Pyrimidinone antibiotics--heterocyclic analogues with improved antibacterial spectrum

We report the synthesis and pharmacological evaluation of new derivatives of the natural dipeptide antibiotic TAN 1057 A,B containing heterocycles either in the beta-amino acid side chain or as mimics of the urea function. In the course of this program, we identified novel analogues that display activity towards a broader panel of Gram-positive bacteriae.     

Facial expressions,their communicatory functions and neuro-cognitive substrates

Human emotional expressions serve a crucial communicatory role allowing the rapid transmission of valence information from one individual to another. This paper will review the literature on the neural mechanisms necessary for this communication: both the mechanisms involved in the production of emotional expressions and those involved in the interpretation of the emotional expressions of others. Finally, reference to the neuro-psychiatric disorders of autism, psychopathy and acquired sociopathy will be made. In these conditions, the appropriate processing of emotional expressions is impaired. In autism, it is argued that the basic response to emotional expressions remains intact but that there is impaired ability to represent the referent of the individual displaying the emotion. In psychopathy, the response to fearful and sad expressions is attenuated and this interferes with socialization resulting in an individual who fails to learn to avoid actions that result in harm to others. In acquired sociopathy, the response to angry expressions in particular is attenuated resulting in reduced regulation of social behaviour.     

Sequential radiation of unrelated organisms: the gall fly Eurosta solidaginis and the tumbling flower beetle Mordellistena convicta

Host shifts and the formation of insect-host races are likely common processes in the speciation of herbivorous insects. The interactions of goldenrods Solidago (Compositae), the gall fly Eurosta solidaginis (Diptera: Tephritidae) and the beetle Mordellistena convicta (Coleoptera: Mordellidae) provide behavioural, ecological and genetic evidence of host races that may represent incipient species forming via sympatric speciation. We summarize evidence for Eurosta host races and show that M. convicta has radiated from goldenrod stems to Eurosta galls to form host-part races and, having exploited the galler's host shift, has begun to differentiate into host races within galls. Thus, host-race formation has occurred in two interacting, but unrelated organisms representing two trophic levels, resulting in 'sequential radiation' (escalation of biodiversity up the trophic system). Distributions of host races and their behavioural isolating mechanisms suggest sympatric differentiation. Such differentiation suggests host-race formation and subsequent speciation may be an important source of biodiversity.     

The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules

CARP, ankrd-2/Arpp, and DARP, are three members of a conserved gene family, referred to here as MARPs (muscle ankyrin repeat proteins). The expression of MARPs is induced upon injury and hypertrophy (CARP), stretch or denervation (ankrd2/Arpp), and during recovery following starvation (DARP), suggesting that they are involved in muscle stress response pathways. Here, we show that MARP family members contain within their ankyrin repeat region a binding site for the myofibrillar elastic protein titin. Within the myofibril, MARPs, myopalladin, and the calpain protease p94 appear to be components of a titin N2A-based signaling complex. Ultrastructural studies demonstrated that all three endogenous MARP proteins co-localize with I-band titin N2A epitopes in adult heart muscle tissues. In cultured fetal rat cardiac myocytes, passive stretch induced differential distribution patterns of CARP and DARP: staining for both proteins was increased in the nucleus and at the I-band region of myofibrils, while DARP staining also increased at intercalated discs. We speculate that the myofibrillar MARPs are regulated by stretch, and that this links titin-N2A-based myofibrillar stress/strain signals to a MARP-based regulation of muscle gene expression.     

In-field labeling of western corn rootworm adults (Coleoptera: Chrysomelidae) with rubidium

Field and laboratory studies were conducted in 2000 and 2001 to determine the feasibility of mass marking western corn rootworm adults, Diabrotica virgifera virgifera LeConte, with RbCl in the field. Results showed that application of rubidium (Rb) in solution to both the soil (1 g Rb/plant) and whorl (1 g Rb/plant) of corn plants was optimal for labeling western corn rootworm adults during larval development. Development of larvae on Rb-enriched corn with this technique did not significantly influence adult dry weight or survival. Rb was also highly mobile in the plant. Application of Rb to both the soil and the whorl resulted in median Rb concentrations in the roots (5,860 ppm) that were 150-fold greater than concentrations in untreated roots (38 ppm) 5 wk after treatment. Additionally, at least 90% of the beetles that emerged during the first 3 wk were labeled above the baseline Rb concentration (5 ppm dry weight) determined from untreated beetles. Because emergence was 72% complete at this time, a significant proportion of the population had been labeled. Results from laboratory experiments showed that labeled beetles remained distinguishable from unlabeled beetles for up to 4 d postemergence. The ability to efficiently label large numbers of beetles under field conditions and for a defined period with virtually no disruption of the population provides an unparalleled opportunity to conduct mark-recapture experiments for quantifying the short-range, intrafield movement of adult corn rootworms.     

Flagellar movement driven by proton translocation

The bacterial flagellar motor couples ion flow to rotary motion at high speed and with apparently fixed stoichiometry. The functional properties of the motor are quite well understood, but its molecular mechanism remains unknown. Recent studies of motor physiology, coupled with mutational and biochemical studies of the components, put significant constraints on the mechanism. Rotation is probably driven by conformational changes in membrane-protein complexes that form the stator. These conformational changes occur as protons move on and off a critical Asp residue in the stator protein MotB, and the resulting forces are applied to the rotor protein FliG.     

A role for the phosphorylation of hRad9 in checkpoint signaling

The integrity of the human genome is preserved by signal transduction pathways called checkpoints, which delay progression through the cell cycle when DNA damage is present. Three checkpoint proteins, hRad9, hRad1, and hHus1, form a proliferating cell nuclear antigen-like, heterotrimeric complex that has been proposed to function in the initial detection of DNA structural abnormalities. hRad9 is highly modified by phosphorylation, in a constitutive manner and in response to both DNA damage and cell cycle position. Here we present evidence that Thr292 of hRad9 is subject to Cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hRad9 phosphorylation sites (Ser277, Ser328, Ser336, and Thr355) being regulated in part by Cdc2. We also identify Ser387 as a novel site of hRad9 constitutive phosphorylation and show that phosphorylation at Ser387 is a prerequisite for one form of DNA damage-induced hyperphosphorylation of hRad9. Characterization of nonphosphorylatable mutants has revealed that hRad9 phosphorylation plays a critical role in checkpoint signaling. Overexpression of these mutants blocks the interaction between hRad9 and the DNA damage-responsive protein TopBP1 and impairs the cellular response to DNA damage during S phase.     

The role of CD154 in organ transplant rejection and acceptance

CD154 plays a critical role in determining the outcome of a transplanted organ. This simple statement is amply supported by experimental evidence demonstrating that anti-CD154 antibodies are potent inhibitors of allograft rejection in many rigorous transplant models. Unfortunately, despite intensive investigation over the past ten years, the precise mechanisms by which antibodies against CD154 exert their anti-rejection effects have remained less obvious. Though originally classified with reference to B-cell function, CD154-CD40 interactions have also been shown to be important in T cell-antigen-presenting cell interactions. Accordingly, CD154 has been classified as a T-cell co-stimulatory molecule. However, mounting data suggest that treatment with anti-CD154 antibodies does not simply block costimulatory signals, but rather that the antibodies appear to induce signalling in receptor-bearing T cells. Other data suggest that anti-CD154 effects may be mediated by endothelial cells and possibly even platelets. In fact, the current literature suggests that CD154 can either stimulate or attenuate an immune response, depending upon the model system under study. CD154 has secured a fundamental place in transplant biology and general immunology that will no doubt be the source of considerable investigation and therapeutic manipulation in the coming decade.