Cyclic Ruthenium-Alkylidene Catalysts for Ring-Expansion Metathesis Polymerization

A series of cyclic Ru-alkylidene catalysts have been prepared and evaluated for their efficiency in ring-expansion metathesis polymerization (REMP). The catalyst structures feature chelating tethers extending from one N-atom of an N-heterocyclic carbene (NHC) ligand to the Ru metal center. The catalyst design is modular in nature, which provided access to Ru complexes having varying tether lengths, as well as electronically different NHC ligands. Structural impacts of the tether length were unveiled through 1H NMR spectroscopy as well as single-crystal X-ray analyses. Catalyst activities were evaluated via polymerization of cyclooctene, and key data are provided regarding propagation rates, intramolecular chain transfer, and catalyst stabilities, three areas necessary for the efficient synthesis of cyclic poly(olefin)s via REMP. From these studies, it was determined that while increasing the tether length of the catalyst leads to enhanced rates of polymerization, shorter tethers were found to facilitate intramolecular chain transfer and release of catalyst from the polymer. Electronic modification of the NHC via backbone saturation was found to enhance polymerization rates to a greater extent than did homologation of the tether. Overall, cyclic Ru complexes bearing 5- or 6-carbon tethers and saturated NHC ligands were found to be readily synthesized, bench-stable, and highly active catalysts for REMP

Ring-Expansion Metathesis Polymerization: Catalyst-Dependent Polymerization Profiles

Ring-expansion metathesis polymerization (REMP) mediated by recently developed cyclic Ru catalysts has been studied in detail with a focus on the polymer products obtained under varied reaction conditions and catalyst architectures. Depending upon the nature of the catalyst structure, two distinct molecular weight evolutions were observed. Polymerization conducted with catalysts bearing six-carbon tethers displayed rapid polymer molecular weight growth which reached a maximum value at ca. 70% monomer conversion, resembling a chain-growth polymerization mechanism. In contrast, five-carbon-tethered catalysts led to molecular weight growth that resembled a step-growth mechanism with a steep increase occurring only after 95% monomer conversion. The underlying reason for these mechanistic differences appeared to be ready release of five-carbon-tethered catalysts from growing polymer rings, which competed significantly with propagation. Owing to reversible chain transfer and the lack of end groups in REMP, the final molecular weights of cyclic polymers was controlled by thermodynamic equilibria. Large ring sizes in the range of 60−120 kDa were observed at equilibrium for polycyclooctene and polycyclododecatriene, which were found to be independent of catalyst structure and initial monomer/catalyst ratio. While six-carbon-tethered catalysts were slowly incorporated into the formed cyclic polymer, the incorporation of five-carbon-tethered catalysts was minimal, as revealed by ICP-MS. Further polymer analysis was conducted using melt-state magic-angle spinning ^(13)C NMR spectroscopy of both linear and cyclic polymers, which revealed little or no chain ends for the latter topology

Real-time depth sectioning: Isolating the effect of stress on structure development in pressure-driven flow

Transient structure development at a specific distance from the channel wall in a pressure-driven flow is obtained from a set of real-time measurements that integrate contributions throughout the thickness of a rectangular channel. This “depth sectioning method” retains the advantages of pressure-driven flow while revealing flow-induced structures as a function of stress. The method is illustrated by applying it to isothermal shear-induced crystallization of an isotactic polypropylene using both synchrotron x-ray scattering and optical retardance. Real-time, depth-resolved information about the development of oriented precursors reveals features that cannot be extracted from ex-situ observation of the final morphology and that are obscured in the depth-averaged in-situ measurements. For example, at 137 °C and at the highest shear stress examined (65 kPa), oriented thread-like nuclei formed rapidly, saturated within the first 7 s of flow, developed significant crystalline overgrowth during flow and did not relax after cessation of shear. At lower stresses, threads formed later and increased at a slower rate. The depth sectioning method can be applied to the flow-induced structure development in diverse complex fluids, including block copolymers, colloidal systems, and liquid-crystalline polymers

Safety and Efficacy of Risuteganib in Intermediate Non-exudative Age-Related Macular Degeneration

Purpose : Risuteganib is a small synthetic peptide that regulates select integrin functions involved in the pathogenesis of dry age-related macular degeneration (AMD). This study evaluated the safety and efficay of risuteganib for the treatment of dry AMD. Methods : Randomized, double-masked, placebo-controlled Phase 2 study in eyes with intermediate dry AMD presenting with best-corrected visual acuity (BCVA) between 20/40-20/200 was conducted across multiple centers in the United States. Patients were randomized to receive either intravitreal 1.0mg risuteganib or sham injection at baseline. At week 16, patients in the risuteganib group received a second dose and the sham group crossed over and receive a single dose of 1.0mg risuteganib. The primary endpoint was the percentage of population with ≥ 8 letters BCVA gain from baseline to week 28 in 1.0mg risuteganib vs baseline to week 12 for sham. Results : Forty-five patients were enrolled in the study. At baseline, mean patient age was 78.8 and 75.9 years and mean baseline BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met; 48% of patients in the risuteganib group at week 28 and 7% of patients in the sham group at week 12 gained > 8 letters from baseline (p=0.013). Of the risuteganib treated patients, 20% gained > 15 letters at week 28; no patients in the sham group at week 12 had this gain. On a post-hoc masked analysis by 2 independent reading centers, greater outer retinal and photoreceptor thickness and volume and smaller ellipsoid zone defect area in the central 1 mm zone at baseline were associated with increased BCVA response to risuteganib. Risuteganib demonstrated a good safety profile in this study. Conclusions : Risuteganib showed significant benefit over sham in patients with dry AMD with respect to proportion of patients gaining > 8 letters of BCVA from baseline. Furthermore, post hoc analysis provides preliminary insights into baseline anatomic features that may help to determine likelihood of BCVA response to risuteganib. These findings will be confirmed in an upcoming larger trial

Properties of small molecular drug loading and diffusion in a fluorinated PEG hydrogel studied by ^1H molecular diffusion NMR and ^(19)F spin diffusion NMR

R_f-PEG (fluoroalkyl double-ended poly(ethylene glycol)) hydrogel is potentially useful as a drug delivery depot due to its advanced properties of sol–gel two-phase coexistence and low surface erosion. In this study, ^1H molecular diffusion nuclear magnetic resonance (NMR) and ^(19)F spin diffusion NMR were used to probe the drug loading and diffusion properties of the R_f-PEG hydrogel for small anticancer drugs, 5-fluorouracil (FU) and its hydrophobic analog, 1,3-dimethyl-5-fluorouracil (DMFU). It was found that FU has a larger apparent diffusion coefficient than that of DMFU, and the diffusion of the latter was more hindered. The result of ^(19)F spin diffusion NMR for the corresponding freeze-dried samples indicates that a larger portion of DMFU resided in the R_f core/IPDU intermediate-layer region (where IPDU refers to isophorone diurethane, as a linker to interconnect the R_f group and the PEG chain) than that of FU while the opposite is true in the PEG–water phase. To understand the experimental data, a diffusion model was proposed to include: (1) hindered diffusion of the drug molecules in the R_f core/IPDU-intermediate-layer region; (2) relatively free diffusion of the drug molecules in the PEG-water phase (or region); and (3) diffusive exchange of the probe molecules between the above two regions. This study also shows that molecular diffusion NMR combined with spin diffusion NMR is useful in studying the drug loading and diffusion properties in hydrogels for the purpose of drug delivery applications

Development and Validation of the Behavioral Tendencies Questionnaire

At a fundamental level, taxonomy of behavior and behavioral tendencies can be described in terms of approach, avoid, or equivocate (i.e., neither approach nor avoid). While there are numerous theories of personality, temperament, and character, few seem to take advantage of parsimonious taxonomy. The present study sought to implement this taxonomy by creating a questionnaire based on a categorization of behavioral temperaments/tendencies first identified in Buddhist accounts over fifteen hundred years ago. Items were developed using historical and contemporary texts of the behavioral temperaments, described as “Greedy/Faithful”, “Aversive/Discerning”, and “Deluded/Speculative”. To both maintain this categorical typology and benefit from the advantageous properties of forced-choice response format (e.g., reduction of response biases), binary pairwise preferences for items were modeled using Latent Class Analysis (LCA). One sample (n1 = 394) was used to estimate the item parameters, and the second sample (n2 = 504) was used to classify the participants using the established parameters and cross-validate the classification against multiple other measures. The cross-validated measure exhibited good nomothetic span (construct-consistent relationships with related measures) that seemed to corroborate the ideas present in the original Buddhist source documents. The final 13-block questionnaire created from the best performing items (the Behavioral Tendencies Questionnaire or BTQ) is a psychometrically valid questionnaire that is historically consistent, based in behavioral tendencies, and promises practical and clinical utility particularly in settings that teach and study meditation practices such as Mindfulness Based Stress Reduction (MBSR)

The grinch who stole wisdom

Dr. Seuss is wise. How the Grinch Stole Christmas (Seuss, 1957) could serve as a parable for our time. It can also be seen as a roadmap for the development of contemplative wisdom. The abiding popularity of How the Grinch Stole Christmas additionally suggests that contemplative wisdom is more readily available to ordinary people, even children, than is normally thought. This matters because from the point of view of contemplatives in any of the world's philosophies or religions, people are confused about wisdom. The content of the nascent field of wisdom studies, they might say, is largely not wisdom at all but rather what it's like to live in a particular kind of prison cell, a well appointed cell perhaps, but not a place that makes possible either personal satisfaction or deep problem solving. I believe that what the contemplative traditions have to say is important; they offer a different orientation to what personal wisdom is, how to develop it, and how to use it in the world than is presently contained in either our popular culture or our sciences. In order to illustrate this I will examine, in some detail, one contemplative path within Buddhism. Buddhism is particularly useful in this respect because its practices are nontheistic and thus avoid many of the cultural landmines associated with the contemplative aspects of Western religions

Spatial Geographic Mosaic in an Aquatic Predator-Prey Network

The geographic mosaic theory of coevolution predicts 1) spatial variation in predatory structures as well as prey defensive traits, and 2) trait matching in some areas and trait mismatching in others mediated by gene flow. We examined gene flow and documented spatial variation in crushing resistance in the freshwater snails Mexipyrgus churinceanus, Mexithauma quadripaludium, Nymphophilus minckleyi, and its relationship to the relative frequency of the crushing morphotype in the trophically polymorphic fish Herichthys minckleyi. Crushing resistance and the frequency of the crushing morphotype did show spatial variation among 11 naturally replicated communities in the Cuatro Ciénegas valley in Mexico where these species are all endemic. The variation in crushing resistance among populations was not explained by geographic proximity or by genetic similarity in any species. We detected clear phylogeographic patterns and limited gene flow for the snails but not for the fish. Gene flow among snail populations in Cuatro Ciénegas could explain the mosaic of local divergence in shell strength and be preventing the fixation of the crushing morphotype in Herichthys minckleyi. Finally, consistent with trait matching across the mosaic, the frequency of the fish morphotype was negatively correlated with shell crushing resistance likely reflecting the relative disadvantage of the crushing morphotype in communities where the snails exhibit relatively high crushing resistance