Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.     

The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence

The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.     

Reduced North Atlantic deep water coeval with the glacial Lake Agassiz freshwater outburst

An outstanding climate anomaly 8200 years before the present (B.P.) in the North Atlantic is commonly postulated to be the result of weakened overturning circulation triggered by a freshwater outburst. New stable isotopic and sedimentological records from a northwest Atlantic sediment core reveal that the most prominent Holocene anomaly in bottom-water chemistry and flow speed in the deep limb of the Atlantic overturning circulation begins at approximately 8.38 thousand years B.P., coeval with the catastrophic drainage of Lake Agassiz. The influence of Lower North Atlantic Deep Water was strongly reduced at our site for approximately 100 years after the outburst, confirming the ocean's sensitivity to freshwater forcing. The similarities between the timing and duration of the pronounced deep circulation changes and regional climate anomalies support a causal link.     

New aspects in the pathogenesis of abomasal displacement

Impaired abomasal motility and an increased accumulation of gas are prerequisites for displacement of the abomasum in the cow. Predisposing factors are the breed (e.g. Holstein-Friesian, Simmental-Red-Holstein cross breeds and Guernsey), genetic background, twin pregnancy, first weeks of lactation, metabolic disorders (ketosis, increased lipomobilisation, insulin resistance), high-concentrate and low-fibre diets, as well as other concomitant diseases, such as endometritis, mastitis and claw disorders. There does not appear to be a strong correlation between increased milk yield or endotoxaemia and abomasal displacement. Recent studies have focused on possible functional disorders of the enteric nervous system within the abomasal wall, since cattle with abomasal displacement have an increased activity of neuronal nitric oxide synthase, as well as decreased acetylcholine sensitivity. In addition, there appear to be significant differences between breeds in the levels of the neurotransmitters substance P (SP) and vasoactive intestinal peptide (VIP) in the abomasal wall. For example, SP (stimulatory) was significantly less in German Holsteins in comparison to the German Fleckvieh, whereas VIP (inhibitory) was markedly increased. These risk factors may explain why Holstein cows are more susceptible to abomasal displacement than other breeds.