Phylogeographical patterns in Coenosia attenuata (Diptera: Muscidae): a widespread predator of insect species associated with greenhouse crops

The tiger‐fly Coenosia attenuata is a globally widespread predatory fly which is not only associated with greenhouse crops, but also occurs in open fields. It is a potential control agent against some of the more common pests in these crops. Assessing the genetic structure and gene flow patterns may be important for planning crop protection strategies and for understanding the historical processes that led to the present distribution of genetic lineages within this species. In the present study, the phylogeographical patterns of this species, based on mitochondrial cytochrome oxidase I and nuclear white and elongation factor‐1α genes, are described, revealing relatively low genetic diversity and weak genetic structure associated with a recent and sudden population expansion of the species. The geographical distribution of mitochondrial haplotypes indicates the Mediterranean as the most likely region of origin of the species. Some dispersal patterns of the species are also revaled, including at least three independent colonizations of North and South America: one from Middle East to North America with a strong bottleneck event, another from Europe to South America (Chile), with both likely to be a result of unintentional introduction, and a third one of still undetermined origin to South America (Ecuador). © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, 114 , 308–326.     

Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling

Much of our knowledge about mammalian evolution comes from examination of dental fossils, because the highly calcified enamel that covers teeth causes them to be among the best-preserved organs. As mammals entered new ecological niches, many changes in tooth number occurred, presumably as adaptations to new diets. For example, in contrast to humans, who have two incisors in each dental quadrant, rodents only have one incisor per quadrant. The rodent incisor, because of its unusual morphogenesis and remarkable stem cell-based continuous growth, presents a quandary for evolutionary biologists, as its origin in the fossil record is difficult to trace, and the genetic regulation of incisor number remains a largely open question. Here, we studied a series of mice carrying mutations in sprouty genes, the protein products of which are antagonists of receptor-tyrosine kinase signaling. In sprouty loss-of-function mutants, splitting of gene expression domains and reduced apoptosis was associated with subdivision of the incisor primordium and a multiplication of its stem cell-containing regions. Interestingly, changes in sprouty gene dosage led to a graded change in incisor number, with progressive decreases in sprouty dosage leading to increasing numbers of teeth. Moreover, the independent development of two incisors in mutants with large decreases in sprouty dosage mimicked the likely condition of rodent ancestors. Together, our findings indicate that altering genetic dosage of an antagonist can recapitulate ancestral dental characters, and that tooth number can be progressively regulated by changing levels of activity of a single signal transduction pathway.     

Immunolocalization of IFN-gamma in the lesions of resistant and susceptible mice to Paracoccidioides brasiliensis infection

The important role of interferon-gamma (IFN-γ) in protective immunity in mycosis is well established, except for its participation in fungal granulomas. Herein, we employ immunohistochemical reactions to describe the in situ localization of IFN-γ in granulomas of susceptible (B10.A) and resistant (A/J) mice to infection with Paracoccidioides brasiliensis (Pb). After infection with the highly virulent Pb18, IFN-γ-positive lymphomononuclear cells were localized mainly at the periphery of granulomas in both mouse strains. The numbers of positive cells found in compact granulomas of A/J mice increased significantly from 15 to 120 days postinfection. At this time, significantly more positive cells were detected in the compact granulomas of resistant mice than in the loose, multifocal lesions of the susceptible ones. In infection with the slightly virulent Pb265, the same pattern of IFN-γ localization was found as in Pb18 infection, but there was decreased staining at 120 days due to the presence of only residual lesions in both mouse strains. The marked IFN-γ staining observed in the granulomas of resistant mice at the later stage of Pb infection confirms its importance in fungal dissemination control, and suggests a contribution to the development of paracoccidioidal granuloma.     

Nicotinic acids: liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy

An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.     

Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors

Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared.     

Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: from systemic to liver-targeting inhibitors

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.     

Genetic analysis of D-xylose metabolism by endophytic yeast strains of Rhodotorula graminis and Rhodotorula mucilaginosa

Two novel endophytic yeast strains, WP1 and PTD3, isolated from within the stems of poplar (Populus) trees, were genetically characterized with respect to their xylose metabolism genes. These two strains, belonging to the species Rhodotorula graminis and R. mucilaginosa, respectively, utilize both hexose and pentose sugars, including the common plant pentose sugar, D-xylose. The xylose reductase (XYL1) and xylitol dehydrogenase (XYL2) genes were cloned and characterized. The derived amino acid sequences of xylose reductase (XR) and xylose dehydrogenase (XDH) were 32%～41% homologous to those of Pichia stipitis and Candida. spp., two species known to utilize xylose. The derived XR and XDH sequences of WP1 and PTD3 had higher homology (73% and 69% identity) with each other. WP1 and PTD3 were grown in single sugar and mixed sugar media to analyze the XYL1 and XYL2 gene regulation mechanisms. Our results revealed that for both strains, the gene expression is induced by D-xylose, and that in PTD3 the expression was not repressed by glucose in the presence of xylose.