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The delta opioid receptor (DOR), a physiologically relevant prototype for G protein–coupled receptors, is retained in intracellular compartments in neuronal cells. This retention is mediated by a nerve growth factor (NGF)-regulated checkpoint that delays the export of DOR from the trans-Golgi network. How DOR is selectively retained in the Golgi, in the midst of dynamic membrane transport and cargo export, is a fundamental unanswered question. Here we address this by investigating sequence elements on DOR that regulate DOR surface delivery, focusing on the C-terminal tail of DOR that is sufficient for NGF-mediated regulation. By systematic mutational analysis, we define conserved dual bi-arginine (RXR) motifs that are required for NGF- and phosphoinositide-regulated DOR export from intracellular compartments in neuroendocrine cells. These motifs were required to bind the coatomer protein I (COPI) complex, a vesicle coat complex that mediates primarily retrograde cargo traffic in the Golgi. Our results suggest that interactions of DOR with COPI, via atypical COPI motifs on the C-terminal tail, retain DOR in the Golgi. These interactions could provide a point of regulation of DOR export and delivery by extracellular signaling pathways.

Cancer is considered one of the leading causes of death in the United States. Although preventive strategies, early detection, and improved treatment options have been developed, novel targets and therapeutics are still needed. Since concluding that cancer is mediated by genetic and epigenetic alterations of the cell, many research groups are now focusing on other means of prevention and therapy via nutrition, epigenetic mechanisms, and non-coding RNAs which have been shown to control gene expression and have many different functions at the cellular level. With the advent of high-throughput sequencing in human cancer, the potential to identify novel biomarkers and therapeutic targets of disease has increased tremendously and led to the identification of many non-coding RNAs that are dysregulated in various cancers. Gene expression and regulation is important in maintaining the homeostasis of normal tissues and cells. Not uncommonly, up- or down-regulation of particular genes are associated with cancer as a result of increased or decreased expression of transcriptional targets. This review focuses on the role of nutrition in cancer and the dysregulation of non-coding RNAs with particular emphasis on long non-coding RNAs and microRNAs in different cancer types.

Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9-3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel, efficacious, non-toxic cancer drugs acting via CB1 and/or CB2Rs.

This study examined the association between ownership of high-risk (“vicious”) dogs and the presence of deviant behaviors in the owners as indicated by court convictions. We also explored whether two characteristics of dog ownership (abiding licensing laws and choice of breed) could be useful areas of inquiry when assessing risk status in settings where children are present. Our matched sample consisted of 355 owners of either licensed or cited dogs that represented high or low-risk breeds. Categories of criminal convictions examined were aggressive crimes, drugs, alcohol, domestic violence, crimes involving children, firearm convictions, and major and minor traffic citations. Owners of cited high-risk (“vicious”) dogs had significantly more criminal convictions than owners of licensed low-risk dogs. Findings suggest that the ownership of a high-risk (“vicious”) dog can be a significant marker for general deviance and should be an element considered when assessing risk for child endangerment.

Determine the seroprevalence of Trypanosoma cruzi infection in Ushuaia, Argentina, which is the southernmost city in the world.Serum samples were analyzed from 2,991 people, obtained between January 1995 and December 1996. The samples were processed using indirect hemagglutination and either enzyme-linked immunosorbent assay or indirect immunofluorescence.The general seroprevalence of T. cruzi infection was 6.8%. According to the residents' country of origin, prevalence was 41.1% among Bolivians, 5.0% among Argentines, and 0.9% among Chileans. The prevalence found in pregnant women was 5.9%; in compulsory examinations (such as for a job or for immigrants settling permanently in Argentina), it was 6.3%; and in examinations done based on clinical or epidemiological reasons to suspect infection with Chagas' disease, it was 30.8%.There is an alarming level of T. cruzi infection in this region, where the insect vector does not even exist. Given the risk of transmission congenitally and from blood transfusions, controls must be maintained on donated blood. In addition, follow-up of children of infected women should be strengthened so that these children receive early diagnosis and timely treatment of the infection.

Drosophila melanogaster larvae require choline for growth but when fed dl-carnitine in place of choline, carnitine is decarboxylated to β-methylcholine and phosphatidyl-β-methylcholine is synthesized to replace phosphatidylcholine. Feeding (−)-carnitine in place of choline results in a moderate deficiency of lecithin-type phospholipid and a corresponding reduction in growth. The capacity of larvae to employ (+)-carnitine for phosphatidyl-β-methylcholine synthesis and subsequently for growth is very limited. Only 41% as much phosphatidyl-β-methylcholine is synthesized by larvae fed 5.7 X 10−4 M (+)-carnitine as is formed when the same concentration of (−)-carnitine is fed. This suggests that (−)-carnitine is the preferred substrate for carnitine decarboxylase, the enzyme that degrades carnitine to form β-methylcholine. Utilization of carnitine for phospholipid synthesis is clearly dependent upon a choline-deficient state. The presence of small quantities of choline, either in body tissues or in the diet, inhibits the incorporation of carnitine derivatives into phospholipid. Intact carnitine is needed for maximum larval growth and adult activity, indicating that D. melanogaster larvae synthesize a suboptimal quantity of carnitine. Thus, dietary carnitine supplements in vivo carnitine synthesis for physiological purposes.