Seasonal trend in movement directions at dawn and dusk: a study on crow and white herons

Crows (Corvus splendens) and white herons (Ardea alba) inhabit the agricultural landscapes nearby human habitats which represent dynamic ecosystem and show seasonal crop patterns. We studied the movement pattern in these birds at dawn and dusk, during solstices (December and June) and equinoxes (March and September). The movement directions were changed from uniform at dawn to a concentrated distribution at dusk all along the season suggesting that morning movements are more exploratory than evening with seasonal differences. Differential use of directions in December than June could be the effect of temperature, food availability or wind direction and speed. During breeding, less number of directions used suggests that birds might be moving towards the directions having high probability of food availability. It is likely that avian dispersal in space and time is dependent on the food availability however, further studies are required to be carried out.     

Methylene amine substituted arylindenopyrimidines as potent adenosine A2A/A1 antagonists

A novel series of arylindenopyrimidines were identified as A_2A and A₁ receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson’s disease when dosed orally.     

Ferritin: a novel mechanism for delivery of iron to the brain and other organs

Traditionally, transferrin has been considered the primary mechanism for cellular iron delivery, despite suggestive evidence for additional iron delivery mechanisms. In this study we examined ferritin, considered an iron storage protein, as a possible delivery protein. Ferritin consists of H- and L-subunits, and we demonstrated iron uptake by ferritin into multiple organs and that the uptake of iron is greater when the iron is delivered via H-ferritin compared with L-ferritin. The delivery of iron via H-ferritin but not L-ferritin was significantly decreased in mice with compromised iron storage compared with control, indicating that a feedback mechanism exists for H-ferritin iron delivery. To further evaluate the mechanism of ferritin iron delivery into the brain, we used a cell culture model of the blood-brain barrier to demonstrate that ferritin is transported across endothelial cells. There are receptors that prefer H-ferritin on the endothelial cells in culture and on rat brain microvasculature. These studies identify H-ferritin as an iron transport protein and suggest the presence of an H-ferritin receptor for mediating iron delivery. The relative amount of iron that could be delivered via H-ferritin could make this protein a predominant player in cellular iron delivery. blood-brain barrier; iron transport; H-ferritin     

Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist

We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.     

Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease: Stereological analysis in the albino Swiss mice model

Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression.Key words: prion disease, optical fractionator, neuropathology, behavioral changes, albino Swiss mice     

Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure

Brain natriuretic peptide (BNP) and monocyte chemotactic protein-1 (MCP-1) are biomarkers of heart failure (HF). The aim of the present study was to determine the role of oxidized low-density lipoprotein (Ox-LDL) in the induction of these biomarkers and the signaling pathways involved in vitro. Incubation of HL-1 cardiomyocytes and human myocytes with Ox-LDL induced the expression of BNP and MCP-1 genes, while native LDL had no effect. When peroxides associated with Ox-LDL were reduced to hydroxides, the ability to induce BNP and MCP-1 gene expression was abolished. Furthermore, exposure of HL-1 cells to ischemic conditions alone had no effect on BNP gene expression, while ischemia followed by reperfusion resulted in increased expression of BNP gene. Inhibitors of ERK and JNK inhibited the induction of BNP. Signaling array results suggested that the induction of both MAPK and NF-κB pathways is involved in the induction of BNP by Ox-LDL. These results suggest that Ox-LDL or peroxidized lipids formed in oxidatively stressed myocytes during ischemia-reperfusion injury may play a role in the induction of BNP and MCP-1.