Mycobacterial Metabolic Syndrome: LprG and Rv1410 Regulate Triacylglyceride Levels,Growth Rate and Virulence in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) mutants lacking rv1411c, which encodes the lipoprotein LprG, and rv1410c, which encodes a putative efflux pump, are dramatically attenuated for growth in mice. Here we show that loss of LprG-Rv1410 in Mtb leads to intracellular triacylglyceride (TAG) accumulation, and overexpression of the locus increases the levels of TAG in the culture medium, demonstrating a role of this locus in TAG transport. LprG binds TAG within a large hydrophobic cleft and is sufficient to transfer TAG from donor to acceptor membranes. Further, LprG-Rv1410 is critical for broadly regulating bacterial growth and metabolism in vitro during carbon restriction and in vivo during infection of mice. The growth defect in mice is due to disrupted bacterial metabolism and occurs independently of key immune regulators. The in vivo essentiality of this locus suggests that this export system and other regulators of metabolism should be considered as targets for novel therapeutics.     

Natural Selection and Spatial Cognition in Wild Food-Caching Mountain Chickadees

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Production of autoantibodies against citrullinated antigens/peptides by human B cells

Autoantibodies against citrullinated protein Ags (ACPA) are associated with the development of rheumatoid arthritis (RA). This immune response against citrullinated protein Ags, which is thought to be facilitated by certain MHC HLA-DR alleles, is highly specific for this disease and has been speculated to be involved in the pathogenesis. We have previously studied cultures of B cells for the production of Abs against HLA Ags. The aim of the current study was to examine the role of B cells in the production of ACPA in patients with RA. Peripheral blood B cells from RA patients and healthy people were cultured with EL4-B5, a murine cell line expressing human CD40L, and with T cell factors to stimulate the in vitro production of Abs by B cells isolated from peripheral blood. ACPA were produced by cultured B cells from RA patients, as determined by reactivity to cyclic citrullinated peptide (CCP). The results showed that 22% of the healthy persons tested also had B cells that could produce ACPA. Patients with HLA-DR alleles carrying the RA-associated shared epitope appeared to have more B cells with autoimmune potential for CCP than those without such HLA alleles (odds ratio 8.1, p = 0.001). In healthy individuals, anti-CCP-producing B cells were also observed more frequently if the RA-associated MHC genes were present (odds ratio 8.0, p = 0.01). Analysis of B cells in cultures may shed light on the interaction of genetic and environmental factors in the development of RA.     

Mycobacterium tuberculosis SigM positively regulates Esx secreted protein and nonribosomal peptide synthetase genes and down regulates virulence-associated surface lipid synthesis

The Mycobacterium tuberculosis genome encodes 12 alternative sigma factors, several of which regulate stress responses and are required for virulence in animal models of acute infection. In this work we investigated M. tuberculosis SigM, a member of the extracytoplasmic function subfamily of alternative sigma factors. This sigma factor is expressed at low levels in vitro and does not appear to function in stress response regulation. Instead, SigM positively regulates genes required for the synthesis of surface or secreted molecules. Among these are genes encoding two pairs of Esx secreted proteins, a multisubunit nonribosomal peptide synthetase operon, and genes encoding two members of the proline-proline-glutamate (PPE) family of proteins. Genes up regulated in a sigM mutant strain include a different PPE gene, as well as several genes involved in surface lipid synthesis. Among these are genes involved in synthesis of phthiocerol dimycocerosate (PDIM), a surface lipid critical for virulence during acute infection, and the kasA-kasB operon, which is required for mycolic acid synthesis. Analysis of surface lipids showed that PDIM synthesis is increased in a sigM-disrupted strain and is undetectable in a sigM overexpression strain. These findings demonstrate that SigM positively and negatively regulates cell surface and secreted molecules that are likely to function in host-pathogen interactions.     

Complex effects of the gastropod Assiminea globulus on benthic community structure in a marine-dominated lagoon

Grazing is a key factor structuring aquatic communities, and can have both positive and negative effects. Here, we report on the effects of an intertidal estuarine gastropod, Assiminea globulus, on sediment bacteria, microphytobenthos and meiofauna, based on field observations and manipulative experiments. Field observations showed inconsistent patterns of chlorophyll-a concentrations in zones occupied by A. globulus relative to zones lacking this species, and meiofaunal density increased downshore. Bacterial density, however, was always consistently and significantly elevated in zones of A. globulus across all sites sampled, suggesting promotion of bacterial density by this snail. Field experiments were more conclusive, showing a significant negative effect of A. globulus on sediment chlorophyll-a levels at both the surface and at a sediment depth of 2 cm, but positive effects on bacterial density at both depths. A. globulus density did not affect overall meiofaunal density, but did affect meiofaunal community structure, generally by depressing the density of harpacticoid copepods but promoting platyhelminthes, and enhancing taxonomic diversity at high density. The complex effects of A. globulus probably reflect the interactive effects of bioturbation, fertilisation, grazing and pelletisation, all of which need to be considered when understanding grazer effects on soft-sediment communities.     

Dissociable Neural Systems for Timing: Evidence from Subjects with Basal Ganglia Lesions

Background

The neural basis of timing remains poorly understood. Although controversy persists, many lines of evidence, including studies in animals, functional imaging studies in humans and lesion studies in humans and animals suggest that the basal ganglia are important for temporal processing [1].

Methodology/Principal Findings

We report data from a wide range of timing tasks from two subjects with disabling neurologic deficits caused by bilateral lesions of the basal ganglia. Both subjects perform well on tasks assessing time estimation, reproduction and production tasks. Additionally, one subject performed normally on psychophysical tasks requiring the comparison of time intervals ranging from milliseconds to seconds; the second subject performed abnormally on the psychophysical task with a 300ms standard but did well with 600ms, 2000ms and 8000ms standards. Both subjects performed poorly on an isochronous rhythm production task on which they are required to maintain rhythmic tapping.

Conclusions/Significance

As studies of subjects with brain lesions permit strong inferences regarding the necessity of brain structures, these data demonstrate that the basal ganglia are not crucial for many sub- or supra-second timing operations in humans but are needed for the timing procedures that underlie the production of movements. This dissociation suggests that distinct and dissociable processes may be employed to measure time intervals. Inconsistencies in findings regarding the neural basis of timing may reflect the availability of multiple temporal processing routines that are flexibly implemented in response to task demands.     

Molecular systematics of the African snake family Lamprophiidae Fitzinger, 1843 (Serpentes: Elapoidea), with particular focus on the genera Lamprophis Fitzinger 1843 and Mehelya Csiki 1903

The snake family Lamprophiidae Fitzinger (Serpentes: Elapoidea) is a putatively Late Eocene radiation of nocturnal snakes endemic to the African continent. It incorporates many of the most characteristic and prolific of Africa's non-venomous snake species, including the widespread type genus Lamprophis Fitzinger, 1843 (house snakes). We used approximately 2500 bases of mitochondrial and nuclear DNA sequence data from 28 (41%) of the approximately 68 recognised lamprophiid species in nine of the eleven genera to investigate phylogenetic structure in the family and to inform taxonomy at the generic level. Cytochrome b, ND4 and tRNA gene sequences (mitochondrial) and c-mos sequences (nuclear) were analysed using Maximum Likelihood, Bayesian Inference and Maximum Parsimony methods. The genus Mehelya Csiki, 1903 was paraphyletic with respect to Gonionotophis Boulenger, 1893. To address this, the concept of Gonionotophis is expanded to include all current Mehelya species. The genus Lamprophis emerged polyphyletic: the enigmatic Lamprophis swazicus was sister to Hormonotus modestus from West Africa, and not closely related to its nominal congeners. It is moved to a new monotypic genus (Inyoka gen. nov.). The remaining Lamprophis species occur in three early-diverging lineages. (1) Lamprophis virgatus and the widely distributed Lamprophis fuliginosus species complex (which also includes Lamprophis lineatus and Lamprophis olivaceus) formed a clade for which the generic name Boaedon Duméril, Bibron & Duméril, 1854 is resurrected. (2) The water snakes (Lycodonomorphus) were nested within Lamprophis (sensu lato), sister to Lamprophis inornatus. We transfer this species to the genus Lycodonomorphus Fitzinger, 1843. (3) We restrict Lamprophis (sensu strictissimo) to a small clade of four species endemic to southern Africa: the type species of Lamprophis Fitzinger, 1843 (Lamprophis aurora) plus Lamprophis fiskii, Lamprophis fuscus and Lamprophis guttatus.     

Lipidomic profiling of model organisms and the world's major pathogens

Lipidomics is a subspecialty of metabolomics that focuses on water insoluble metabolites that form membrane barriers. Most lipidomic databases catalog lipids from common model organisms, like humans or Escherichia coli. However, model organisms' lipid profiles show surprisingly little overlap with those of specialized pathogens, creating the need for organism-specific lipidomic databases. Here we review rapid progress in lipidomic platform development with regard to chromatography, detection and bioinformatics. We emphasize new methods of comparative lipidomics, which use aligned datasets to identify lipids changed after introducing a biological variable. These new methods provide an unprecedented ability to broadly and quantitatively describe lipidic change during biological processes and identify changed lipids with low error rates.     

Elevation‐Related Differences in Parental Risk‐Taking Behavior are Associated with Cognitive Variation in Mountain Chickadees

Breeding animals must balance their current reproductive effort with potential costs to their own survival and consequently to future reproduction. Life‐history theory predicts that variation in reproductive investment should be based on fecundity and life expectancy with longer‐lived species favoring their own survival over parental investment. Recently, variation in parental risk taking was also linked with differences in cognition suggesting a potential trade‐off between cognitive ability and risk taking. Here, we tested whether mountain chickadees from two different elevations with known differences in cognitive ability differ in their parental risk taking by comparing the responses of nesting birds to a potential predator. Higher elevations are associated with shorter breeding season limiting renesting opportunities, but chickadees at high elevations also have better cognitive abilities, which might be potentially associated with better survival. Compared to lower elevations, high‐elevation chickadees laid larger clutches, showed longer latencies to return to the nest in the presence of a hawk, had lower fledging success, and exhibited higher rate of complete nest failures. Nestling development among successful nests, however, was similar between elevations. These data are not consistent with life‐history hypothesis because birds at high elevation invest more in the clutch, while at the same time take less risk when facing potential danger to themselves, which could jeopardize their current reproductive success. These data, however, are consistent with the hypothesis that better cognitive abilities might be associated with less parental risk taking.     

Design of peptide mimetics of HIV-1 gp120 for prevention and therapy of HIV disease.

It has been reported that the C-terminus of the second conserved region (C2) of the envelope glycoprotein gp120, encompassing peptide RSANFTDNAKTIIVQLNESVEIN (NTM), is important for infectivity and neutralization of the human immunodeficiency virus type 1 (HIV-1). It was also demonstrated that human natural anti-vasoactive intestinal peptide (VIP) antibodies reactive with this gp120 region play an important role in control of HIV disease progression. The bioinformatic analysis based on the time-frequency signal processing revealed non-obvious similarities between NTM and VIP. When tested against a battery of sera from 46 AIDS patients, these peptides, in spite of a significant difference in their primary structures, showed a similar reactivity profiles (r = 0.83). Presented results point out that similarity in the periodical pattern of some physicochemical properties in primary structures of peptides plays a significant role in determination of their immunological crossreactivity. Based on these findings, we propose this bioinformatic criterion be used for design of VIP/NTM peptide mimetics for prevention and treatment of HIV disease.