Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives : Ligands with mixed NOP and opioid receptor profile

© 2018 Kumar, Polgar, Cami-Kobeci, Thomas, Khroyan, Toll and Husbands.A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.Peer reviewedFinal Published versio

Late Quaternary intraplate deformation defined by the Las Chacras Fault Zone, West‐Central Argentina

Several major (up to MW 7.5) earthquakes over the past 320 years have shaken the thick-skinned Sierras Pampeanas region of Argentina, despite exhibiting much lower GPS-shortening rates than across the thin-skinned Precordillera region to its west. Whether geodetic shortening rates indicate an actual long-term shortening gradient, and whether shortening rates translate to higher uplift rates due to steeper faults in the Sierras Pampeanas, remain uncertain due to the limited spatio-temporal coverage and the inherently large error in the vertical component of deformation of GPS measurements. We measure geomorphic offsets and use 10Be terrestrial cosmogenic nuclide surface exposure dating to determine slip rates on the Las Chacras Fault Zone (LCFZ)—an ∼30 km long, NNW-trending, steeply dipping (55–65°E) reverse fault that branches off of the longest, westernmost, thick-skinned Valle Fértil range-front fault in the western Sierras Pampeanas. Average shortening and uplift rates measured on the LCFZ are ∼0.2 and ∼0.3–0.4 mm/yr, respectively. Despite an uplift rate similar to most other faults in the region, the LCFZ shortening rate is lower than faults to its west; this is in agreement with the inferred west-east decrease in shortening rates from GPS data, indicating consistent regional deformation patterns since the Late Pleistocene. The decrease in shortening to the east coincides spatially with the termination of the flat portion of the subducted Nazca plate between 67 and 68°W. From scaling relationships among magnitude, slip rate, and fault length, the LCFZ is capable of generating earthquakes of MW 6.7–7.1.Fil: Rimando, Jeremy. University of Toronto; CanadáFil: Schoenbohm, Lindsay. University of Toronto; CanadáFil: Ortiz, Gustavo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; Argentina. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Geofísica y Astronomía; ArgentinaFil: Alvarado, Patricia Monica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; Argentina. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Geofísica y Astronomía; ArgentinaFil: Venerdini, Agostina Lia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; Argentina. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Geofísica y Astronomía; ArgentinaFil: Owen, Lewis. North Carolina State University; Estados UnidosFil: Seagren, Erin. University of Toronto; CanadáFil: Marques Figueiredo, Paula. North Carolina State University; Estados UnidosFil: Hammer, Sarah. University of Cincinnati; Estados Unido

Development of a 3D tissue-engineered skeletal muscle and bone co‐culture system

In vitro three‐dimensional (3D) tissue engineered (TE) structures have been shown to better represent in vivo tissue morphology and biochemical pathways than monolayer culture, and are less ethically questionable than animal models. However, to create systems with even greater relevance, multiple integrated tissue systems should be recreated in vitro. In the present study, the effects and conditions most suitable for the co‐culture of TE skeletal muscle and bone were investigated. High‐glucose Dulbecco's Modified Eagle Medium (HG‐DMEM) supplemented with 20% foetal bovine serum (FBS) followed by HG‐DMEM with 2% horse serum was found to enable proliferation of both C2C12 muscle precursor cells and TE85 human osteosarcoma cells, fusion of C2C12s into myotubes, as well as an up‐regulation of RUNX2/CBFa1 in TE85s. Myotube formation was also evident within indirect contact monolayer cultures. Finally, in 3D co‐cultures, TE85 collagen/hydroxyapatite constructs had significantly greater expression of RUNX2/CBFa1 and osteocalcin/BGLAP in the presence of collagen‐based C2C12 skeletal muscle constructs; however, fusion within these constructs appeared reduced. This work demonstrates the first report of the simultaneous co‐culture and differentiation of 3D TE skeletal muscle and bone, and represents a significant step towards a full in vitro 3D musculoskeletal junction model

Recruitment of patients with Chronic Obstructive Pulmonary Disease (COPD) from the Clinical Practice Research Datalink (CPRD) for research.

Databases of electronic health records (EHR) are not only a valuable source of data for health research but have also recently been used as a medium through which potential study participants can be screened, located and approached to take part in research. The aim was to assess whether it is feasible and practical to screen, locate and approach patients to take part in research through the Clinical Practice Research Datalink (CPRD). This is a cohort study in primary care. The CPRD anonymised EHR database was searched to screen patients with Chronic Obstructive Pulmonary Disease (COPD) to take part in a research study. The potential participants were contacted via their General Practitioner (GP) who confirmed their eligibility. Eighty two practices across Greater London were invited to the study. Twenty-six (31.7%) practices consented to participate resulting in a pre-screened list of 988 patients. Of these, 632 (63.7%) were confirmed as eligible following the GP review. Two hundred twenty seven (36%) response forms were received by the study team; 79 (34.8%) responded 'yes' (i.e., they wanted to be contacted by the research assistant for more information and to talk about enrolling in the study), and 148 (65.2%) declined participation. This study has shown that it is possible to use EHR databases such as CPRD to screen, locate and recruit participants for research. This method provides access to a cohort of patients while minimising input needed by GPs and allows researchers to examine healthcare usage and disease burden in more detail and in real-life settings

The antiparallel loops in gal DNA

Interactions between proteins bound to distant sites along a DNA molecule require bending and twisting deformations in the intervening DNA. In certain systems, the sterically allowed protein–DNA and protein–protein interactions are hypothesized to produce loops with distinct geometries that may also be thermodynamically and biologically distinct. For example, theoretical models of Gal repressor/HU-mediated DNA-looping suggest that the antiparallel DNA loops, A1 and A2, are thermodynamically quite different. They are also biologically different, since in experiments using DNA molecules engineered to form only one of the two loops, the A2 loop failed to repress in vitro transcription. Surprisingly, single molecule measurements show that both loop trajectories form and that they appear to be quite similar energetically and kinetically

Formation and evolution of early-type galaxies. II. Models with quasi-cosmological initial conditions

In this study, with the aid of N-Body simulations based on quasi-cosmological initial conditions, we have followed the formation and evolution of two models of early-type galaxies, from their separation from global expansion of the Universe to their collapse to virialized structures, the formation of stars and subsequent nearly passive evolution. The cosmological background we have considered is the Standard CDM. The models have significantly different nitial total mass. Particular care has been paid to the star formation process, heating and cooling of gas, and chemical enrichment. In both models star formation is completed within the first Gyrs of evolution. The structural properties of the present-day models are in good agreement with current observations. The chemical properties, mean metallicity and metallicity gradients also agree with available observational data. Finally, conspicuous galactic winds are found to occur. The models conform to the so-called revised monolithic scheme, because mergers of substructures have occurred very early in the galaxy life. Our results agree with those obtained in other similar recent studies, thus strengthening the idea that the revised monolithic scheme is the right trail to follow in the forest of galaxy formation and evolution.Comment: 21 pages, 19 figures, 3 tables. To be published on Astronomy & Astrophysics (accepted April 12, 2006

Simulating galaxy Clusters -II: global star formation histories and galaxy populations

Cosmological (LambdaCDM) TreeSPH simulations of the formation and evolution of galaxy groups and clusters have been performed. The simulations invoke star formation, chemical evolution with non-instantaneous recycling, metal dependent radiative cooling, strong star burst and (optionally) AGN driven galactic super winds, effects of a meta-galactic UV field and thermal conduction. The properties of the galaxy populations in two clusters, one Virgo-like (T~3 keV) and one (sub) Coma-like (T~6 keV), are discussed. The global star formation rates of the cluster galaxies are found to decrease very significantly with time from redshift z=2 to 0, in agreement with observations. The total K-band luminosity of the cluster galaxies correlates tightly with total cluster mass, and for models without additional AGN feedback, the zero point of the relation matches the observed one fairly well. The match to observed galaxy luminosity functions is reasonable, except for a deficiency of bright galaxies (M_B < -20), which becomes increasingly significant with super-wind strength. Results of a high resolution test indicate that this deficiency is not due to ``over--merging''. The redshift evolution of the luminosity functions from z=1 to 0 is mainly driven by luminosity evolution, but also by merging of bright galaxies with the cD. The colour--magnitude relation of the cluster galaxies matches the observed "red sequence" very well and, on average, galaxy metallicity increases with luminosity. As the brighter galaxies are essentially coeval, the colour--magnitude relation results from metallicity rather than age effects, as observed.Comment: 15 pages, 10 figures. Final version accepted by MNRAS, presenting new simulations and major changes. Printing in colour recommende

Public engagement and collaboration for carbon dioxide removal: lessons from a project in the Dominican Republic

Despite an increase in literature on public perceptions of carbon dioxide removal (CDR), there remains a paucity of evidence describing the social and developmental processes involved in the implementation of projects in-situ. This research illustrates a case study documenting a planned research project for coastal enhanced weathering - a form of ocean alkalinity enhancement - in a remote, rural area of the Northwestern Dominican Republic, a Small Island Developing State particularly at risk from climate change impacts. This paper is a collaboration between the company responsible for the project (Vesta) and researchers located in the Dominican Republic and the United Kingdom, We draw upon two years’ worth of surveys, interviews, focus groups, group information sessions, and reflexive documentation by the Dominican Republic researchers, to present a first-hand account of local community responses to the planned research project and to coastal enhanced weathering and climate change more broadly. We discuss themes of climate vulnerability, justice, and adaptive capacity through the lens of the collaborative governance and social diffusion principles that the project was designed with. We also reflect on a program of outreach and participatory activities which was established to support community development in the areas surrounding the field trial site, as informed by exploration of community needs drawn from the research

Risk factors for hepatitis B virus infection in Rio de Janeiro, Brazil

BACKGROUND: Despite international efforts to prevent hepatitis B virus (HBV) infection through global vaccination programs, new cases are still being reported throughout the world. METHODS: To supply data that might assist in improving preventive measures and national surveillance for HBV infection, a cross-sectional study was conducted among individuals referred to the Brazilian National Reference Center for Viral Hepatitis (Rio de Janeiro) during a two-year period. Reported risk factors among infected subjects ("HBV-positive") were compared to those of subjects never exposed ("HBV-negative") to HBV. Two subgroups were further identified within the HBV-positive group, "acute" infection and "non-acute" infection. RESULTS: A total of 1,539 subjects were tested for HBV, of which 616 were HBV-positive (79 acute infection and 537 non-acute infection). HBV-positive subjects were more likely to be of male gender (63% versus 47%); and to report multiple sexual partners (12% versus 6%) and illicit drug use (IDU and/or intranasal cocaine use) (6% versus 3%). Among the HBV-positive subgroups, age differed significantly, with 48% being under 30 years of age in subjects acutely infected compared to 17% in those with non-acute infection. CONCLUSIONS: The association of multiple sexual partners with past HBV infection and the age distribution of currently infected subjects suggest that sexual transmission played a major role in the transmission of HBV in this study population. Thus, vaccination during adolescence should be considered

Low-Altitude UAV Imaging Accurately Quantifies Eelgrass Wasting Disease From Alaska to California

Declines in eelgrass, an important and widespread coastal habitat, are associated with wasting disease in recent outbreaks on the Pacific coast of North America. This study presents a novel method for mapping and predicting wasting disease using Unoccupied Aerial Vehicle (UAV) with low-altitude autonomous imaging of visible bands. We conducted UAV mapping and sampling in intertidal eelgrass beds across multiple sites in Alaska, British Columbia, and California. We designed and implemented a UAV low-altitude mapping protocol to detect disease prevalence and validated against in situ results. Our analysis revealed that green leaf area index derived from UAV imagery was a strong and significant (inverse) predictor of spatial distribution and severity of wasting disease measured on the ground, especially for regions with extensive disease infection. This study highlights a novel, efficient, and portable method to investigate seagrass disease at landscape scales across geographic regions and conditions