An improved synthesis of adefovir and related analogues.

An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium -butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions.

Cytosolic phospholipase A(2)α protects against ischemia/reperfusion injury in the heart.

Studies with sPLA(2) Group X, and cPLA(2) α gene-targeted mice suggest that absence of sPLA(2) Group X results in protection from ischemia/reperfusion (I/R) injury in the heart, and absence of cPLA(2) α Group IV is protective in the brain. Although latter studies might suggest a similar deleterious role for cPLA(2) α in I/R injury in the heart, the pathophysiology of stroke is intricately related to excitotoxicity and cannot necessarily be extrapolated to the heart. We report here that unlike findings in the brain, cPLA(2) α((-/-)) mice have exaggerated injury following I/R in vivo.

TIM2 gene deletion results in susceptibility to cisplatin-induced kidney toxicity.

T-cell Immunoglobulin and Mucin domain 2 (TIM2) belongs to the receptor family of cell surface molecules expressed on kidney, liver, and T cells. Previous studies have revealed that TIM2-deficient mice (TIM2(-/-)) are more susceptible to the Th2-mediated immune response in an airway inflammation model. Here, we investigated the phenotypic response of TIM2(-/-) mice to cisplatin-induced kidney toxicity.

Delivering a safe and effective strain-specific vaccine to control an epidemic of group B meningococcal disease.

In response to a devastating group B meningococcal disease epidemic in New Zealand, a case was prepared for new health funding and a new outer membrane vesicle vaccine, MeNZB, developed. Following clinical trials demonstrating satisfactory immunogenicity and safety profiles a national implementation strategy was prepared. MeNZB was introduced halfway through the 14th year of the epidemic with a campaign targeting children and young people aged under 20 years delivered over 2 years.

Identification of PP2A as a novel interactor and regulator of TRIP-Br1.

TRIP-Br proteins are a novel family of transcriptional coregulators involved in E2F-mediated cell cycle progression. Three of the four mammalian members of TRIP-Br family, including TRIP-Br1, are known oncogenes. We now report the identification of the Balpha regulatory subunit of serine/threonine protein phosphatase 2A (PP2A) as a novel TRIP-Br1 interactor, based on an affinity binding assay coupled with mass spectrometry.

Cytosolic phospholipase A2alpha regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation.

The products of arachidonic acid metabolism are key mediators of inflammatory responses in the central nervous system, and yet we do not know the mechanisms of their regulation. The phospholipase A(2) enzymes are sources of cellular arachidonic acid, and the enzymes cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) are essential for the synthesis of inflammatory PGE(2) in the brain. These studies seek to determine the function of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) in inflammatory PGE(2) production in the brain.

Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2.

Epidemiological investigations suggest that chronic lung inflammation increases lung cancer risk. Pharmacologic and genetic evidence in mouse models indicates that lipid mediators released during pulmonary inflammation enhance lung tumor formation. Cytosolic phospholipase A2 (cPLA2) catalyzes arachidonic acid (AA) release from membrane phospholipids.

Deletion of cytosolic phospholipase A2 promotes striated muscle growth.

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2.

Human group V phospholipase A2 induces group IVA phospholipase A2-independent cysteinyl leukotriene synthesis in human eosinophils.

We previously reported that exogenously added human group V phospholipase A2 (hVPLA2) could elicit leukotriene B4 biosynthesis in human neutrophils through the activation of group IVA phospholipase A2 (cPLA2) (Kim, Y. J., Kim, K.