Feedback control architecture and the bacterial chemotaxis network.

PMCID: PMC3088647This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Bacteria move towards favourable and away from toxic environments by changing their swimming pattern. This response is regulated by the chemotaxis signalling pathway, which has an important feature: it uses feedback to 'reset' (adapt) the bacterial sensing ability, which allows the bacteria to sense a range of background environmental changes. The role of this feedback has been studied extensively in the simple chemotaxis pathway of Escherichia coli. However it has been recently found that the majority of bacteria have multiple chemotaxis homologues of the E. coli proteins, resulting in more complex pathways. In this paper we investigate the configuration and role of feedback in Rhodobacter sphaeroides, a bacterium containing multiple homologues of the chemotaxis proteins found in E. coli. Multiple proteins could produce different possible feedback configurations, each having different chemotactic performance qualities and levels of robustness to variations and uncertainties in biological parameters and to intracellular noise. We develop four models corresponding to different feedback configurations. Using a series of carefully designed experiments we discriminate between these models and invalidate three of them. When these models are examined in terms of robustness to noise and parametric uncertainties, we find that the non-invalidated model is superior to the others. Moreover, it has a 'cascade control' feedback architecture which is used extensively in engineering to improve system performance, including robustness. Given that the majority of bacteria are known to have multiple chemotaxis pathways, in this paper we show that some feedback architectures allow them to have better performance than others. In particular, cascade control may be an important feature in achieving robust functionality in more complex signalling pathways and in improving their performance

Evaluation of moderate alcohol use and cognitive function among men using a mendelian randomization design in the guangzhou biobank cohort study

Observational studies usually show that moderate alcohol use is associated with better cognitive function. Such studies are vulnerable to residual confounding arising from systematic differences between moderate alcohol users and others. A Mendelian randomization study carried out in a suitable population, such as southern Chinese men, in which alcohol use is low to moderate and is influenced by genotype, offers an alternative and superior approach for clarifying the causal effect of moderate alcohol use on cognitive function. The authors used aldehyde dehydrogenase 2 (ALDH2) genotype (AA, GA, or GG) as an instrumental variable in 2-stage least squares analysis to obtain unbiased estimates of the relation of alcohol consumption (measured in alcohol units (10 g ethanol) per day) with cognitive function, assessed from delayed 10-word recall score (n = 4,707) and Mini-Mental State Examination (MMSE) score (n = 2,284), among men from the Guangzhou Biobank Cohort Study (2003-2008). ALHD2 genotype was strongly associated with alcohol consumption, with an F statistic of 71.0 in 2-stage least squares analysis. Alcohol consumption was not associated with delayed 10-word recall score (-0.03 words per alcohol unit, 95% confidence interval:-0.18, 0.13) or MMSE score (0.06 points per alcohol unit, 95% confidence interval:-0.22, 0.34). Moderate alcohol use is unlikely to be cognitively protective. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.postprin

Estimated birth weight and adult cardiovascular risk factors in a developing southern Chinese population: a cross sectional study

Background. Birth weight is negatively associated with cardiovascular diseases and diabetes, but the associations are less well-established in developing populations where birth weight is often unavailable. We studied the association of birth weight and cardiovascular risk, using birth rank as an instrumental variable, in Southern China. Methods. We used published data on birth weight by birth rank from an appropriate population and baseline data from the Guangzhou Biobank Cohort Study phases 2 & 3 (2005-8) to examine the adjusted associations, using instrumental variable analysis, of birth weight with clinically measured cardiovascular risk factors and the metabolic syndrome in older (≥ 50 years) men (n = 5,051) and women (n = 13,907). Results. Estimated birth weight was associated with lower blood pressure (systolic -0.25 mm Hg 95% confidence interval (CI), -0.53 to 0.03 and diastolic -0.33 mm Hg 95% CI -0.48 to -0.18 per standard deviation higher birth weight), but had little association with glucose, lipids, waist-hip ratio, body mass index or the metabolic syndrome, adjusted for age, sex, early environment and number of offspring. Conclusion. Birth weight may impact blood pressure; however associations of birth weight with other cardiovascular risk factors may not be related to foetal exposures, but speculatively could be an historical co-incidence, with corresponding implications for prevention. © 2010 Schooling et al; licensee BioMed Central Ltd.published_or_final_versio

Kank Is an EB1 Interacting Protein that Localises to Muscle-Tendon Attachment Sites in Drosophila

Little is known about how microtubules are regulated in different cell types during development. EB1 plays a central role in the regulation of microtubule plus ends. It directly binds to microtubule plus ends and recruits proteins which regulate microtubule dynamics and behaviour. We report the identification of Kank, the sole Drosophila orthologue of human Kank proteins, as an EB1 interactor that predominantly localises to embryonic attachment sites between muscle and tendon cells. Human Kank1 was identified as a tumour suppressor and has documented roles in actin regulation and cell polarity in cultured mammalian cells. We found that Drosophila Kank binds EB1 directly and this interaction is essential for Kank localisation to microtubule plus ends in cultured cells. Kank protein is expressed throughout fly development and increases during embryogenesis. In late embryos, it accumulates to sites of attachment between muscle and epidermal cells. A kank deletion mutant was generated. We found that the mutant is viable and fertile without noticeable defects. Further analysis showed that Kank is dispensable for muscle function in larvae. This is in sharp contrast to C. elegans in which the Kank orthologue VAB-19 is required for development by stabilising attachment structures between muscle and epidermal cells

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Anti-HIV-1 activity of cellulose acetate phthalate: Synergy with soluble CD4 and induction of "dead-end" gp41 six-helix bundles

BACKGROUND: Cellulose acetate phthalate (CAP), a promising candidate microbicide for prevention of sexual transmission of the human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted disease (STD) pathogens, was shown to inactivate HIV-1 and to block the coreceptor binding site on the virus envelope glycoprotein gp120. It did not interfere with virus binding to CD4. Since CD4 is the primary cellular receptor for HIV-1, it was of interest to study CAP binding to HIV-1 complexes with soluble CD4 (sCD4) and its consequences, including changes in the conformation of the envelope glycoprotein gp41 within virus particles. METHODS: Enzyme-linked immunosorbent assays (ELISA) were used to study CAP binding to HIV-1-sCD4 complexes and to detect gp41 six-helix bundles accessible on virus particles using antibodies specific for the α-helical core domain of gp41. RESULTS: 1) Pretreatment of HIV-1 with sCD4 augments subsequent binding of CAP; 2) there is synergism between CAP and sCD4 for inhibition of HIV-1 infection; 3) treatment of HIV-1 with CAP induced the formation of gp41 six-helix bundles. CONCLUSIONS: CAP and sCD4 bind to distinct sites on HIV-1 IIIB and BaL virions and their simultaneous binding has profound effects on virus structure and infectivity. The formation of gp41 six-helical bundles, induced by CAP, is known to render the virus incompetent for fusion with target cells thus preventing infection

Protective CD8+ T lymphocytes in Primates Immunized with Malaria Sporozoites

Live attenuated malaria vaccines are more potent than the recombinant protein, bacterial or viral platform vaccines that have been tested, and an attenuated sporozoite vaccine against falciparum malaria is being developed for humans. In mice, attenuated malaria sporozoite vaccines induce CD8+ T cells that kill parasites developing in the liver. We were curious to know if CD8+ T cells were also important in protecting primates against malaria. We immunized 9 rhesus monkeys with radiation attenuated Plasmodium knowlesi sporozoites, and found that 5 did not develop blood stage infections after challenge with live sporozoites. We then injected 4 of these protected monkeys with cM-T807, a monoclonal antibody to the CD8 molecule which depletes T cells. The fifth monkey received equivalent doses of normal IgG. In 3 of the 4 monkeys receiving cM-T807 circulating CD8+ T cells were profoundly depleted. When re-challenged with live sporozoites all 3 of these depleted animals developed blood stage malaria. The fourth monkey receiving cM-T807 retained many circulating CD8+ T cells. This monkey, and the vaccinated monkey receiving normal IgG, did not develop blood stage malaria at re-challenge with live sporozoites. Animals were treated with antimalarial drugs and rested for 4 months. During this interval CD8+ T cells re-appeared in the circulation of the depleted monkeys. When all vaccinated animals received a third challenge with live sporozoites, all 5 monkeys were once again protected and did not develop blood stage malaria infections. These data indicate that CD8+ T cells are important effector cells protecting monkeys against malaria sporozoite infection. We believe that malaria vaccines which induce effector CD8+ T cells in humans will have the best chance of protecting against malaria

Genome wide association mapping of grain arsenic, copper, molybdenum and zinc in rice (Oryza sativa L.) grown at four international field sites

Peer reviewedPublisher PD

Strongly linked current flow in polycrystalline forms of the new superconductor MgB2

The discovery of superconductivity at 39 K in MgB2[1] raises many issues. One of the central questions is whether this new superconductor resembles a high-temperature-cuprate superconductor or a low-temperature metallic superconductor in terms of its current carrying characteristics in applied magnetic fields. In spite of the very high transition temperatures of the cuprate superconductors, their performance in magnetic fields has several drawbacks[2]. Their large anisotropy restricts high bulk current densities to much less than the full magnetic field-temperature (H-T) space over which superconductivity is found. Further, weak coupling across grain boundaries makes transport current densities in untextured polycrystalline forms low and strongly magnetic field sensitive[3,4]. These studies of MgB2 address both issues. In spite of the multi-phase, untextured, nano-scale sub-divided nature of our samples, supercurrents flow throughout without the strong sensitivity to weak magnetic fields characteristic of Josephson-coupled grains[3]. Magnetization measurements over nearly all of the superconducting H-T plane show good temperature scaling of the flux pinning force, suggestive of a current density determined by flux pinning. At least two length scales are suggested by the magnetization and magneto optical (MO) analysis but the cause of this seems to be phase inhomogeneity, porosity, and minority insulating phase such as MgO rather than by weakly coupled grain boundaries. Our results suggest that polycrystalline ceramics of this new class of superconductor will not be compromised by the weak link problems of the high temperature superconductors, a conclusion with enormous significance for applications if higher temperature analogs of this compound can be discovered