Current perspectives of the <Emphasis Type="Italic">Escherichia coli</Emphasis> RNA degradosome

Many biological processes in the cell are linked to RNA metabolism and therefore have implications for a wide range of biotechnological applications. The processing and degradation of RNA plays an important role in RNA metabolism with often the same enzymes being involved in both processes. In this review, we highlight the dynamic nature of the structural components of the Escherichia coli RNA degradosome which is a large multiprotein complex that plays an important role in RNA degradation. The activities of the individual components of the degradosome are also discussed. The RNA degradosome forms part of the bacterial cytoskeleton and associated proteins, such as molecular chaperones, may aid in the compartmentalization of enzymatic activities and cytoskeletal organization. An enhanced understanding of the components of the RNA degradosome in other bacterial species will certainly aid in their evaluation as potential antimicrobial agents.     

Towards the prevention of potential aluminum toxic effects and an effective treatment for Alzheimer's disease

In 1991, treatment with low dose intramuscular desferrioxamine (DFO), a trivalent chelator that can remove excessive iron and/or aluminum from the body, was reported to slow the progression of Alzheimer's disease (AD) by a factor of two. Twenty years later this promising trial has not been followed up and why this treatment worked still is not clear. In this critical interdisciplinary review, we provide an overview of the complexities of AD and involvement of metal ions, and revisit the neglected DFO trial. We discuss research done by us and others that is helping to explain involvement of metal ion catalyzed production of reactive oxygen species in the pathogenesis of AD, and emerging strategies for inhibition of metal-ion toxicity. Highlighted are insights to be considered in the quests to prevent potentially toxic effects of aluminum toxicity and prevention and intervention in AD.     

Steroidal C-21 mercapto derivatives as dissociated steroids: discovery of an inhaled dissociated steroid

A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.     

Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation

We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease.     

K11-linked ubiquitin chains as novel regulators of cell division

Modification of proteins with ubiquitin chains is an essential regulatory event in cell cycle control. Differences in the connectivity of ubiquitin chains are believed to result in distinct functional consequences for the modified proteins. Among eight possible homogenous chain types, canonical Lys48-linked ubiquitin chains have long been recognized to drive the proteasomal degradation of cell cycle regulators, and Lys48 is the only essential lysine residue of ubiquitin in yeast. It thus came as a surprise that in higher eukaryotes atypical K11-linked ubiquitin chains regulate the substrates of the anaphase-promoting complex and control progression through mitosis. We discuss recent findings that shed light on the assembly and function of K11-linked chains during cell division.     

Parental prey selection affects risk-taking behaviour and spatial learning in avian offspring

Early nutrition shapes life history. Parents should, therefore, provide a diet that will optimize the nutrient intake of their offspring. In a number of passerines, there is an often observed, but unexplained, peak in spider provisioning during chick development. We show that the proportion of spiders in the diet of nestling blue tits, Cyanistes caeruleus, varies significantly with the age of chicks but is unrelated to the timing of breeding or spider availability. Moreover, this parental prey selection supplies nestlings with high levels of taurine particularly at younger ages. This amino acid is known to be both vital and limiting for mammalian development and consequently found in high concentrations in placenta and milk. Based on the known roles of taurine in mammalian brain development and function, we then asked whether by supplying taurine-rich spiders, avian parents influence the stress responsiveness and cognitive function of their offspring. To test this, we provided wild blue tit nestlings with either a taurine supplement or control treatment once daily from the ages of 2-14 days. Then pairs of size- and sex-matched siblings were brought into captivity for behavioural testing. We found that juveniles that had received additional taurine as neonates took significantly greater risks when investigating novel objects than controls. Taurine birds were also more successful at a spatial learning task than controls. Additionally, those individuals that succeeded at a spatial learning task had shown intermediate levels of risk taking. Non-learners were generally very risk-averse controls. Early diet therefore has downstream impacts on behavioural characteristics that could affect fitness via foraging and competitive performance. Fine-scale prey selection is a mechanism by which parents can manipulate the behavioural phenotype of offspring.     

Anti-apoptotic effects of arachidonic acid and prostaglandin E2 in pancreatic beta-cells.

BACKGROUND/AIMS: The polyunsaturated fatty acid arachidonic acid (AA) has been implicated in beta-cell defence mechanisms and prostaglandin (PG) products of cyclooxygenase (COX) 2 action confer resistance to alloxan-induced apoptosis in insulin-secreting RIN cells. We have now investigated the anti-apoptotic effects of AA and its metabolite, PGE(2), in the MIN6 mouse insulin-secreting beta-cell line and mouse islets. METHODS: Apoptosis was determined in MIN6 beta-cell and mouse islet extracts by measurement of capase-3 activity, and COX2 mRNA levels were quantified by real-time RT-PCR. RESULTS: Exposure of MIN6 cells to AA (3.1-12.5 microM) caused concentration-dependent reductions in apoptosis, and similar results were obtained when endogenous AA levels were elevated in cytosolic phospholipase A(2)-overexpressing MIN6 cells. 25mM glucose caused both a significant up-regulation of MIN6 cell COX2 mRNA levels and a decrease in apoptosis. Inhibition of MIN6 cell COX2 activity with a selective inhibitor, NS-398 (10-100 microM), increased apoptosis and exogenous PGE(2) (0.2-5 microM) reduced NS-398-induced apoptosis in a concentration-dependent manner. The protective effects of AA and PGE(2) were also observed in primary mouse islets. CONCLUSION: These data show that AA and its COX2-generated metabolite, PGE(2), can protect beta-cells from apoptosis.     

Approaches to the study of higher cognitive functions related to creativity in nonhuman animals

Fundamental to creativity is prior knowledge and learning capability. One can be creative only to the extent that one's prior knowledge and learning abilities enable. Many of the mental functions of humans that are affected by neuropathology involve levels of learning ability that supercede those used by most animal researchers. Yet there is literature showing that there are similarities in structure and function in the cerebrum within class Mammalia and that nonhuman animals are capable of higher levels of learning than those typically studied by neuroscientists. Reviews of abstracts from the 2005 meeting of the Society for Neuroscience reveal that most neurobehavioral research with animals has involved relatively low levels of learning ability. Thomas's [R.K. Thomas, Brain, Behav. Evol. 17 (1980) 452-474.] hierarchy of learning abilities has been revised here to better include Learning Set Formation which is fundamental to most forms of higher learning. This paper summarizes both the rationale and the methodologies that might be used to assess the roles of neuroanatomical structures involved in the psychological processes that serve as the bases of creativity.