Association between Genotype of the Serotonin Transporter-Linked Polymorphic Region of the Serotonin Transporter Gene and Age of Onset of Methamphetamine Use: a Preliminary Analysis

Early-onset methamphetamine use increases the lifetime prevalence of methamphetamine dependence. An earlier onset of methamphetamine use leads to greater damage to the terminal ends of serotonin neurons, more reduction in serotonin transporter (5-HTT) density, and an increased propensity toward further methamphetamine use. Because the 5-HTT-linked polymorphic region (5′-HTTLPR) within the promoter region of the 5-HTT gene leads to differential expression of the 5-HTT, we examined, for the first time, whether there is a differential association between the long (L) and short (S) alleles of the 5′-HTTLPR and the age of first methamphetamine use (AMU). The study included 120 methamphetamine-dependent adults of European descent. Diagnosis of methamphetamine dependence and AMU were collected using structured questionnaires, and the 5′-HTTLPR genotypes were determined using the polymerase chain reaction–restriction fragment length polymorphism method. Statistical analysis with the general linear model detected a significant interactive effect of 5′-HTTLPR genotypes (SS vs. L-carriers) and gender, associated with AMU (F = 3.99; p = 0.048). Further analysis of 5′-HTTLPR effects on AMU in males and females separately showed that the SS genotype compared with L-carriers had about two times greater risk of an earlier onset of methamphetamine use in men (hazard ratio = 1.839; 95% confidence interval = 1.042–3.246; p = 0.036) but not in women. Together, our findings in this preliminary study suggest a greater risk for earlier onset methamphetamine use associated with the SS genotype of the 5′-HTTLPR among methamphetamine-dependent Caucasian males

An optimised assay for quantitative, high-throughput analysis of polysialyltransferase activity

YesThe polysialyltransferases are biologically important glycosyltransferase enzymes responsible for the biosynthesis of polysialic acid, a carbohydrate polymer that plays a critical role in the progression of several diseases, notably cancer. Having improved the chemical synthesis and purification of the fluorescently-labelled DMB-DP3 acceptor, we report optimisation and validation of a highly sensitive cell-free high-throughput HPLC-based assay for assessment of human polysialyltransferase activity

Polysialic acid sustains cancer cell survival and migratory capacity in a hypoxic environment

Polysialic acid (polySia) is a unique carbohydrate polymer expressed on the surface of NCAM (neuronal cell adhesion molecule) in a number of cancers where it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis and is strongly associated with poor clinical prognosis. We have carried out the first investigation into the effect of polySia expression on the behaviour of cancer cells in hypoxia, a key source of chemoresistance in tumours. The role of polysialylation and associated tumour cell migration and cell adhesion were studied in hypoxia, along with effects on cell survival and the potential role of HIF-1. Our findings provide the first evidence that polySia expression sustains migratory capacity and is associated with tumour cell survival in hypoxia. Initial mechanistic studies indicate a potential role for HIF-1 in sustaining polySia-mediated migratory capacity, but not cell survival. These data add to the growing body of evidence pointing to a crucial role for the polysialyltransferases (polySTs) in neuroendocrine tumour progression and provide the first evidence to suggest that polySia is associated with an aggressive phenotype in tumour hypoxia. These results have significant potential implications for polyST inhibition as an anti-metastatic therapeutic strategy and for targeting hypoxic cancer cells

Synaptic Neurotransmission Depression in Ventral Tegmental Dopamine Neurons and Cannabinoid-Associated Addictive Learning

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction

The effects of delayed annealing on the luminescent activity of heavy metal cadmium zinc phosphate glasses activated by: Er3+ and Tb3+ ions

Abstract The luminescent spectra of the RE2O3-doped P2O5–CdO–ZnO glasses (RE = Er, and Tb) were investigated to separate the effects of two studied rare-earth elements and the annealing regime on the emission performance of the prepared glasses. The glasses undergo a series of collective measurements including UV–visible absorption, luminescence, thermal expansion, XRD, TEM, and FTIR. The optical UV–visible spectra of the two doped glasses reveal a UV band due to undoped glass beside and extra extended 11 peaks with the Er3+ ions with high distinct features while the Tb3+ ions samples exhibit peaks within the visible region. These peaks are correlated with transitions from the ground state in each case to specific energy transitions. The overall optical data indicate that the two rare earth ions are present in a stable trivalent state. Under UV excitation, both Er3+ and Tb3+ emit a characteristic green light corresponding to 4S3/2 → 4I15/2 and 5D4 → 7F5 transitions, respectively. The performance of the green light was identified to be enhanced by increasing the concentration of rare earth and the effect of annealing temperature. Moreover, the intensity of the infrared emission of Er3+ at 1532 nm corresponds to the (4I13/2 → 4I15/2) transition which is assumed to be developed with the effect of heating. The resultant IR spectra show distinct vibrational peaks due to phosphate groups that undergo only minor modifications when doped with rare earth elements or over-annealed

Advantages of joint modeling of component HIV risk behaviors and non-response: application to randomized trials in cocaine-dependent and methamphetamine-dependent populations

The HIV risk-taking behavior scale (HRBS) is an 11-item instrument designed to assess the risks of HIV infection due self-reported injection drug use and sexual behavior. A retrospective analysis was performed on HRBS data collected from approximately 1,000 participants pooled across seven clinical trials of pharmacotherapies for either the treatment of cocaine-dependence or methamphetamine-dependence. Analysis faced three important challenges. The sample contained a high proportion of missing assessments after randomization. Also, the HRBS scale consists of two distinct behavioral components which may or may not coincide in response patterns. In addition, distributions of responses on the subscales were highly concentrated at just a few values (e.g., 0, 6). To address these challenges, a single probit regression model was fit to three outcomes variables simultaneously—the two subscale totals plus an indicator variable for assessments not obtained (non-response). This joint-outcome regression model was able to identify that those who left assessment early had higher self-reported risk of injection-drug use and lower self-reported risky sexual behavior because the model was able to draw on information on associations among the three outcomes collectively. These findings were not identified in analyses performed on each outcome separately. No evidence for an effect of pharmacotherapies was observed, except to reduce missing assessments. Univariate-outcome modeling is not recommended for the HRBS

A facile synthesis of new beta-lactams

Several new beta-lactams have been synthesized in good yields, via the cyclization of 3-chloro-N-arylpropionamides in a mixture of N,N-dimethylformamide and anhydrous sodium carbonate under a nitrogen atmosphere