woodlands in the studied landscapes.

Synthesis of Semi-Natural Grassland Vegetation of a Biogeographically Heterogeneous Area: Mesophilous Species-Rich Meadows in Switzerland

For a hundred years semi-natural species-rich meadow vegetation has been described from various areas of Switzerland. The first description dates from 1892 by Stebler and Schröter. In the present study, relevés of 65 semi-natural mesophilous meadow associations and communities reported by 26 authors, which were collected throughout the century, are summarized. An increasing number of descriptions dating from the 1980s and 1990s is included. A numerical classification of these 65 types resulted in four main groups of meadow-types. When compared with the existing literature of alliances a high correlation is found with the Polygono-Trisetion Br.-Bl. et R. Tx. ex Marshall 1947, the Arrhenatherion W. Koch 1926, the Agrostio-Festucion Puscaru et al. 1956, the Mesobromion Br.-Bl. et Moor 1938 em. Oberdorfer 1957, and with the Chrysopogonetum W. Koch 1943. The Agrostio-Festucion is characteristic for the montane belt in southern Switzerland and was until recently poorly known. This alliance is discussed in detail. Some classifications of meadow types by the original authors had to be rearranged for the present purpose. The present classification coincides well with the one Stebler and Schröter gave in 1892. Today, after a century of intensive changes in land use, their four main types are still valid.

Promoting Student Collaboration in a Detracked, Heterogeneous Secondary Mathematics Classroom

Detracking and heterogeneous groupwork are two educational practices that have been shown to have promise for affording all students needed learning opportunities to develop mathematical proficiency. However, teachers face significant pedagogical challenges in organizing productive groupwork in these settings. This study offers an analysis of one teacher’s role in creating a classroom system that supported student collaboration within groups in a detracked, heterogeneous geometry classroom. The analysis focuses on four categories of the teacher’s work that created a set of affordances to support within group collaborative practices and links the teacher’s work with principles of complex systems.

Asset Pricing with Heterogeneous Agents, Incomplete Markets and Trading Constraints

The consumption capital asset pricing model is the standard economic model used to capture stock market behavior. However, empirical tests have pointed out to its inability to account quantitatively for the high average rate of return and volatility of stocks over time for plausible parameter values. Recent research has suggested that the consumption of stockholders is more strongly correlated with the performance of the stock market than the consumption of non-stockholders. We model two types of agents, non-stockholders with standard preferences and stock holders with preferences that incorporate elements of the prospect theory developed by Kahneman and Tversky (1979). In addition to consumption, stockholders consider fluctuations in their financial wealth explicitly when making decisions. Data from the Panel Study of Income Dynamics are used to calibrate the labor income processes of the two types of agents. Each agent faces idiosyncratic shocks to his labor income as well as aggregate shocks to the per-share dividend but markets are incomplete and agents cannot hedge consumption risks completely. In addition, consumers face both borrowing and short-sale constraints. Our results show that in equilibrium, agents hold different portfolios. Our model is able to generate a time-varying risk premium of about 5.5% while maintaining a low risk free rate, thus suggesting a plausible explanation for the equity premium puzzle reported by Mehra and Prescott (1985).

Mechanisms Underlying the Heterogeneous Sensitivities of Cancer Cells to Proteasome Inhibitors

The mechanisms underlying cellular response to proteasome inhibitors have not been clearly elucidated in solid tumor models. Evidence suggests that the ability of a cell to manage the amount of proteotoxic stress following proteasome inhibition dictates survival. In this study using the FDA-approved proteasome inhibitor bortezomib (Velcade®) in solid tumor cells, we demonstrated that perhaps the most critical response to proteasome inhibition is repression of global protein synthesis by phosphorylation of the eukaryotic initiation factor 2-α subunit (eIF2α). In a panel of 10 distinct human pancreatic cancer cells, we showed marked heterogeneity in the ability of cancer cells to induce eIF2α phosphorylation upon stress (eIF2α-P); lack of inducible eIF2α-P led to excessive accumulation of aggregated proteins, reactive oxygen species, and ultimately cell death. In addition, we examined complementary cytoprotective mechanisms involving the activation of the heat shock response (HSR), and found that induction of heat shock protein 70 kDa (Hsp72) protected against proteasome inhibitor-induced cell death in human bladder cancer cells. Finally, investigation of a novel histone deacetylase 6 (HDAC6)-selective inhibitor suggested that the cytoprotective role of the cytoplasmic histone deacetylase 6 (HDAC6) in response to proteasome inhibition may have been previously overestimated.

Development and implementation of a dynamic heterogeneous proton equivalent anthropomorphic thorax phantom for the assessment of scanned proton beam therapy

DEVELOPMENT AND IMPLEMENTATION OF A DYNAMIC HETEROGENEOUS PROTON EQUIVALENT ANTHROPOMORPHIC THORAX PHANTOM FOR THE ASSESSMENT OF SCANNED PROTON BEAM THERAPY by James Leroy Neihart, B.S. APPROVED: ______________________________David Followill, Ph.D. ______________________________Peter Balter, Ph.D. ______________________________Narayan Sahoo, Ph.D. ______________________________Kenneth Hess, Ph.D. ______________________________Paige Summers, M.S. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston DEVELOPMENT AND IMPLEMENTATION OF A DYNAMIC HETEROGENEOUS PROTON EQUIVALENT ANTHROPOMORPHIC THORAX PHANTOM FOR THE ASSESSMENT OF SCANNED PROTON BEAM THERAPY A THESIS Presented to the Faculty of The University of Texas Health Science Center at Houston andThe University of TexasMD Anderson Cancer CenterGraduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE by James Leroy Neihart, B.S. Houston, Texas Date of Graduation August, 2013 Acknowledgments I would like to acknowledge my advisory committee members, chair David Followill, Ph.D., Peter Balter, Ph.D, Narayan Sahoo, Ph.D., Kenneth Hess, Ph.D., Paige Summers M.S. and, for their time and effort contributed to this project. I would additionally like to thank the faculty and staff at the PTC-H and the RPC who assisted in many aspects of this project. Falk Pӧnisch, Ph.D. for his breath hold proton therapy treatment expertise, Matt Palmer and Jaques Bluett for proton dosimetry assistance, Matt Kerr for verification plan assistance, Carrie Amador, Nadia Hernandez, Trang Nguyen, Andrea Molineu, Lynda McDonald for TLD and film dosimetry assistance. Finally, I would like to thank my wife and family for their support and encouragement during my research and studies. Development and implementation of a dynamic heterogeneous proton equivalent anthropomorphic thorax phantom for the assessment of scanned proton beam therapy By: James Leroy Neihart, B.S. Chair of Advisory Committee: David Followill, Ph.D Proton therapy has been gaining ground recently in radiation oncology. To date, the most successful utilization of proton therapy is in head and neck cases as well as prostate cases. These tumor locations do not suffer from the resulting difficulties of treatment delivery as a result of respiratory motion. Lung tumors require either breath hold or motion tracking, neither of which have been assessed with an end-to-end phantom for proton treatments. Currently, the RPC does not have a dynamic thoracic phantom for proton therapy procedure assessment. Additionally, such a phantom could be an excellent means of assessing quality assurance of the procedures of proton therapy centers wishing to participate in clinical trials. An eventual goal of this phantom is to have a means of evaluating and auditing institutions for the ability to start clinical trials utilizing proton therapy procedures for lung cancers. Therefore, the hypothesis of this study is that a dynamic anthropomorphic thoracic phantom can be created to evaluate end-to-end proton therapy treatment procedures for lung cancer to assure agreement between the measured and calculated dose within 5% / 5 mm with a reproducibility of 2%. Multiple materials were assessed for thoracic heterogeneity equivalency. The phantom was designed from the materials found to be in greatest agreement. The phantom was treated in an end-to-end treatment four times, which included simulation, treatment planning and treatment delivery. Each treatment plan was delivered three times to assess reproducibility. The dose measured within the phantom was compared to that of the treatment plan. The hypothesis was fully supported for three of the treatment plans, but failed the reproducibility requirement for the most aggressive treatment plan.

Simulating heterogeneous multinational firms

This paper develops a micro-simulation framework for multinational entry and sales activities across countries. The model is based on Eaton, Kortum, and Kramarz's (2010) quantitative trade model adapted towards multinational production. Using micro data on Japanese manufacturing firms, we first stylize the empirical regularities of multinational entry and sales activity and estimate the model's structural parameters with simulated method of moments. We then demonstrate that our adapted model is able to replicate important dimensions of the in-sample moments conditioned in our estimation strategy. Importantly, it is able to replicate activity under an economic period with a far different level of FDI barriers than was conditioned upon in our estimation sample. Overall, our research highlights the richness of the simulation framework for performing counterfactual analysis of various FDI policies.

Heterogeneous multinational firms and productivity gains from falling FDI barriers

During the past decade of declining FDI barriers, small domestic firms disproportionately contracted while large multinational firms experienced a substantial growth in Japan’s manufacturing sector. This paper quantitatively assesses the impact of FDI globalization on intra-industry reallocations and aggregate productivity. We calibrate the firm-heterogeneity model of Eaton, Kortum, and Kramarz (2011) to micro-level data on Japanese multinational firms. Estimating the structural parameters of the model, we demonstrate that the model can strongly replicate the entry and sales patterns of Japanese multinationals. Counterfactual simulations show that declining FDI barriers lead to a disproportionate expansion of foreign production by more efficient firms relative to less efficient firms. A hypothetical 20% reduction in FDI barriers is found to generate a 30.7% improvement in aggregate productivity through market-share reallocation.