The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase

The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.     

Lymphatic development

The lymphatic system is essential for fluid homeostasis, immune responses, and fat absorption, and is involved in many pathological processes, including tumor metastasis and lymphedema. Despite its importance, progress in understanding the origins and early development of this system has been hampered by lack of defining molecular markers and difficulties in observing lymphatic cells in vivo and performing genetic and experimental manipulation of the lymphatic system. Recent identification of new molecular markers, new genes with important functional roles in lymphatic development, and new experimental models for studying lymphangiogenesis has begun to yield important insights into the emergence and assembly of this important tissue. This review focuses on the mechanisms regulating development of the lymphatic vasculature during embryogenesis. Birth Defects Research (Part C) 87:222–231, 2009. © 2009 Wiley‐Liss, Inc.     

Peripheral ghrelin interacts with orexin neurons in glucostatic signalling

Ghrelin interactions with glycemia in appetite control as well as the potential mechanisms involving the orexin and melanin-concentrating hormone (MCH) neurons in the orexigenic ghrelin signals were investigated by using a specific anti-ghrelin antibody (AGA). Our results confirm that peripheral ghrelin is an important signal in meal initiation and appetite. Employing immunohistochemistry techniques, we found that c-fos positive neurons in the lateral hypothalamus (LH) and perifornical area (PFA) increased after insulin or 2-deoxyglucose administration. Moreover, we have also demonstrated that peripheral ghrelin blockade by the AGA, reduces the orexigenic signal induced by insulin and 2-DG administration probably partly producing a decrease of c-fos immunoreactivity in the LH and PFA as well as a lower activation of orexin neurons. In contrast, the c-fos positive MCH neurons were not apparently affected. In summary, our findings suggest that peripheral ghrelin plays an important role in regulatory "glucostatic" feeding mechanisms by means of its role as a "hunger" signal affecting the LH and PFA areas, which may contribute to energy homeostasis through orexin neurons.     

Role of IL-4 in aversion induced by food allergy in mice

To ascertain the role of IL-4 in aversion to antigen induced by food allergy, wild type and IL-4 deficient BALB/c mice were sensitized with ovalbumin and challenged orally with egg white. Sensitized wild type mice had increased production of IL-4 by spleen and mesenteric lymph node cells in vitro, higher levels of serum anti-ovalbumin IgE and IgG1, aversion to ingestion of the antigen and loss of body weight after continuous oral challenge. Intestinal changes in wild type sensitized mice included eosinophil infiltration and increased mucus production. The IL-4 deficiency impaired the development of food allergy and the aversion to antigen, suggesting the involvement of the antigen specific antibodies. When IL-4 deficient mice received serum from sensitized wild type donors, the aversion was restored. These results indicate that production of IL-4 and specific IgE/IgG1 antibodies correlate with aversion to antigen induced by food allergy in mice.     

The mechanistic,genetic and evolutionary causes of bird eye colour variation

Birds display a rainbow of eye colours, but this trait has been little studied compared with plumage coloration. Avian eye colour variation occurs at all phylogenetic scales: it can be conserved throughout whole families or vary within one species, yet the evolutionary importance of this eye colour variation is under-studied. Here, we summarize knowledge of the causes of eye colour variation at three primary levels: mechanistic, genetic and evolutionary. Mechanistically, we show that avian iris pigments include melanin and carotenoids, which also play major roles in plumage colour, as well as purines and pteridines, which are often found as pigments in non-avian taxa. Genetically, we survey classical breeding studies and recent genomic work on domestic birds that have identified potential ‘eye colour genes’, including one associated with pteridine pigmentation in pigeons. Finally, from an evolutionary standpoint, we present and discuss several hypotheses explaining the adaptive significance of eye colour variation. Many of these hypotheses suggest that bird eye colour plays an important role in intraspecific signalling, particularly as an indicator of age or mate quality, although the importance of eye colour may differ between species and few evolutionary hypotheses have been directly tested. We suggest that future studies of avian eye colour should consider all three levels, including broad-scale iris pigment analyses across bird species, genome sequencing studies to identify loci associated with eye colour variation, and behavioural experiments and comparative phylogenetic analyses to test adaptive hypotheses. By examining these proximate and ultimate causes of eye colour variation in birds, we hope that our review will encourage future research to understand the ecological and evolutionary significance of this striking avian trait.     

Concurrent measurement of (Na+,K+)-ATPase activity and lipid peroxides in rat brain following reversible global ischemia

Lipid peroxides, quantitated as lipid conjugated dienes, and (Na⁺,K⁺)-ATPase activity were assayed concurrently in brains of control rats and in three groups subjected to 30 min of reversible forebrain ischemia followed by 0, 1, and 4 hr of recirculation. Multiple small samples were taken from lateral, dorsolateral and medial cortex, hippocampus, thalamus and striatum following in situ freezing. (Na⁺,K⁺)-ATPase activity was elevated in hippocampus, dorsolateral and lateral cortex (P<0.10) and in thalamus (P<0.05) following 30 min ischemia. ATPase activity in medial cortex continued to increase during the first 1 hr of recirculation (P<0.10). Following 4 hr of recirculation, decreased enzyme activities were observed in all of these regions (lateral cortex and hippocampus,P<0.10). No changes in ATPase activity were observed in samples from striatum. Of the regional samples assayed for lipid peroxide content, the incidence of conjugated dienes as a function of recirculation time was 6% (0 hr), 23% (1 hr), and 17% (4 hr). For these samples, plots of normalized ATPase activity vs. tissue conjugated diene concentration revealed that normalized ATPase activity varied with recirculation time, but was independent of the magnitude of the lipid peroxidative process (expressed in terms of tissue conjugated diene concentration). These results suggest that disturbances in membrane structure and function presumed to arise from lipid peroxidation are not responsible for the behavior of the ATPase under the current in vivo conditions.