The monoamine stabilizer (-)-OSU6162 : a potential novel treatment for alcohol use disorders

Alcohol use disorder (AUD) represent a major health problem worldwide. Despite the severe consequences of AUD, only four medications are approved in Sweden for this disease. In addition, the prescription rates are low, partly due to varying clinical efficacy of these medications. Consequently, new, more effective pharmacotherapies are needed. A main problem in the treatment of AUD is the long-lasting vulnerability to relapse. Relapse is typically triggered by: stress, acute exposure to the drug, or drug-associated cues or context. Impaired impulsive control, often seen in AUD individuals, might further contributes to relapse to alcohol drinking. The dopamine (DA) system is one possible treatment target for AUD. Dopamine D2 receptors has been suggested to be involved in mediating alcohol’s reinforcing properties and a decrease in DA release and a reduction in D2 receptors have been found in detoxified AUD patients. This DA down-regulation is hypothesized to induce alcohol craving and contribute to relapse even after a long period of abstinence. In addition to the role of DA in AUD, DA has also been suggested to be involved in impulse behavior. The monoamine stabilizer (-)-OSU6162 (OSU6162) has the ability to stimulate, inhibit, or show no effect on DA-related behaviors depending upon the prevailing dopaminergic tone. In this thesis, we evaluated the potential of OSU6162 as a new treatment for AUD using validated preclinical models of behaviors related to AUD. We have, in this thesis, identified OSU6162 as a potential novel treatment for AUD. Using a battery of animal models, we showed that OSU6162 attenuated voluntary alcohol intake, alcohol withdrawal symptoms (tail stiffness and walking with broad gait), the motivation to seek alcohol, cue/priming-induced reinstatement (relapse) of alcohol seeking, and relapse-like drinking in in rats that had been drinking alcohol for a long period of time. Moreover, we showed that OSU6162 pre-treatment improved motor impulsivity in both alcohol and alcohol-naïve rats. Furthermore, OSU6162 did not induce conditioned place preference in either alcohol-naïve rats or rats that had been drinking alcohol before the experiment, indicating that OSU6162 does not possess any abuse liability on its own. Together these results highlights OSU6162’s potential to prevent relapse triggered by alcohol craving, alcohol related cues, re-exposure to alcohol and or an urge to relieve abstinence symptoms. In addition, the improved impulse control following OSU6162 treatment might help AUD individuals to override a compulsive drug-taking behavior in response to craving and thereby possibly prevent relapse to alcohol drinking. In addition to the global health problems related to alcohol, an opioid addiction epidemic is ongoing in the United State. We therefore decided to examine the potential of OSU6162 to attenuate self-administration of the opioid oxycodone in rats. The results showed that OSU6162 attenuated operant oxycodone self-administration but had no effect on context-induced reinstatement, at least in the dose tested. These preliminary results indicate that OSU612 might have potential to decrease intake of oxycodone, however, further studies are needed to fully evaluate the potential of OSU6162 on oxycodone self-administration and reinstatement. In conclusion, the results in this thesis indicate that OSU6162 may serve as a novel treatment for AUD and provided the necessary rational for a clinical “proof-of-concept” study with OSU6162 in alcohol dependent patients. The clinical study was successfully executed and supported our preclinical findings by showing that OSU6162 attenuated alcohol craving in alcohol dependent patients. Thus, the rapid and fruitful transition of OSU6162 from bench to clinic highlights the importance of the preclinical medication development program used in this thesis work

Customer Information Usage: Improving Supply Chain Performance and Advancing Logistics Services in Construction Projects

This study investigates how continuous improvement of logistics services in a project- based context such as construction can be enhanced by a “priority matrix for service improvements”. Construction services in general, and logistic services in specific, have great impact on efficiency and sustainability (environmental as well as social). Solutions and experience from e.g. manufacturing and retailing that have undergone major transformation through industrialization and, more recently, servitization, to improve the quality and novelty of their offerings, there is a great potential in addressing the complex coordination, inefficient processes, and waste of materials in the project-based context of the construction industry. Whilst improvement initiatives concerning product quality are important inspiration of such transformation, they are based on continuous production processes and become a challenge when this experience is transferred to the project-based, construction industry. As response, this study draws upon the concept of service quality as the basis for improvement initiatives – a concept based on relations between actors that last beyond individual projects

Extended Chiral Transformations Including Diquark Fields as Parameters

We introduce extended chiral transformation, which depends both on pseudoscalar and diquark fields as parameters and determine its group structure. Assuming soft symmetry breaking in diquark sector, bosonisation of a quasi-Goldstone $ud$-diquark is performed. In the chiral limit the $ud$-diquark mass is defined by the gluon condensate, $m_{ud}\approx 300 MeV$. The diquark charge radius is $\langle r^2_{ud}\rangle^{1/2}\approx 0.5 fm$.Comment: Latex file, to apear in Phis. Lett.

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Background and Purpose: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse-related measures and heroin versus food choice. Experimental Approach: For relapse assessment, we trained male and female rats to self-administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin-seeking in a non-drug Context B, (2) extinction responding reinforced by heroin-associated discrete cues in Context B, (3) reinstatement of heroin-seeking induced by re-exposure to Context A and (4) re-acquisition of heroin self-administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re-acquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. Conclusions and Implications: Chronic BU08028 delivery had both beneficial and detrimental, sex-dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.</p

Quark-diquark Systematics of Baryons: Spectral Integral Equations for Systems Composed by Light Quarks

For baryons composed by the light quarks ($q=u,d$) we write spectral integral equation using the notion of two diquarks: (i) axial--vector state, $D^{1}_{1}$, with the spin $S_D=1$ and isospin $I_D=1$ and (ii) scalar one, $D^{0}_{0}$, with the spin $S_D=0$ and isospin $I_D=0$. We present spectral integral equations for the $qD^{0}_{0}$ and $qD^{1}_{1}$ states taking into account quark--diquark confinement interaction.Comment: 13 pages, 2 figure

Large trees drive forest aboveground biomass variation in moist lowland forests accross the tropics

peer reviewedaudience: researcher, professional, studentAim Large trees (d.b.h. 70 cm) store large amounts of biomass. Several studies suggest that large trees may be vulnerable to changing climate, potentially leading to declining forest biomass storage. Here we determine the importance of large trees for tropical forest biomass storage and explore which intrinsic (species trait) and extrinsic (environment) variables are associated with the density of large trees and forest biomass at continental and pan-tropical scales. Location Pan-tropical. Methods Aboveground biomass (AGB) was calculated for 120 intact lowland moist forest locations. Linear regression was used to calculate variation in AGB explained by the density of large trees. Akaike information criterion weights (AICcwi) were used to calculate averaged correlation coefficients for all possible multiple regression models between AGB/density of large trees and environmental and species trait variables correcting for spatial autocorrelation. Results Density of large trees explained c. 70% of the variation in pan-tropical AGB and was also responsible for significantly lower AGB in Neotropical [287.8 (mean) 105.0 (SD) Mg ha-1] versus Palaeotropical forests (Africa 418.3 91.8 Mg ha-1; Asia 393.3 109.3 Mg ha-1). Pan-tropical variation in density of large trees and AGB was associated with soil coarseness (negative), soil fertility (positive), community wood density (positive) and dominance of wind dispersed species (positive), temperature in the coldest month (negative), temperature in the warmest month (negative) and rainfall in the wettest month (positive), but results were not always consistent among continents. Main conclusions Density of large trees and AGB were significantly associated with climatic variables, indicating that climate change will affect tropical forest biomass storage. Species trait composition will interact with these future biomass changes as they are also affected by a warmer climate. Given the importance of large trees for variation in AGB across the tropics, and their sensitivity to climate change, we emphasize the need for in-depth analyses of the community dynamics of large trees

An estimate of the number of tropical tree species

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher’s alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between ∼40,000 and ∼53,000, i.e. at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of ∼19,000–25,000 tree species. Continental Africa is relatively depauperate with a minimum of ∼4,500–6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa

The global abundance of tree palms

Aim Palms are an iconic, diverse and often abundant component of tropical ecosystems that provide many ecosystem services. Being monocots, tree palms are evolutionarily, morphologically and physiologically distinct from other trees, and these differences have important consequences for ecosystem services (e.g., carbon sequestration and storage) and in terms of responses to climate change. We quantified global patterns of tree palm relative abundance to help improve understanding of tropical forests and reduce uncertainty about these ecosystems under climate change. Location Tropical and subtropical moist forests. Time period Current. Major taxa studied Palms (Arecaceae). Methods We assembled a pantropical dataset of 2,548 forest plots (covering 1,191 ha) and quantified tree palm (i.e., ≥10 cm diameter at breast height) abundance relative to co‐occurring non‐palm trees. We compared the relative abundance of tree palms across biogeographical realms and tested for associations with palaeoclimate stability, current climate, edaphic conditions and metrics of forest structure. Results On average, the relative abundance of tree palms was more than five times larger between Neotropical locations and other biogeographical realms. Tree palms were absent in most locations outside the Neotropics but present in >80% of Neotropical locations. The relative abundance of tree palms was more strongly associated with local conditions (e.g., higher mean annual precipitation, lower soil fertility, shallower water table and lower plot mean wood density) than metrics of long‐term climate stability. Life‐form diversity also influenced the patterns; palm assemblages outside the Neotropics comprise many non‐tree (e.g., climbing) palms. Finally, we show that tree palms can influence estimates of above‐ground biomass, but the magnitude and direction of the effect require additional work. Conclusions Tree palms are not only quintessentially tropical, but they are also overwhelmingly Neotropical. Future work to understand the contributions of tree palms to biomass estimates and carbon cycling will be particularly crucial in Neotropical forests

Consistent patterns of common species across tropical tree communities

Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations1,2,3,4,5,6 in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.Publisher PDFPeer reviewe

Large trees drive forest aboveground biomass variation in moist lowland forests across the tropics, Global

ABSTRACT Aim Large trees (d.b.h. Ն 70 cm) store large amounts of biomass. Several studies suggest that large trees may be vulnerable to changing climate, potentially leading to declining forest biomass storage. Here we determine the importance of large trees for tropical forest biomass storage and explore which intrinsic (species trait) and extrinsic (environment) variables are associated with the density of large trees and forest biomass at continental and pan-tropical scales. Location Pan-tropical. Methods Aboveground biomass (AGB) was calculated for 120 intact lowland moist forest locations. Linear regression was used to calculate variation in AGB explained by the density of large trees. Akaike information criterion weights (AICcwi) were used to calculate averaged correlation coefficients for all possible multiple regression models between AGB/density of large trees and environmental and species trait variables correcting for spatial autocorrelation. Results Density of large trees explained c. 70% of the variation in pan-tropical AGB and was also responsible for significantly lower AGB in Neotropical [287.8 (mean) Ϯ 105.0 (SD) Mg ha ). Pan-tropical variation in density of large trees and AGB was associated with soil coarseness (negative), soil fertility (positive), community wood density (positive) and dominance of wind dispersed species (positive), temperature in the coldest month (negative), temperature in the warmest month (negative) and rainfall in the wettest month (positive), but results were not always consistent among continents. Main conclusions Density of large trees and AGB were significantly associated with climatic variables, indicating that climate change will affect tropical forest biomass storage. Species trait composition will interact with these future biomass changes as they are also affected by a warmer climate. Given the importance of large trees for variation in AGB across the tropics, and their sensitivity to climate change, we emphasize the need for in-depth analyses of the community dynamics of large trees. bs_bs_banner Global Ecology and Biogeography, (Global Ecol. Biogeogr.