Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Abstract Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

Surrogacy : is it harder to relinquish genes?

Surrogacy has produced some positive outcomes creating an opportunity for otherwise childless couples to live their dream of parenthood. However it has also been problematic, particularly where the surrogate mother fails to relinquish a child born as a result of the surrogacy arrangement. This article examines whether a surrogate mother, who is genetically related to the child she delivers, is less likely to relinquish the child than one who has no genetic ties. An examination of empirical evidence provides support for this argument. Legislation and case law in three jurisdictions, Australia, the United States and the United Kingdom, is examined to determine which, if any, of these jurisdictions take into account the existence, or otherwise, of a genetic link between the surrogate mother and the child she bears. The article concludes that surrogacy legislation should, subject to exceptional circumstances, encourage surrogacy arrangements where the child and the surrogate are not genetically related.

Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identified in a proportion of melanoma kindreds. In the case of CDK4, only one specific mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identification of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these efforts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1beta) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M531 substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous findings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the 'CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1beta mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.

Apoptosis-related genes confer resistance to Fusarium wilt in transgenic ‘Lady Finger’ bananas

Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense (Foc), is one of the most devastating diseases of banana (Musa spp.). Apart from resistant cultivars, there are no effective control measures for the disease. We investigated whether the transgenic expression of apoptosis-inhibition related genes in banana could be used to confer disease resistance. Embryogenic cell suspensions of the banana cultivar, ‘Lady Finger’, were stably transformed with animal genes that negatively regulate apoptosis, namely Bcl-xL, Ced-9 and Bcl-2 3’ UTR, and independently transformed plant lines were regenerated for testing. Following a 12 week exposure to Foc race 1 in small-plant glasshouse bioassays, seven transgenic lines (2 x Bcl-xL, 3 x Ced-9 and 2 x Bcl-2 3’ UTR) showed significantly less internal and external disease symptoms than the wild-type susceptible ‘Lady Finger’ banana plants used as positive controls. Of these, one Bcl-2 3’ UTR line showed resistance that was equivalent to that of wild-type Cavendish bananas that were included as resistant negative controls. Further, the resistance of this line continued for 23 weeks post-inoculation at which time the experiment was terminated. Using TUNEL assays, Foc race 1 was shown to induce apoptosis-like features in the roots of wild-type ‘Lady Finger’ plants consistent with a necrotrophic phase in the lifecycle of this pathogen. This was further supported by the observed reduction of these effects in the roots of the resistant Bcl-2 3’ UTR transgenic line. This is the first report on the generation of transgenic banana plants with resistance to Fusarium wilt.

Investing in the future : analysis of TxDOT 1547 Over-Axle Weight Tolerance Permits

The trucking industry has played a significant role in the economic growth in Texas by transporting and distributing commodities using commercial motor vehicles. The Texas Department of Transportation (TxDOT), however, has recognized that the large number of overweight trucks operating on the state highway system has resulted in the deterioration of pavement condition. In addition, the permit fee to carry higher loads above legal limits is much lower than the cost to treat the increase in pavement damage. The primary purpose of the research presented in this paper is to investigate current TxDOT overweight permit structures to support pavement management. The research team analyzed the TxDOT “1547” Over-axle Weight Tolerance Permit structure to support an increase in the fee structure, bringing it more in line with the actual pavement damage. The analysis showed that the revised overweight permit structure could provide an additional $9.3 million annually for pavement maintenance needs by increasing current permit fees. These results were supported by the 2030 Committee for recommendation to the Texas Transportation Commission and consideration by the State Legislature [1]. The research team recommends conducting further research to identify methods for working cooperatively with the trucking industry to develop improved methods for assessing weight damage relationships and developing more effective and accurate means for assessing overweight permit fees.

Tolerance, Freedom, Justice and Peace?: Britain, Australia and anti-Muslim Racism in the UK and Australia before 11 September 2001

Since 11 September 2001, Muslim minorities have experienced intensive "othering" in “Western” countries, above all in those US-led anglophone nations which invaded Afghanistan and Iraq to prosecute their "war on terror". This paper examines the cases of Britain and Australia, where whole communities of Muslims have been criminalised as "evil" and a "fifth column" enemy within by media, politicians, the security services and the criminal justice system. Although constituted by disparate ethnic groups, the targeted communities in each of these nations have experienced similar treatment in the State's anti-terrorist measures, as well as ideological responses and everyday racism, making comparable the two cases.