Alcoholism and Alternative Splicing of Candidate Genes

Gene expression studies have shown that expression patterns of several genes have changed during the development of alcoholism. Gene expression is regulated not only at the level of transcription but also through alternative splicing of pre-mRNA. In this review, we discuss some of the evidence suggesting that alternative splicing of candidate genes such as DRD2 (encoding dopamine D2 receptor) may form the basis of the mechanisms underlying the pathophysiology of alcoholism. These reports suggest that aberrant expression of splice variants affects alcohol sensitivities, and alcohol consumption also regulates alternative splicing. Thus, investigations of alternative splicing are essential for understanding the molecular events underlying the development of alcoholism

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the β2-adrenoceptor

G-PROTEIN-COUPLED receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling1–3. But new evidence suggests a two-state model4–19 in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig. 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations7,8 and in vitro systems5,9–12,20–23. We have used a transgenic mouse model in which there is such marked myocardial overexpression of β2-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist24. We show that the β2-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation

The molecular logic of endocannabinoid signalling

The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. © 2003, Nature Publishing Group. All rights reserved

Inhibition of calcium oxalate monohydrate by poly(acrylic acid)s with different end groups

Water-soluble low molecular weight polymers are known to affect the crystal habit of scale-forming minerals and their rates of deposition. Poly(acrylic acid) (PAA) and poly(maleic acid) are commonly used to control scale formation in sugar mill evaporators. Calcium oxalate (both mono- and dihydrate) forms the bulk of the hard intractable scale found in Australian sugar mills, causing efficiency losses of significant economic importance. In this work, the formation of calcium oxalate monohydrate in a synthetic juice solution was investigated in the presence of PAAs of varying molecular weights and end-group functionality and a strong dependency on both of these factors was observed. Terminal functionality was controlled using three chain-transfer agents (CTA): thioethanol, thioglycolic acid, and dodecanthiol. Effectiveness of inhibition varied with CTA in the order thioethanol thioglycolic acid > dodecanthiol for all molecular weights. This suggests that polymer end groups play a role in scale inhibition. The polymers that were prepared with dodecanthiol accelerated rather than inhibited calcium oxalate formation, implying a different mode of action on calcium oxalate crystallization. Consistent with previous reports for other scales, the calcium oxalate inhibition tests show optimum effectiveness for PAAs of molecular weight 2000-4000

The photochemical telomerisation of methyl methacrylate

The photochemically initiated polymerisation-transfer reaction between bromotrichloromethane and methyl methacrylate has been studied. Under suitable conditions low polymers of methyl methacrylate can be produced, and quantitative element analysis or vapour phase chromatography can be used to determine their composition. Correlation of the latter with feed composition enables values of Mayo’s transfer constant (C) to be found for methyl methacrylate type radicals of different size. These values can be resolved into their component propagation and specific transfer rate constants by determining overall reaction rates, rates of initiation, and the lifetime of the appropriate sized radical. Dilatometry has been used to obtain these latter measurements, the techniques of radical scavenging and intermittent illumination being utilised to evaluate the initiation rate and the radical lifetime respectively. It was found that in going from the trimeric radical to the tetrameric there is a pronounced increase in reactivity in the debromination reaction, though a subsequent drop occurs when the radical becomes still larger. Propagation and termination reactivities for the corresponding radicals are, however, independent of radical size. The results are discussed

New Techniques to Monitor and Characterize Landslide Behavior and Controls Using Digital Terrain Models

Coastal landslides and erosion are major natural hazards resulting in unstable slopes, constituting immense challenges to modern infrastructure. Developing, maintaining, and performing risk assessments of infrastructure on, or close to, these hazards require a detailed understanding of the geophysical processes destabilizing the slope. These efforts start with the collection of high-quality monitoring data to assess the current rates of slope deformation. In the last several decades, geospatial technologies including lidar (Light Detection and Ranging), and photogrammetric SfM-MVS (Structure from Motion – Multi View Stereopsis) have been used to perform high-resolution surveys of unstable slopes. Such technologies have proven to be effective, capable of detecting slope deformation at the cm-level scale. Improvements in initial processing techniques, decreasing sensor costs, and wide-scale acceptance have made these approaches more accessible than ever. However, after initial processing of data, present day methodologies are often overly simplistic, or require expert design of site-specific algorithms with fine-tuning of non-intuitive parameters that are time consuming to produce. In addition, current remote-sensing based workflows often do not utilize data from in-situ monitoring sensors, such as GNSS (Global Navigation Satellite System), inclinometers, or extensometers. Rather, survey data collected is processed and analyzed in isolation missing an opportunity to leverage the advantages of each data source. Lastly, there are still major gaps in our understanding of the environmental and morphological processes driving sea cliff erosion, especially at the hyperspatial scale. This work advances the current state of slope monitoring techniques to enable improvements in the use of remote-sensing data to quantify and model the geophysical processes of slope deformation through three fundamental contributions. First, a new automated method to derive dense landslide surface displacement information from sequential DEMs (Digital Elevation Models) that is easy to implement and requires no parameter tuning is presented. Second, leveraging this approach, a computationally efficient novel method of fusing remotely-sensed and in-situ monitoring data to produce a high-spatial high-temporal interpolation of deformation is developed. Finally, this dissertation contributes to the overall understanding of the governing geophysical processes driving coastal erosion using a unique monitoring dataset compiled on the Oregon Coast. In summary, this work presents and rigorously evaluates a new framework and associated tools for slope deformation monitoring and contributes to the overall understanding of the complex processes governing coastal erosion behavior over time

Relative reactivity of chloroprene and methyl methacrylate toward initiator radicals

The relative rates of addition of chloroprene (CP) and methyl methacrylate (MMA) toward small model radicals structurally similar to the poly(MMA), poly(methacrylonitrile) and poly(styrene) radical was investigated following the method of Bevington and Huckerby [J Polym Sci Polym Chem 20 (1982) 2655]. Results indicate that these small radicals are significantly more selective toward CP than the corresponding polymer radicals, consistent with earlier reports that penultimate unit effects may be important in the copolymerisation of CP with MMA and styrene. As previous investigations of substituted dienes by the end-group method have given similar results for polymer radicals and small model radicals, this may constitute evidence for a penultimate unit effect that is predominantly electronic rather than steric in origin