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Princeton, NJ, United States

Rothfuchs A.G.,National Institute of Allergy and Infectious Diseases | Rothfuchs A.G.,Karolinska Institutet | Roffe E.,National Institute of Allergy and Infectious Diseases | Gibson A.,National Institute of Allergy and Infectious Diseases | And 8 more authors.
PLoS ONE | Year: 2013

Mannose-binding lectin (MBL) is a humoral pattern-recognition molecule important for host defense. Although recent genetic studies suggest an involvement of MBL/MASP2-associated pathways in Chagas' disease, it is currently unknown whether MBL plays a role in host resistance to the intracellular protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. In this study we employed MBL-/- mice to assess the role of MBL in resistance to experimental infection with T. cruzi. T. cruzi infection enhanced tissue expression of MBL both at the mRNA and protein level. Similarly, symptomatic acute Chagas' disease patients displayed increased serum concentrations of MBL compared to patients with indeterminate, asymptomatic forms of the disease. Furthermore, increased parasite loads in the blood and/or tissue were observed in MBL-/- mice compared to WT controls. This was associated with reduced systemic levels of IL-1-/-3p40 in MBL-/- mice. Importantly, MBL-/- mice infected with a cardiotropic strain of T. cruzi displayed increased myocarditis and cardiac fibrosis compared to WT controls. The latter was accompanied by elevated hydroxyproline content and mRNA levels of collagen-1 and -6 in the heart. These observations point to a previously unappreciated role for MBL in regulating host resistance and cardiac inflammation during infection with a major human pathogen.

Simen A.A.,Merck And Co. | Simen A.A.,Pfizer | Ma J.,Merck And Co. | Svetnik V.,Merck And Co. | And 14 more authors.
Journal of Sleep Research | Year: 2015

Summary: Non-nucleoside reverse transcriptase inhibitors are important antiretroviral agents for the treatment of human immunodeficiency virus. Some non-nucleoside reverse transcriptase inhibitors, in particular efavirenz, have prominent effects on sleep, cognition and psychiatric variables that limit their tolerability. To avoid confounds due to drug-drug and drug-disease interactions, we assessed the effects of efavirenz in healthy volunteers on sleep, cognition and psychological endpoints during the first week of treatment. Forty healthy male subjects were randomized to receive placebo or efavirenz 600 mg nightly for 7 days after completion of a 3-day placebo run-in period. Treatment with efavirenz was associated with reduced time to sleep onset in the Maintenance of Wakefulness Test, an increase in non-rapid eye movement sleep, a large exposure-related decrease in sigma band spectral density and sleep spindle density during non-rapid eye movement sleep, and reduced performance on an attention switching task. Because efavirenz has been shown to have serotonin 2A receptor partial-agonist properties, we reasoned that antagonism of serotonin 2A receptor signalling in the thalamic reticular nucleus, which generates sleep spindles and promotes attention, may be responsible. Consistent with predictions, treatment of healthy volunteers with a single dose of a serotonin 2A receptor antagonist was found to significantly suppress sigma band spectral density in an exposure-related manner and modulated the overall spectral profile in a manner highly similar to that observed with efavirenz, consistent with the notion that efavirenz exhibits serotonin 2A receptor partial-agonist pharmacology in humans. © 2014 European Sleep Research Society.

Abide Therapeutics | Entity website

Abides platform exploits the power of chemoproteomics to mine the serine hydrolase superfamily for novel drug targets. Our platform includes a proprietary chemical library that is designed to interact with serine hydrolases, and cutting-edge chemoproteomics techniques that rapidly read out target engagement and off-target selectivity ...

Abide Therapeutics and Scripps Research Institute | Date: 2013-03-15

Provided herein are carbamate compounds which may be useful in the treatment of for example, pain, solid tumors and/or obesity.

Abide Therapeutics and Scripps Research Institute | Date: 2013-01-07

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.

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