Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

Influenza virus is the main cause of an infectious disease called influenza affecting the respiratory system including the throat, nose and lungs. Neuraminidase inhibitors are reagents used to block the enzyme called neuraminidase to prevent the influenza infection from spreading. Neuraminidase inhibitors are widely used in the treatment of influenza infection, but still there is a need to develop more potent agents for the more effective treatment of influenza. Complications of the influenza disease lead to death, and one of these complications is drug resistance; hence, there is an urgent need to develop more effective agents. This review focuses on the recent advances in chemical synthesis pathways used for the development of new neuraminidase agents along with the medicinal aspects of chemically modified molecules, including the structure–activity relationship, which provides further rational designs of more active small molecules.

Influenza virus is the main cause of an infectious disease called influenza affecting the respiratory system including the throat, nose and lungs.     

Social interactions tune aggression and stress responsiveness in a territorial cichlid fish (Archocentrus nigrofasciatus)

We examined the relative influences of pre-fight housing condition, contest intensity, and contest outcome in modulating post-fight stress hormone concentrations in territorial male convict cichlids (Archocentrus nigrofasciatus). Individuals were housed either in isolation or in semi-natural communal tanks. Pairs of male cichlids that differed considerably in body mass were selected from the same housing regime. Pre-fight water-borne cortisol levels were obtained before allowing the dyad to interact until contest resolution, after which time post-fight cortisol levels were obtained from the winner and loser. There were no outcome-related differences in post-fight cortisol concentrations following escalated or non-escalated contests, a result that held true for both housing regimes. Pre-fight cortisol levels were significantly higher than post-fight cortisol levels, suggesting that initial confinement in a beaker for the water-borne hormone samples was a stressor, but that the animals acclimated quickly to confinement. Fights involving previously isolated participants were significantly more intense than those involving group-housed animals, which we explain as being a function of established relationships between social isolation, heightened acute cortisol responsiveness, and the expression of excessive aggressive behavior. Only group-housed losers demonstrated the ability to modulate aggression or hypothalamic-pituitary-interrenal (HPI) activity in a graded fashion to acute increases in cortisol or changes in contest intensity, respectively. We discuss a variety of factors that could disrupt the ability of isolates to appropriately modulate interactions between social behavior and the HPI axis, and we examine a number of functional hypotheses underlying the sensitivity of group-housed losers to changes in contest dynamics.     

Measles vaccine effectiveness and risk factors for measles in Dhaka,Bangladesh

OBJECTIVE: To evaluate vaccine effectiveness and to assess risk factors for measles in Dhaka, Bangladesh. METHOD: A case-control study, involving 198 cases with 783 age-matched neighbourhood controls and 120 measles cases with 365 age-matched hospital controls, was conducted in 1995-96 in three large hospitals in Dhaka. FINDINGS: Measles vaccine effectiveness was estimated at 80% (95% confidence interval (CI) = 60-90%) using neighbourhood controls; very similar results were obtained using hospital controls. Visits to a health facility 7-21 days before onset of any symptoms were associated with increased risk of measles compared with neighbourhood (adjusted odds ratio (OR) = 7.0, 95% CI = 4.2-11.6) or hospital (adjusted OR = 1.7, 95% CI = 1.01-2.8) controls. Cases were more likely than controls to come from a household where more than one child lived (adjusted OR = 1.6, 95% CI = 1.1-2.5 versus neighbourhood controls; adjusted OR = 1.8, 95% CI = 1.02-3.0 versus hospital controls). CONCLUSIONS: To improve measles control in urban Dhaka missed immunization opportunities must be reduced in all health care facilities by following WHO guidelines. For measles elimination, more than one dose of vaccine would be required.     

Cubilin Maintains Blood Levels of HDL and Albumin

Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL₃ particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL₂ particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.HDL and albumin are major blood components with links to cardiovascular disease.^1–3 As such, understanding the metabolism and homeostatic regulatory mechanisms of these constituents may hold keys to new therapeutic approaches.Cubilin is a multiligand receptor capable of mediating the endocytosis of albumin and HDL, as well as its major apolipoprotein component, apoA-I.^4–6 However, the significance of cubilin to the homeostasis of HDL and albumin in the blood has not been studied. Cubilin and its coreceptor LDL-related protein-2 (megalin) are expressed by absorptive cells, including proximal tubule cells (PTCs).⁷ At present, cubilin- and megalin-mediated endocytic uptake represents the only established process by which PTCs reabsorb proteins from the glomerular filtrate.^5,6,8,9 Genetic alterations that affect renal cubilin expression in humans, dogs, and mice result in urinary wastage of an array of macromolecules, including albumin and apoA-I.^10,11Although several studies demonstrate the role of cubilin in mediating renal uptake of apoA-I and albumin,^5,10,11 the precise fate of these proteins following PTC uptake has been an open question. Although a general view is that ligand endocytosis by cubilin and megalin leads to lysosomal degradation of ligands, several lines of evidence indicate that cubilin-megalin–mediated uptake may also participate in a process by which certain ligands are targeted for transcytosis and delivery back to the blood. For example, in cultured renal PTCs, megalin mediates transcytosis of transcobalamin–B₁₂ complex¹² and retinol-binding protein in complex with retinol/vitamin A.¹³ Megalin also mediates transcytosis of thyroglobulin,¹⁴ Shh,¹⁵ and the megalin-cubilin binding protein, receptor-associated protein.¹⁶ Indirect evidence for cubilin playing a similar role in ligand transcytosis comes from findings showing that albumin is transcytosed back to circulation via the proximal tubule epithelium,^17–19 as well as the fact that cubilin-mediated uptake of intrinsic factor–B₁₂ complex in the gut leads to its release into blood in the form of transcobalamin–B₁₂.²⁰Whether or not renal cubilin-mediated uptake of apoA-I and albumin from the glomerular filtrate might be part of a salvage process that affects levels of these proteins in the blood is not known. Here, we sought to define the relationships between genetic cubilin deficiency and renal uptake/urinary loss of apoA-I and albumin, along with the extent to which cubilin deficiency influences blood levels of each constituent, as well as HDL.