Novel, potent antagonists of capsaicin.

The aim of this project was to explore and refine the conformational rationale for the activity of capsazepine (CPZ) as a blocker of the ion channel TRPV1 (transient receptor potential vanilloid type 1), by the synthesis and biological evaluation of further conformational constrained capsaicin analogues. The resolution of the stereoisomers of Af-(4-chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquino-line 29, Af-(4-chlorophenethylthio-carbamoyl)-6,7-dihydroxy-3-methyl-1,2,3,4-tetra-hydroisoquinoline 30 and N-(4-chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1,3-dimethyl-1,2,3,4-tetrahydroiso-quinoline 31 by stereoselective synthetic methodology is described, and some of the more unusual and interesting mechanisms are discussed. The novel asyrnmetric chemistry described includes the separation of the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by crystallisation with the enantiomers of mandelic acid, the use of sodium triacetoxyborohydride in the stereoselective reduction of 6,7-dimethoxy-l,3-dimethyl-3,4-dihydroiso-quinoline 171, to give the cw-diastereomers of 6,7-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 44, and the novel stereoselective route to the trans-diastereomers of 6,7-dimethoxy-l,3-dimethyl-l,2,3,4-tetrahydroisoquinoline 44 from the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by the Michael addition of A-benzyl-2-(3,4-dimethoxyphenyl)-l-methylethylamine 155 to ethynyl-4-tolylsulfone 150, followed by TFA-mediated cyclisation, single electron reductive desulfonylation and palladium-catalysed hydrogenolysis. The results of investigations into the conformational behaviour of the resolved stereoisomers of 29, 30 and 31 by techniques of NMR spectroscopy and molecular modelling, the evaluation of their biological activity at the rat and human orthologues of the ion channel TRPV1, and the attempted correlation of the two sets of data, with respect to the published conformational rationale for the activity of CPZ, are also described

Avoiding Chaos in Wonderland

Wonderland, a compact, integrated economic, demographic and environmental model is investigated using methods developed for studying critical phenomena. Simulation results show the parameter space separates into two phases, one of which contains the property of long term, sustainable development. By employing information contain in the phase diagram, an optimal strategy involving pollution taxes is developed as a means of moving a system initially in a unsustainable region of the phase diagram into a region of sustainability while ensuring minimal regret with respect to long term economic growth.Comment: 22 pages, 9 figures. Submitted to Physica

Experimental study of bore-driven swash hydrodynamics on permeable rough slopes

Peer reviewedPublisher PD

No Far-Infrared-Spectroscopic Gap in Clean and Dirty High-TC_C Superconductors

We report far infrared transmission measurements on single crystal samples derived from Bi$_{2}$Sr$_{2}$CaCu$_{2}$O$_{8}$. The impurity scattering rate of the samples was varied by electron-beam irradiation, 50MeV $^{16}$O$^{+6}$ ion irradiation, heat treatment in vacuum, and Y doping. Although substantial changes in the infrared spectra were produced, in no case was a feature observed that could be associated with the superconducting energy gap. These results all but rule out ``clean limit'' explanations for the absence of the spectroscopic gap in this material, and provide evidence that the superconductivity in Bi$_{2}$Sr$_{2}$CaCu$_{2}$O$_{8}$ is gapless.Comment: 4 pages and 3 postscript figures attached. REVTEX v3.0. Accepted for publication in Phys. Rev. Lett. IRDIRT

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .)

Techno economic and life cycle assessment of olefin production through CO2 hydrogenation within the power-to-X concept

The paper deals with exhaustive process modelling, techno-economic and life cycle assessment (TEA/LCA) of olefin (ethylene and propylene) production through captured CO2 and electrolytic hydrogen. Olefins are important building block chemicals with several applications and carbon capture and utilisation (CCU) can provide a sustainable production route. The proposed system involves direct air capture (DAC) of CO2; proton exchange membrane (PEM) water electrolysis for hydrogen production, methanol synthesis, methanol to olefins (MTO) upgrade, and power generation from off-shore wind turbines. This study proposes a new integrated process as the first attempt to holistically assess a whole CCU assembly aiming at olefins production. Processing modelling has been implemented using the Aspen plus V12.1 and MATLAB R2022a software to solve the mass and energy balances of each unit operation. The modelling results showed a carbon efficiency of 72.3% to ethylene and propylene. In addition, the process is designed and integrated in such a way that no external heat supply is required. A specific energy consumption (SEC) of 150 MJ/kg olefins (41 kWh/kg) has been estimated. A minimum selling price of £3.67 per kg of olefins is required for the proposed process to break-even. The sensitivity analysis has revealed that the major cost driver is the cost of electricity. In addition, the life cycle assessment (LCA) has exposed that the proposed synthesis route of olefins has the potential to reduce the global warming potential (GWP) by 47% compared to fossil - based production. The outcomes of this study can be beneficial to engineering conceptual studies, policy makers and contribute new information to the CCU academic community

The Supernova Relic Neutrino Background

An upper bound to the supernova relic neutrino background from all past Type II supernovae is obtained using observations of the Universal metal enrichment history. We show that an unambiguous detection of these relic neutrinos by the Super-Kamiokande detector is unlikely. We also analyze the event rate in the Sudbury Neutrino Observatory (where coincident neutrons from anti-nu_e + D --> n + n + e+ might enhance background rejection), and arrive at the same conclusion. If the relic neutrino flux should be observed to exceed our upper bound and if the observations of the metal enrichment history (for z<1) are not in considerable error, then either the Type II supernova rate does not track the metal enrichment history or some mechanism may be responsible for transforming anti-nu_{mu,tau} --> anti-nu_e.Comment: Matches version accepted for publication in Phys. Rev.

Re-establishment of the genus Pseudalbizzia (Leguminosae, Caesalpinioideae, mimosoid clade): the New World species formerly placed in Albizia

Following recent mimosoid phylogenetic and phylogenomic studies demonstrating the non-monophyly of the genus Albizia, we present a new molecular phylogeny focused on the neotropical species in the genus, with much denser taxon sampling than previous studies. Our aims were to test the monophyly of the neotropical section Arthrosamanea, resolve species relationships, and gain insights into the evolution of fruit morphology. We perform a Bayesian phylogenetic analysis of sequences of nuclear internal and external transcribed spacer regions and trace the evolution of fruit dehiscence and lomentiform pods. Our results find further support for the non-monophyly of the genus Albizia, and confirm the previously proposed segregation of Hesperalbizia, Hydrochorea, Balizia and Pseudosamanea. All species that were sampled from section Arthrosamanea form a clade that is sister to a clade composed of Jupunba, Punjuba, Balizia and Hydrochorea. We find that lomentiform fruits are independently derived from indehiscent septate fruits in both Hydrochorea and section Arthrosamanea. Our results show that morphological adaptations to hydrochory, associated with shifts into seasonally flooded habitats, have occurred several times independently in different geographic areas and different lineages within the ingoid clade. This suggests that environmental conditions have likely played a key role in the evolution of fruit types in Albizia and related genera. We resurrect the name Pseudalbizzia to accommodate the species of section Arthrosamanea, except for two species that were not sampled here but have been shown in other studies to be more closely related to other ingoid genera and we restrict the name Albizia s.s. to the species from Africa, Madagascar, Asia, Australia, and the Pacific. Twenty-one new nomenclatural combinations in Pseudalbizzia are proposed, including 16 species and 5 infraspecific varietal names. In addition to the type species Pseudalbizzia berteroana, the genus has 17 species distributed across tropical regions of the Americas, including the Caribbean. Finally, a new infrageneric classification into five sections is proposed and a distribution map of the species of Pseudalbizzia is presented