Changes in the organization of the genome during the mammalian cell cycle

By using chromosome conformation capture technology, a recent study has revealed two alternative three-dimensional folding states of the human genome during the cell cycle.     

Oxygen and carbon isotope studies in recent foraminifera from the southwest Indian ocean

Eighteen species of planktonic foraminifera have been analyzed for their oxygen and carbon isotopic composition in five Recent samples of deep-sea sediment from the southwest Indian Ocean; one sample of glacial age and one mid-Holocene sample were also studied. On the basis of oxygen isotopic composition three groups are recognized. Species in the first group (Globigerinoides ruber, G. sacculifer and G. conglobatus; G. Globigerina rubescens and Globigerinita glutinata) calcity in the near-surface Tropical Water, so that the oxygen isotopic composition of their test carbonate may be used to indicate surface temperature. Species in the second group (Pulleniatina obliquiloculata, Neogloboquadrina dutertrei, Orbulina universa, Globigerinella siphonifera and Sphaeroidinella dehiscens) are associated with the sub-surface high-salinity Subtropical Water, so that their oxygen isotope composition indicates trends in the temperature of this water mass. The third group (the species of Globorotalia) calcity in the deeper Central Water. The average oxygen isotopic composition of each Globorotalia species is more or less constant over the range studied and does not reflect the surface temperature trend.The carbon isotopic composition of three species (Globigerina rubescens, Globigerinoides ruber and Globigerinita glutinata indicate departure from isotopic equilibrium by at least 3%₀. Among the remaining species the variation of carbon isotopic composition with depth (where depth is inferred from the temperature estimated from oxygen isotopic composition) implies that N. dutertrei, P. obliquiloculata and G. siphonifera occupy the shallow subsurface oxygen minimum, while the deeper-dwelling globorotaliids approach the deeper oxygen minimum. Hence it is possible, despite scatter among the data, to discern the pattern of oxygen content with depth in the overlying water masses from an examination of oxygen and carbon isotopic composition among foraminiferal species in the sediment. This promises to be an exciting new tool for palaeo-oceanographic investigations.     

Antibiotics from gliding bacteria

In recent years the discovery of some most important antibiotic compounds obtained by fermenting environmental microbes has been reported, providing proof that isolation and fermentation of producer strains is a significant approach to decifer novel structural types of antibiotics. Whereas many microbial taxa and environments have been well investigated in the past (e.g. soil-borne actinomycetes), the high diversity of microbial populations in certain habitats, e.g. marine sediments, has to date only been exploited marginally. Myxobacteria, the most prominent class of gliding bacteria, are well known for their ability to produce structurally intriguing natural products; however, so far no myxobacterial antibiotic has been developed for clinical use. In our studies, the antibacterial activity of the myxobacterial metabolite corallopyronin A was further investigated. Feeding studies with labeled precursors allowed to deduce all building blocks for the formation of corallopyronin A, whereby its biosynthesis from two chains probably connected by a Claisen-type reaction and the incorporation of bicarbonate into the methyl carbamate functionality can be regarded as unusual characteristics. A trans-AT type mixed PKS/NRPS gene cluster containing a β-branching cassette was identified as the putative basis for corallopyronin A biosynthesis in Corallococcus coralloides. Our research also resulted in the cultivation of several unusual marine myxobacteria which produce antibiotically active molecules.     

Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection

αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.     

Design,synthesis and structure–activity relationships of 3,5-diaryl-1H-pyrazoles as inhibitors of arylamine N-acetyltransferase

The synthesis and inhibitory potencies of a novel series of 3,5-diaryl-1H-pyrazoles as specific inhibitors of prokaryotic arylamine N-acetyltransferase enzymes is described. The series is based on hit compound 1 3,5-diaryl-1H-pyrazole identified from a high-throughout screen that has been carried out previously and found to inhibit the growth of Mycobacterium tuberculosis.