Complement driven innate immune response to malaria: fuelling severe malarial diseases

Severe malaria remains a major cause of global mortality. The innate immune response to infection is a key determinant of malaria severity and outcome. The complement system plays a key role in initiating and augmenting innate immune responses, including inflammation, endothelial activation, opsonization and coagulation, processes which have been implicated in malaria pathogenesis. In this review, we discuss the evidence supporting a role for excessive complement activation in the pathogenesis of severe malaria.     

High temperature effects on photosynthesis and water relations of grain legumes

Effects of high temperature on photosynthesis, and its interaction with water relations in common bean (Phaseolus vulgaris), cowpea (Vigna unguiculata), faba bean (Vicia faba), and five cultivars of field pea (Pisum sativum) were investigated. Responses of all species were compared at 20/15, 30/15, or 30/25 °C day/night, and cowpea and pea were compared at 20/15 and 30/25 °C under well-watered and limited-water conditions. Response of pea to 20/15 and 30/25 °C during flowering was ascertained, and sensitivity of the photosystem of pea and faba bean to 40 °C was determined.High temperature decreased chlorophyll variable fluorescence (F_v), a measure of injury to photosynthesis, in all species except cowpea, which was highly tolerant. Leaf chlorophyll and most measures of growth were favored by high day temperature but not by high night temperature, and photosynthetic rates were enhanced by high temperatures that increased leaf chlorophyll and nitrogen (N) contents. High temperature diminished growth less than water deficiency and increased water use of all three species but only lowered the water potential in faba bean. Water deficiency generally decreased growth, water use, and water potential more at 30/25 °C than at 20/15 °C. Stress from high temperature during flowering of pea decreased all components of yield at maturity, particularly at nodes that flowered latest. Whole-chain photosynthetic activity in thylakoids of pea, faba bean, and wheat (Triticum aestivum) were equally sensitive to high temperature, suggesting that Photosystem Il was the most labile component. The results show that high temperature affects photosynthesis, growth, and water relations of grain legumes, and sensitivity to the stress differs among species and genotypes.     

A nuclear factor that binds purine-rich, single-stranded oligonucleotides derived from S1-sensitive elements upstream of the CFTR gene and the MUC1 gene.

We have identified two regions of non-random purine/pyrimidine strand asymmetry that were nearly identical in sequence in the 5' flanking (promoter) regions of the human cystic fibrosis transmembrane conductance regulator (CFTR) gene and the human MUC1 gene. These regions contain perfect mirror repeat elements, a sequence motif previously found to be associated with the formation of H-DNA conformations. In this report we demonstrate that a single-stranded non-B DNA conformation exists at low pH in supercoiled plasmids containing the similar mirror repeat elements, and that S1 nuclease digestion maps the single-stranded region to the position of the mirror repeats. In addition, we identify a nuclear protein of approximately 27 kD that binds to single-stranded oligonucleotides corresponding to the purine-rich strand of this region, but not to the pyrimidine-rich strands or to double-stranded oligonucleotides with corresponding purine/pyrimidine strand asymmetry.     

The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain

1. Download : Download high-res image (337KB)
2. Download : Download full-size image

Highlights? ESCRT-I subunit UBAP1 is essential for degradation of antiviral protein tetherin ? UBAP1 has a domain consisting of a solenoid of overlapping UBAs (SOUBA) ? Each of the three UBAs in the SOUBA binds monoubiquitin     

Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food‐predictive stimuli

Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food‐predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal‐directed behaviors, including behaviors elicited by food‐predictive cues. Food‐seeking behavior is also strongly influenced by physiological state (i.e., hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood‐brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food‐predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS?). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub‐second fluctuations in NAc dopamine using fast‐scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS?, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue‐evoked mesolimbic signals that underlie food‐directed behaviors.

     

The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation

The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N-terminal 135 residues of hERG contains a previously described Per-Arnt-Sim (PAS) domain (residues 26-135) as well as an amphipathic α-helix (residues 13-23) and an initial unstructured segment (residues 2-9). Deletion of residues 2-25, only the unstructured segment (residues 2-9) or replacement of the α-helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α-helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N-terminal α-helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel.     

Detection of methanotrophs with highly divergent pmoA genes from Arctic soils

Tundra soil samples from the Canadian Arctic community, Kuujjuaq, were analyzed for the presence of the soluble (sMMO) and particulate (pMMO) methane monooxygenase genes. Total genomic DNA extracted from these soils was used as template for PCR using sMMO- and pMMO-specific primers, mmoX1-mmoX2 and A189-A682, respectively. pMMO and sMMO genes were detected in the Kuujjuaq soil samples. Isolation of sMMO-possessing methanotrophic microorganisms from the three soils, as determined by the colony naphthalene oxidation assay, was carried out using direct plating (5 degrees C) and methane enrichment studies (5 degrees C and 25 degrees C). Direct plating did not yield sMMO-possessing methanotrophic bacteria, whereas methane enrichments yielded isolates possessing and expressing sMMO activity. Analysis of derived amino acid sequences of pmoA genes and partial 16S rRNA genes obtained by PCR, using DNA isolated directly from this environment and from isolates, revealed the presence of highly divergent PmoA/AmoA sequences and 16S rRNA sequences that cluster closely with but are distinct from the genes from the genera Methylosinus and Methylocystis.     

Host cell RecA activates a mobile element-encoded mutagenic DNA polymerase

Homologs of the mutagenic Escherichia coli DNA polymerase V (pol V) are encoded by numerous pathogens and mobile elements. We have used Rum pol (RumA′₂B), from the integrative conjugative element (ICE), R391, as a model mobile element-encoded polymerase (MEPol). The highly mutagenic Rum pol is transferred horizontally into a variety of recipient cells, including many pathogens. Moving between species, it is unclear if Rum pol can function on its own or requires activation by host factors. Here, we show that Rum pol biochemical activity requires the formation of a physical mutasomal complex, Rum Mut, containing RumA′₂B-RecA-ATP, with RecA being donated by each recipient bacteria. For R391, Rum Mut specific activities in vitro and mutagenesis rates in vivo depend on the phylogenetic distance of host-cell RecA from E. coli RecA. Rum pol is a highly conserved and effective mobile catalyst of rapid evolution, with the potential to generate a broad mutational landscape that could serve to ensure bacterial adaptation in antibiotic-rich environments leading to the establishment of antibiotic resistance.