Arthropoda of the subantarctic islands of New Zealand

Ischyroplectron isolatum (Hutton) is redescribed from the Bounty Islands, south‐east of New Zealand. The relationships of the subantarctic Orthoptera are discussed. A key is given to the four genera of Rhaphidophoridae.     

Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups

We report an optimized set of CGenFF parameters that can be used to model small molecules containing acylphosphate and N-phosphonosulfonimidoyl functional groups in combination with the CHARMM force field. Standard CGenFF procedures were followed to obtain bonded interaction parameters, which were validated by geometry optimizations, comparison to the results of calculations at the MP2/6-31+G(d) level of theory, and molecular dynamics simulations. In addition, partial atomic charges were assigned so that the energy of hydrogen bonding of the model compounds with water was correctly reproduced. The availability of these parameters will facilitate computational studies of enzymes that generate acyladenylate intermediates during catalytic turnover. In addition, given that the N-phosphonosulfonimidoyl moiety is a stable transition state analog for the reaction of ammonia with an acyladenylate, the parameters developed in this study should find use in efforts to develop novel and potent inhibitors of various glutamine-dependent amidotransferases that have been validated as drug targets. Topology and parameter files for the model compounds used in this study, which can be combined with other CGenFF parameters in computational studies of more complicated acylphosphates and N-phosphonosulfonimidates are made available.     

Discovery of N-{[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]methyl}benzamides as novel,selective and potent GlyT1 inhibitors

Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues.     

Short term changes in the expression of lipogenic genes in broilers (Gallus gallus)

The purpose of these experiments were to determine possible relationships between certain indices of lipid metabolism and specific gene expression in chickens fed graded levels of dietary crude protein. Male, broiler chickens growing from 7 to 28 days of age were fed diets containing 12 or 30% protein ad libitum. Both groups were then switched on day 28 to the diets containing the opposite level of protein. Birds were killed on day 28 (basal values prior to the switch) and at 12, 18 and 24 h post switch. Measurements taken included in vitro lipogenesis, malic enzyme activity the expression of the genes for malic enzyme, fatty acid synthase and acetyl coenzyme carboxylase. In vitro lipogenesis and malic enzyme activity were inversely related to dietary protein levels (12 to 30%) and to acute changes from 12 to 30%. Malic enzyme, fatty acid synthase and acetyl coenzyme A carboxylase genes were constant over a dietary protein range of 12 to 21% as in previous experiments, but decreased by feeding a 30% protein diet in the present experiments (acute or chronic feeding). Results of the present study demonstrate a continued role for protein in the regulation of broiler metabolism. Metabolic regulation at the gene level only occurs when feeding very high levels of dietary protein.     

Disease and secondary sexual traits: effects of pneumonia on horn size of bighorn sheep

Secondary sexual traits (e.g., horns and antlers) have ecological and evolutionary importance and are of management interest for game species. Yet, how these traits respond to emerging threats like infectious disease remains underexplored. Infectious pneumonia threatens bighorn sheep (Ovis canadensis) populations across North America and we hypothesized it may also reduce horn growth in male sheep. We assess the effect of pneumonia on horn size in male bighorn sheep using 12 herd datasets from across the western United States that had horn growth and disease data. Disease resulted in 12–35% reduction in increment (yearly) length and 3–13% reduction in total horn length in exposed individuals. The disease effect was prolonged when pathogens continued to circulate in sheep populations. Further, disease likely delays the age at which horns reach ¾-curl and prevents achievement of full-curl. This is further evidenced with 6 of the 12 herds experiencing an increase in average age at harvest following die-off events.     

Integrating coalescent and ecological niche modeling in comparative phylogeography

Understanding the factors that contribute to the formation of population genetic structure is a central goal of phylogeographic research, but achieving this goal can be complicated by the stochastic variance inherent to genetic processes. Statistical approaches to testing phylogeographic hypotheses accommodate this stochasticity by evaluating competing models of putative historical population structure, often by simulating null distributions of the expected variance. The effectiveness of these tests depends on the biological realism of the models. Information from the fossil record can aid in reconstructing the historical distributions of some taxa. However, for the majority of taxa, which lack sufficient fossils, paleodistributional modeling can provide valuable spatial-geographic data concerning ancestral distributions. Paleodistributional models are generated by projecting ecological niche models, which predict the current distribution of each species, onto a model of past climatic conditions. Here, we generate paleodistributional models describing the suitable habitat during the last glacial maximum for lineages from the mesic forests of the Pacific Northwest of North America, and use these models to generate alternative phylogeographic hypotheses. Coalescent simulations are then used to test these hypotheses to improve our understanding of the historical events that promoted the formation of population genetic structure in this ecosystem. Results from Pacific Northwest mesic forest organisms demonstrate the utility of these combined approaches. Paleodistribution models and population genetic structure are congruent across three amphibian lineages, suggesting that they have responded in a concerted manner to environmental change. Two other species, a willow and a water vole, despite being currently codistributed and having similar population genetic structure, were predicted by the paleodistributional model to have had markedly different distributions during the last glacial maximum. This suggests that congruent phylogeographic patterns can arise from incongruent ancestral distributions. Paleodistributional models introduce a much-needed spatial-geographic perspective to statistical phylogeography. In conjunction with coalescent models of population genetic structure, they have the potential to improve our understanding of the factors that promote population divergence and ultimately produce regional patterns of biodiversity.     

Serotonergic effects on feeding, but not hypothalamus-pituitary-adrenal secretion, are altered in ovine pregnancy

In ovine pregnancy, as in human pregnancy, hypothalamus-pituitary-adrenal activity is chronically increased. These studies were designed to test the hypotheses that expression of serotonergic genes and responsiveness to serotonin are increased in pregnancy. We tested the stimulatory effect of an acute, intracerebroventricular injection of the serotonin reuptake inhibitor fluoxetine on plasma ACTH and cortisol in ewes during late pregnancy or postpartum. We also tested the effect of lower-dose, longer-term stimulation by intracerebroventricular infusion of fluoxetine in pregnant and nonpregnant ewes over 6 days. Overall, we found that the stimulatory effect of fluoxetine on ACTH and cortisol was not significantly different between late-gestation and nonpregnant ewes, although the effect of acute fluoxetine administration was inversely related to plasma progesterone concentrations. Also, there were no differences in hypothalamic expression of the glucocorticoid and mineralocorticoid receptors, corticotropin-releasing hormone, AVP, the serotonin reuptake transporter, or the serotonin [5-hydroxytryptamine (5-HT)] receptors 5-HT(1A) and 5-HT(2A) with pregnancy or fluoxetine treatment. However, chronic fluoxetine infusion reduced food intake in the nonpregnant, but not pregnant, ewes. Expression of proopiomelanocortin mRNA in the hypothalamus was reduced in pregnant compared with nonpregnant ewes. Our results indicate that pregnancy does not increase responsiveness of ACTH and cortisol to serotonergic stimulation but, rather, that progesterone reduces the ACTH response. In addition, we found a reduced ability of serotonin to inhibit feeding in the pregnant ewes, consistent with a reduction in anorexic mechanisms in the pregnant state.     

Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists

The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.