The effect of protein-energy malnutrition on appositional bone growth in the rat.

During protein-energy malnutrition appositional bone growth in the seventh caudal vertebra of the rat slows and finally ceases. During rehabilitation appositional growth begins agains and attains a rate in excess of that of the controls. This may account for alterations in skeletal proportions resulting from malnutrition.     

Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.     

Endangered species: Pan-Atlantic leatherback turtle movements

The overall extent of habitat use by leatherback turtles in the North Atlantic, and hence their possible interactions with longline fisheries, is unknown. Here we use long-term satellite telemetry to reveal that leatherbacks range throughout the North Atlantic, indicating that closing limited areas to longline fisheries will probably have only partial success in reducing turtle bycatch. Although turtles dive very deeply on occasion (one descended to a maximum depth of 1,230 metres, which represents the deepest dive ever recorded for a reptile), they generally restrict their diving to less than 250 metres, which increases the chance that they will encounter longline hooks.     

An integrated approach to characterize genetic interaction networks in yeast metabolism

Although experimental and theoretical efforts have been applied to globally map genetic interactions, we still do not understand how gene-gene interactions arise from the operation of biomolecular networks. To bridge the gap between empirical and computational studies, we i, quantitatively measured genetic interactions between ～185,000 metabolic gene pairs in Saccharomyces cerevisiae, ii, superposed the data on a detailed systems biology model of metabolism and iii, introduced a machine-learning method to reconcile empirical interaction data with model predictions. We systematically investigated the relative impacts of functional modularity and metabolic flux coupling on the distribution of negative and positive genetic interactions. We also provide a mechanistic explanation for the link between the degree of genetic interaction, pleiotropy and gene dispensability. Last, we show the feasibility of automated metabolic model refinement by correcting misannotations in NAD biosynthesis and confirming them by in vivo experiments.     

Feeding in infancy: Short- and long-term effects on cardiovascular function

Cardiovascular responses of adult organisms to feeding are well characterized and, in general, are understood as acute adaptations required for processing and distributing nutrients. Research over the past several years has shown that infants also have important cardiovascular responses to nutrient intake and that these are regulated by changes in autonomic activity to the heart and vasculature. Recent studies have provided results that suggest these responses in infancy may make an important contribution to the long-term development of cardiovascular function, in particular, adult blood pressure (BP). The purpose of this presentation will be to review the evidence that has led to this conclusion, offer ideas about how this potential early-life shaping of subsequent cardiovascular function may come about, and suggest further studies that will be required in order to characterize the mechanisms responsible for these effects.     

Isoquinolines,beta-carbolines and alcohol drinking: Involvement of opioid and dopaminergic mechanisms

Summary Two classes of amine-aldehyde adducts, the tetrahydroisoquinoline (TIQ) and beta-carboline (THBC) compounds, have been implicated in the mechanism in the brain underlying the addictive drinking of alcohol. One part of this review focuses on the large amount of evidence unequivocally demonstrating not only the corporeal synthesis of the TIQs and THBCs but their sequestration in brain tissue as well. Experimental studies published recently have revealed that exposure to alcohol enhances markedly the endogenous formation of condensation products. Apart from their multiple neuropharmacological actions, certain adducts when delivered directly into the brain of either the rat or monkey, to circumvent the brain's blood-barrier system, can evoke an intense and dose-dependent increase in the voluntary drinking of solutions of alcohol even in noxious concentrations. That the abnormal intake of alcohol is related functionally to opioid receptors in the brain is likely on the basis of several dinstinct lines of evidence which include: the attenuation of alcohol drinking by opioid receptor antagoists; binding of a TIQ to opiate receptors in the brain; and marked differences in enkephalin values in animals genetically predisposed to the ingestion of alcohol. Finally, it is proposed that the dopaminergic reward pathways which traverse the meso-limbic-forebrain systems of the brain more than likely constitute an integrative anatomical substrate for the adduct-opioid cascade of neuronal events which promote and sustain the aberrant drinking of alcohol.     

Human recombination hot spots hidden in regions of strong marker association

The fine-scale distribution of meiotic recombination events in the human genome can be inferred from patterns of haplotype diversity in human populations but directly studied only by high-resolution sperm typing. Both approaches indicate that crossovers are heavily clustered into narrow recombination hot spots. But our direct understanding of hot-spot properties and distributions is largely limited to sperm typing in the major histocompatibility complex (MHC). We now describe the analysis of an unremarkable 206-kb region on human chromosome 1, which identified localized regions of linkage disequilibrium breakdown that mark the locations of sperm crossover hot spots. The distribution, intensity and morphology of these hot spots are markedly similar to those in the MHC. But we also accidentally detected additional hot spots in regions of strong association. Coalescent analysis of genotype data detected most of the hot spots but showed significant differences between sperm crossover frequencies and historical recombination rates. This raises the possibility that some hot spots, particularly those in regions of strong association, may have evolved very recently and not left their full imprint on haplotype diversity. These results suggest that hot spots could be very abundant and possibly fluid features of the human genome.     

Radiation-induced leukemia in rats: Synergistic effect of urethan

Zusammenfassung Nachweis, dass i.p.-Injektion von Urethan und Ganzkörper-Röntgenbestrahlungen bei Ratten eine potenzierte leukämogene Wirkung hat, während die Zahl der entstandenen Haut- und Mamma-Tumoren geringer war als bei der Einzelbehandlung.