Insulin regulates menin expression, cytoplasmic localization, and interaction with FOXO1

Menin is the ubiquitously expressed nuclear protein product of the MEN1 gene, which interacts with PKB/Akt in the cytoplasm to inhibit its activity. This study describes a novel insulin-dependent mechanism of menin regulation and interaction with other metabolic proteins. We show that insulin downregulated menin in a time-dependent manner via the human insulin receptor. Inhibition analysis indicated a critical role for the protein kinase Akt in regulation of menin expression and localization. Insulin-mediated decrease in menin expression was abrogated by the PI3K/Akt inhibitor LY-294002 at early time points, from 2 to 7 h. Furthermore, exposure to insulin resulted in the cytoplasmic localization of menin and increased interaction with FOXO1. Fasting followed by refeeding modulates serum insulin levels, which corresponded to an increase in menin interaction with FOXO1 in the liver. Liver-specific hemizygous deletion of menin resulted in increased expression of FOXO1 target genes, namely IGFBP-1, PGC-1α, insulin receptor, Akt, and G-6-Pase. This study provides evidence that menin expression and localization are regulated by insulin signaling and that this regulation triggers an increase in its interaction with FOXO1 via Akt with metabolic consequences.     

Receptor binding profiles of avian influenza virus hemagglutinin subtypes on human cells as a predictor of pandemic potential

The host adaptation of influenza virus is partly dependent on the sialic acid (SA) isoform bound by the viral hemagglutinin (HA). Avian influenza viruses preferentially bind the α-2,3 SA and human influenza viruses the α-2,6 isoform. Each isoform is predominantly associated with different surface epithelial cell types of the human upper airway. Using recombinant HAs and human tracheal airway epithelial cells in vitro and ex vivo, we show that many avian HA subtypes do not adhere to this canonical view of SA specificity. The propensity of avian viruses to adapt to human receptors may thus be more widespread than previously supposed.     

Parameter inference for an individual based model of chytridiomycosis in frogs

Individual based models (IBMs) and Agent based models (ABMs) have become widely used tools to understand complex biological systems. However, general methods of parameter inference for IBMs are not available. In this paper we show that it is possible to address this problem with a traditional likelihood-based approach, using an example of an IBM developed to describe the spread of chytridiomycosis in a population of frogs as a case study. We show that if the IBM satisfies certain criteria we can find the likelihood (or posterior) analytically, and use standard computational techniques, such as MCMC, for parameter inference.     

Rabies prevalence in migratory tree-bats in Alberta and the influence of roosting ecology and sampling method on reported prevalence of rabies in bats

The migratory tree-roosting hoary bat (Lasiurus cinereus) and silver-haired bat (Lasionycteris noctivagans) are among the bat species with the highest reported prevalence of rabies in North America. However, bats submitted for rabies testing typically have been those that have come in contact with humans or pets. Given the roosting ecology of L. cinereus and L. noctivagans, contact with healthy individuals of these species is expected to be rare, with a bias in contact and submission of infected individuals and thus an overestimation of rabies prevalence. We tested 121 L. cinereus and 96 L. noctivagans specimens, collected during mortality surveys at wind energy facilities in Southern Alberta, Canada in 2007 and 2008, for rabies. None of the L. cinereus (0%) and one L. noctivagans (1%) tested positive for rabies. Prevalence of rabies was significantly lower than previously reported estimates, passive and active, for L. cinereus and L. noctivagans. In a review of the literature including multiple bat species, we found a significant difference in estimates of rabies prevalence based on passive versus active surveillance testing. Furthermore, roosting ecology influenced estimates of rabies prevalence, with significantly higher prevalence among passive surveillance submissions of nonsynanthropic species compared to synanthropic species, a trend not evident in active surveillance reports. We conclude that rabies prevalence in randomly collected L. cinereus and L. noctivagans is low and comparable to active surveillance estimates from other species (≤ 1%), and that roosting ecology influences estimates of rabies prevalence among bats submitted to public health laboratories in North America.     

Genomic sweep and potential genetic rescue during limiting environmental conditions in an isolated wolf population

Genetic rescue, in which the introduction of one or more unrelated individuals into an inbred population results in the reduction of detrimental genetic effects and an increase in one or more vital rates, is a potentially important management tool for mitigating adverse effects of inbreeding. We used molecular techniques to document the consequences of a male wolf (Canis lupus) that immigrated, on its own, across Lake Superior ice to the small, inbred wolf population in Isle Royale National Park. The immigrant's fitness so exceeded that of native wolves that within 2.5 generations, he was related to every individual in the population and his ancestry constituted 56 per cent of the population, resulting in a selective sweep of the total genome. In other words, all the male ancestry (50% of the total ancestry) descended from this immigrant, plus 6 per cent owing to the success of some of his inbred offspring. The immigration event occurred in an environment where space was limiting (i.e. packs occupied all available territories) and during a time when environmental conditions had deteriorated (i.e. wolves' prey declined). These conditions probably explain why the immigration event did not obviously improve the population's demography (e.g. increased population numbers or growth rate). Our results show that the beneficial effects of gene flow may be substantial and quickly manifest, short-lived under some circumstances, and how the demographic benefits of genetic rescue might be masked by environmental conditions.     

Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.     

Sexually dimorphic serotonergic dysfunction in a mouse model of Huntington's disease and depression

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.