Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system

The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (1) is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure-activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB2 receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of 1. While most changes on this element were detrimental for activity, ring-opening cross metathesis of 1 with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (11a, 11b, 11c) that not only retained the CB2 receptor functional agonism of 1 but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors 11e and 11f, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs.

The relationship between top management team innovation orientation and firm growth: The mediating role of firm innovativeness

Upper echelon theory and research on innovation have considered top management teams and their behaviour and characteristics as important factors that positively influence innovativeness and organizational outcomes. Yet, innovation research has mostly focused on individual new product projects, and their performance and impact on firm performance. Recent research has started to apply a more holistic view in terms of innovation, by considering firm-wide innovation instead of single new products. Upper echelon research has concentrated on direct relationships between top management team characteristics and organizational outcomes. But recent research calls for mediating effects of the relationship between top management team characteristics and organizational outcomes. Hence, this study introduces firm innovativeness as a mediator between top management team innovation orientation and firm growth. Focusing on small and medium-sized firms, which often represent highly innovative firms, results show that firm innovativeness fully mediates the relationship between top management team innovation orientation and firm growth. Implications and future research are discussed.

Life-span development of self-esteem and its effects on important life outcomes

We examined the life-span development of self-esteem and tested whether self-esteem influences the development of important life outcomes, including relationship satisfaction, job satisfaction, occupational status, salary, positive and negative affect, depression, and physical health. Data came from the Longitudinal Study of Generations. Analyses were based on 5 assessments across a 12-year period of a sample of 1,824 individuals ages 16 to 97 years. First, growth curve analyses indicated that self-esteem increases from adolescence to middle adulthood, reaches a peak at about age 50 years, and then decreases in old age. Second, cross-lagged regression analyses indicated that self-esteem is best modeled as a cause rather than a consequence of life outcomes. Third, growth curve analyses, with self-esteem as a time-varying covariate, suggested that self-esteem has medium-sized effects on life-span trajectories of affect and depression, small to medium-sized effects on trajectories of relationship and job satisfaction, a very small effect on the trajectory of health, and no effect on the trajectory of occupational status. These findings replicated across 4 generations of participants— children, parents, grandparents, and their great-grandparents. Together, the results suggest that self-esteem has a significant prospective impact on real-world life experiences and that high and low self-esteem are not mere epiphenomena of success and failure in important life domains.

Digital Personal Assistant for Cognitive Cities: A Paper Prototype

This chapter presents an evaluation and initial testing of a meta-application (meta-app) for enhanced communication and improved interaction (e.g., appointment scheduling) between stakeholders (e.g., citizens) in cognitive cities. The underlying theoretical models as well as the paper prototype are presented to ensure the comprehensibility of the user interface. This paper prototype of the meta-app was evaluated through interviews with various experts in different fields (e.g., a strategic consultant, a small and medium-sized enterprises cofounder in the field of online marketing, an IT project leader, and an innovation manager). The results and implications of the evaluation show that the idea behind this meta-app has the potential to improve the living standards of citizens and to lead to a next step in the realization and maturity of the meta-app. The meta-app helps citizens more effectively manage their time and organize their personal schedules and thus allows them to have more leisure time and take full advantage of it to ensure a good work-life balance to enable them to be the most efficient and productive during their working time.

Accuracy of conventional radiography and computed tomography in predicting implant position in relation to the vertebral canal in dogs.

OBJECTIVE To compare the accuracy of radiography and computed tomography (CT) in predicting implant position in relation to the vertebral canal in the cervical and thoracolumbar vertebral column. STUDY DESIGN In vitro imaging and anatomic study. ANIMALS Medium-sized canine cadaver vertebral columns (n=12). METHODS Steinmann pins were inserted into cervical and thoracolumbar vertebrae based on established landmarks but without predetermination of vertebral canal violation. Radiographs and CT images were obtained and evaluated by 6 individuals. A random subset of pins was evaluated for ability to distinguish left from right pins on radiographs. The ability to correctly identify vertebral canal penetration for all pins was assessed both on radiographs and CT. Spines were then anatomically prepared and visual examination of pin penetration into the canal served as the gold standard. RESULTS Left/right accuracy was 93.1%. Overall sensitivity of radiographs and CT to detect vertebral canal penetration by an implant were significantly different and estimated as 50.7% and 93.4%, respectively (P<.0001). Sensitivity was significantly higher for complete versus partial penetration and for radiologists compared with nonradiologists for both imaging modalities. Overall specificity of radiographs and CT to detect vertebral canal penetration was 82.9% and 86.4%, respectively (P=.049). CONCLUSIONS CT was superior to radiographic assessment and is the recommended imaging modality to assess penetration into the vertebral canal. CLINICAL RELEVANCE CT is significantly more accurate in identifying vertebral canal violation by Steinmann pins and should be performed postoperatively to assess implant position.

Abies – Circum-Mediterranean firs in Europe: distribution, habitat, usage and threats

Most European firs occur predominantly in small to medium-sized populations in the Mediterranean region, sometimes with fragmented and limited distributions, except for silver fir (Abies alba). They all are genetically closely related and can easily hybridise, perhaps as a consequence of late speciation during the late Quaternary. Circum-Mediterranean firs occur principally in mountain areas with medium to high precipitations rates which are mostly concentrated during the winter period. The species are able to tolerate long droughts in summer and tend to form pure stands when in optimal habitats. In the past firs have been extensively logged for construction and fire wood and their stands were replaced by other more disturbance adapted species or converted into rural areas. Nowadays with the exception of silver fir and Caucasian fir (Abies nordmanniana), circum-Mediterranean firs do not have a wide commercial interest. In Turkey they are still exploited for timber wood, while other firs have an ornamental use in gardening. Great importance is given to their preservation, especially to those populations which have very limited areas and specimens, with the creation of protected reserves and conservation programmes. Wild fires, livestock grazing and genetic drift represent actually their main threats.

Fraxinus excelsior in Europe: distribution, habitat, usage and threats

Common ash (Fraxinus excelsior L.) is a medium-sized deciduous tree with large compound leaves that develop relatively late in spring. It flowers before leaf-buds burst and trees can carry male, female, or hermaphrodite flowers, or different combinations of the flower types. It grows throughout the European temperate zone, but is absent from the driest Mediterranean areas because it does not tolerate extended summer drought, and from the northern boreal regions, with its seedlings in particular being vulnerable to late spring frost. Soils exert a strong control on common ash distribution locally. The species grows best on fertile soils where soil pH exceeds 5.5. It rarely forms pure stands, more often it is found in small groups in mixed stands. Ash trees produce high quality timber that combines light weight, strength, and flexibility. Before the mass use of steel, it was used for a wide range of purposes, from agricultural implements to construction of boat and car frames. Today

A Student Manual for Venture Consulting

This manual is written to provide students taking the venture consulting class a better understanding of how to consult a small or medium sized business. It covers topics such as how to find a client, how to determine the business problem, how to collect data from customers as well as managers and employees, and how to come up with solution recommendations. By reading the manual, students will gain a better understanding of the consulting industry and will have a guide to help them through the project.

Alexander’s Dictum and the Reality of Familiar Objects

Alexander's Dictum--"to be is to have causal powers"--appears to furnish an argument against the reality of familiar medium-sized objects. For every time a familiar object appears to cause a familiar macro-event, it sets up a rival claim by its component microparticles to have caused the complex swarm of microphysical events that composes into that macro-event. But this argument, argues this paper, wrongly assumes that even after familiar objects are removed from the picture, there is a phenomenon of joint causation which unites all and only the microparticles within each familiar object.

Charity care and community benefits by hospital type in Texas

Hospital care is the largest component of the health care sector. This industry is made up of for profit hospital (FPH) organizations, not for profit (NFP) hospitals, and government (GOV) run hospital facilities. Objectives of this analysis were: (a) to conduct a literature review on NFP hospital legislation at the state level in Texas and at the federal level in the broader U.S.; and (b) to describe the types of charity care and community benefits currently being provided: by NFP hospitals compared to FPH hospitals and GOV hospitals; by hospitals geographic proximity to the Texas-Mexico border; and by hospital community type (rural, suburban, and urban); and (c) propose specific policy changes that may be needed to improve the current Texas State statute. Methods. In describing the historical and current policy context of NFP hospital legislation in the United States, federal legislation was reviewed from 1913 to the present and Texas State legislation was reviewed from 1980 to the present. In describing the provision of charity care, data from the 2008 Annual Cooperative Hospital Survey were examined by hospital organizational type, size, proximity to the border, and community type using linear regression and chi-squared tests to assess differences in charity care and community benefits. Results. The data included 123 NFP hospitals, 114 GOV hospitals, and 123 FPH. Results. Small sized (p<0.001) and medium sized (p<0.001) NFP hospitals provide a greater percent of total charity care when compared to FPH hospitals and to both GOV and FPH hospitals respectively; however, no significant difference in total charity care was found among large sized NFP hospitals when compared to FPH hospitals alone (p=.345) and both GOV and FPH facilities (p=.214). The amount of charity care provided was not found to be different based on proximity to the border or community type. Community benefit planning and budgeting was found to be similar regardless of community type and proximity to the border. Conclusion. No differences in charity care in Texas were found for large sized NFP hospitals compared to FPH and GOV hospitals. Contrary to widely held beliefs, this study did not find the border region to provide a greater amount of charity care or bad debt. Charity care also did not vary by community type. These findings underscore the need for continued collection of transparent data from all hospitals in order to provide policy makers and consumers with information on utilization trends to ensure benefits are being provided to the community. Policy changes or revoking tax-benefits may occur as charity care utilization declines with the implementation of health reform in the next few years.^

Delayed Thrombus Resolution and Fibroproliferative Vascular Wound Healing From Deficiency of Type III Collagen: a Paradoxical Mechanism for Tissue Fragility

Vascular Ehlers-Danlos syndrome is a heritable disease of connective tissue caused by mutations in COL3A1, conferring a tissue deficiency of type III collagen. Cutaneous wounds heal poorly in these patients, and they are susceptible to spontaneous and catastrophic rupture of expansible hollow organs like the gut, uterus, and medium-sized to large arteries, which leads to premature death. Although the predisposition for organ rupture is often attributed to inherent tissue fragility, investigation of arteries from a haploinsufficient Col3a1 mouse model (Col3a1+/-) demonstrates that mutant arteries withstand even supraphysiologic pressures comparably to wild-type vessels. We hypothesize that injury that elicits occlusive thrombi instead unmasks defective thrombus resolution resulting from impaired production of type III collagen, which causes deranged remodeling of matrix, persistent inflammation, and dysregulated behavior by resident myofibroblasts, culminating in the development of penetrating neovascular channels that disrupt the mechanical integrity of the arterial wall. Vascular injury and thrombus formation following ligation of the carotid artery reveals an abnormal persistence and elevated burden of occlusive thrombi at 21 post-operative days in vessels from Col3a1+/- mice, as opposed to near complete resolution and formation of a patent and mature neointima in wild-type mice. At only 14 days, both groups harbor comparable burdens of resolving thrombi, but wild-type mice increase production of type III collagen in actively resolving tissues, while mutant mice do not. Rather, thrombi in mutant mice contain higher burdens of macrophages and proliferative myofibroblasts, which persist through 21 days while wild-type thrombi, inflammatory cells, and proliferation all regress. At the same time that increased macrophage burdens were observed at 14 and 21 days post ligation, the medial layer of mutant arterial walls concurrently harbored a significantly higher incidence of penetrating neovessels compared with those in wild-type mice. To assess whether limited type III collagen production alters myofibroblast behavior, fibroblasts from vEDS patients with COL3A1 missense mutations were seeded into three-dimensional fibrin gel constructs and stimulated with transforming growth factor-β1 to initiate myofibroblast differentiation. Although early signaling events occur similarly in all cell lines, late extracellular matrix- and mechanically-regulated events like transcriptional upregulation of type I and type III collagen secretion are delayed in mutant cultures, while transcription of genes encoding intracellular contractile machinery is increased. Sophisticated imaging of collagen synthesized de novo by resident myofibroblasts visualizes complex matrix reorganization by control cells but only meager remodeling by COL3A1 mutant cells, concordant with their compensatory contraction to maintain tension in the matrix. Finally, administration of immunosuppressive rapamycin to mice following carotid ligation sufficiently halts the initial inflammatory phase of thrombus resolution and fully prevents both myofibroblast migration into the thrombus and the differential development of neovessels between mutant and wild-type mice, suggesting that pathological defects in mutant arteries develop secondarily to myofibroblast dysfunction and chronic inflammatory stimulation, rather than as a manifestation of tissue fragility. Together these data establish evidence that pathological defects in the vessel wall architecture develop in mutant arteries as sequelae to abnormal healing and remodeling responses activated by arterial injury. Thus, these data support the hypothesis that events threatening the integrity of type III collagen-deficient vessels develop not as a result of inherent tissue weakness and fragility at baseline but instead as an episodic byproduct of abnormally persistent granulation tissue and fibroproliferative intravascular remodeling.

(Table 1) Iceberg characteristics and start and end date and location of iceberg buoys in the Weddell Sea

The drift of 52 icebergs tagged with GPS buoys in the Weddell Sea since 1999 has been investigated with respect to prevalent drift tracks, sea ice/iceberg interaction, and freshwater fluxes. Buoys were deployed on small- to medium-sized icebergs (edge lengths ? 5 km) in the southwestern and eastern Weddell Sea. The basin-scale iceberg drift of this size class was established. In the western Weddell Sea, icebergs followed a northward course with little deviation and mean daily drift rates up to 9.5 ± 7.3 km/d. To the west of 40°W the drift of iceberg and sea ice was coherent. In the highly consolidated perennial sea ice cover of 95% the sea ice exerted a steering influence on the icebergs and was thus responsible for the coherence of the drift tracks. The northward drift of buoys to the east of 40°W was interrupted by large deviations due to the passage of low-pressure systems. Mean daily drift rates in this area were 11.5 ± 7.2 km/d. A lower threshold of 86% sea ice concentration for coherent sea ice/iceberg movement was determined by examining the sea ice concentration derived from Special Sensor Microwave Imager (SSM/I) and Advanced Microwave Scanning Radiometer for EOS (AMSR-E) satellite data. The length scale of coherent movement was estimated to be at least 200 km, about half the value found for the Arctic Ocean but twice as large as previously suggested. The freshwater fluxes estimated from three iceberg export scenarios deduced from the iceberg drift pattern were highly variable. Assuming a transit time in the Weddell Sea of 1 year, the iceberg meltwater input of 31 Gt which is about a third of the basal meltwater input from the Filchner Ronne Ice Shelf but spreads across the entire Weddell Sea. Iceberg meltwater export of 14.2 × 103 m3 s?1, if all icebergs are exported, is in the lower range of freshwater export by sea ice.

Avances metodológicos del proceso de adopción de los Planes de Ordenamiento de segunda generación frente a los vacios jurídicos de la Legislación Colombiana en materia de Ordenamiento Territorial a la luz del P.O.T. Armenia 2007/2019 “Una Ciudad para la Vida"

Las nuevas realidades territoriales, bajo el innovador panorama constitucional colombiano, requieren de procesos de planificación coherentes, ajustados a las necesidades reales de desarrollo de nuestras sociedades en constante crecimiento. Se requieren acciones inmediatas y contundentes de fortalecimiento, asistencia técnica, desarrollo institucional e implementación de instrumentos de Gestión y financiación del suelo, para responder a la insuficiente capacidad de los entes territoriales para asumir con responsabilidad la formulación e implementación de los instrumentos de planificación y ordenamiento territorial planteados por la ley y la normatividad urbanística vigente. Dicha normatividad, dada su falta de reglamentación y regulación, hace compleja su aplicación en pequeñas y medianas ciudades, debido a la deficiente capacidad operativa y ejecutoria que tienen sus administraciones. El 24 de enero de 1999 el Concejo Municipal de Armenia aprobaba el primer plan de ordenamiento territorial para un municipio Colombiano bajo el marco de la Ley de Desarrollo Territorial 388 de 1997. Veinticuatro horas después se produce un sismo de 6.4 grados (Richter) con epicentro a 24 kilómetros de distancia, generando devastadoras consecuencias en toda la región del eje cafetero, tanto en lo físico como en lo social: “Cuando teníamos las respuestas… cambiaron las preguntas". Las nuevas determinantes territoriales generadas como efecto de la tragedia pondrían el proceso de implementación del plan en un escenario complejo y contradictorio. A pesar de que el concepto de gestión del riesgo había sido abordado por el P.O.T., las realidades del desastre superaban la expectativa planificadora, desbordando cualquier escala de ejecutabilidad de la norma recientemente aprobada. El equipo de formulación del nuevo plan, bajo la coordinación del D.A.P.M. y con apoyo de la academia identificó de manera inmediata la complejidad del proceso. Además, realizó aportes que permitieran a los demás municipios Colombianos evitar cometer los mismos errores, superar los obstáculos, agilizar procesos particulares de planificación territorial y dotar así a sus municipios de unos Planes de Ordenamiento mas aterrizados, realizables y sobretodo mas consecuentes con las necesidades particulares de sus municipios.

Calcareous nannofossil bioevents of early-middle Pleistocene sediments from the Mediterranean Sea and the Noth Atlantic

Quantitative distributions of calcareous nannofossils are analysed in the early-middle Pleistocene at the small Gephyrocapsa and Pseudoemiliania lacunosa zone transition in deep-sea cores from the Mediterranean Sea and North Atlantic Ocean (Ocean Drilling Program [ODP] Sites 977, 964 and 967, Deep Sea Drilling Project [DSDP] Site 607). The temporal and spatial mode of occurrence of medium-sized gephyrocapsids and reticulofenestrids has been examined to refine biostratigraphic constraints and evaluate possible relationships of stratigraphic patterns to environmental changes during a period of global climatic deterioration. The timing of bioevents has been calibrated using high-resolution sampling and correlation to the delta18O record in chronologically well-constrained sections. Newly identified events and ecostratigraphical signals enhance the stratigraphic resolution at the early-middle Pleistocene. The first occurrence (FO) of intermediate morphotypes between Pseudoemiliania and Reticulofenestra (Reticulofenestra sp.) is proposed as a reliable event within marine isotope stage (MIS) 35 or at the MIS 35/34 transition. The distribution of Reticulofenestra asanoi is characterized by rare and scattered occurrences in its lowest range, but the first common occurrence (FCO) is consistently identified at MIS 32 or 32/31; the last common occurrence (LCO) of the species is a distinctive event at MIS 23. In the studied interval, Gephyrocapsa omega dominates among medium-sized Gephyrocapsa. The FO of G. omega and contemporaneous re-entry of medium-sized gephyrocapsids at the lower-middle Pleistocene transition are diachronous between the Atlantic Ocean and Mediterranean Sea and from the western to eastern Mediterranean. In the Mediterranean, the LO of G. omega falls at MIS 15, insolation cycle 54 and is isochronous among the sites. Abundance fluctuations of G. omega show notable relations to early-middle Pleistocene climate changes; they considerably increase in abundance at the interglacial stages, suggesting warm water preferences. Gephyrocapsa omega temporarily disappears during the glacial MIS 22 and MIS 20. Above MIS 20, an impoverishment in G. omega and in the total abundance of medium-sized gephyrocapsids occurs. A decrease in abundance of G. omega is observed between the western Site 977 and the easternmost Site 967 in the Mediterranean Sea, as a possible response to high salinity and/or low nutrient content. Possible environmental influences on the distribution of R. asanoi and of Reticulofenestra sp. are discussed.

Nannofossil datums and abundance in sediments from ODP Leg 164 sites

Twenty routinely used nannofossil datums in the late Neogene and Quaternary were identified at three Blake Ridge sites drilled during Leg 164. The quantitative investigation of the nannofossil assemblages in 236 samples selected from Hole 994C provide new biostratigraphic and paleoceanographic information. Although mostly overlooked previously, Umbilicosphaera aequiscutum is an abundant component of the late Neogene flora, and its last occurrence at ~2.3 Ma is a useful new biostratigraphic event. Small Gephyrocapsa evolved within the upper part of Subzone CN11a (~4.3 Ma), and after an initial acme, it temporarily disappeared for 400 k.y., between 2.9 and 2.5 Ma. Medium-sized Gephyrocapsa evolved in the latest Pliocene ~2.2 Ma), and after two short temporary disappearances, common specimens occurred continuously just above the Pliocene/Pleistocene boundary. The base of Subzone CN13b should be recognized as the beginning of the continuous occurrence of medium-sized (>4 µm) Gephyrocapsa. Stratigraphic variation in abundance of the very small placoliths and Florisphaera profunda alternated, indicating potential of the former as a proxy for the paleoproductivity. At this site, it is likely that upwelling took place during three time periods in the late Neogene (6.0-4.6 Ma, 2.3-2.1 Ma, and 2.0-1.8 Ma) and also in the early Pleistocene (1.4-0.9 Ma). Weak upwelling is also likely to have occurred intermittently through the late Pliocene. Due to the sharp and abrupt turnover of the nannofossils, which resulted from an evolution of very competitive species, the paleoproductivity of the late Pleistocene is not clear. The site was mostly in an oligotrophic central gyre setting during the 4.6- to 2.3-Ma interval, intermittently between 2.1 and 1.4 Ma, and continuously for the last several tens of thousand years.