Lantibiotic Immunity: Inhibition of Nisin Mediated Pore Formation by NisI

Nisin, a 3.4 kDa antimicrobial peptide produced by some Lactococcus lactis strains is the most prominent member of the lantibiotic family. Nisin can inhibit cell growth and penetrates the target Gram-positive bacterial membrane by binding to Lipid II, an essential cell wall synthesis precursor. The assembled nisin-Lipid II complex forms pores in the target membrane. To gain immunity against its own-produced nisin, Lactococcus lactis is expressing two immunity protein systems, NisI and NisFEG. Here, we show that the NisI expressing strain displays an IC₅₀ of 73±10 nM, an 8–10-fold increase when compared to the non-expressing sensitive strain. When the nisin concentration is raised above 70 nM, the cells expressing full-length NisI stop growing rather than being killed. NisI is inhibiting nisin mediated pore formation, even at nisin concentrations up to 1 µM. This effect is induced by the C-terminus of NisI that protects Lipid II. Its deletion showed pore formation again. The expression of NisI in combination with externally added nisin mediates an elongation of the chain length of the Lactococcus lactis cocci. While the sensitive strain cell-chains consist mainly of two cells, the NisI expressing cells display a length of up to 20 cells. Both results shed light on the immunity of lantibiotic producer strains, and their survival in high levels of their own lantibiotic in the habitat.     

Exploring mechanisms of multiple insecticide resistance in a population of the malaria vector Anopheles funestus in Benin

Background

The insecticide resistance status of the malaria vector Anopheles funestus and the underlying resistance mechanisms remain uncharacterised in many parts of Africa, notably in Benin, West Africa. To fill this gap in our knowledge, we assessed the susceptibility status of a population of this species in Pahou, Southern Benin and investigated the potential resistance mechanisms.

Methodology/Principal Findings

WHO bioassays revealed a multiple resistance profile for An. funestus in Pahou. This population is highly resistant to DDT with no mortality in females after 1h exposure to 4%DDT. Resistance was observed against the Type I pyrethroid permethrin and the carbamate bendiocarb. A moderate resistance was detected against deltamethrin (type II pyrethroids). A total susceptibility was observed against malathion, an organophosphate. Pre-exposure to PBO did not change the mortality rates for DDT indicating that cytochrome P450s play no role in DDT resistance in Pahou. No L1014F kdr mutation was detected but a correlation between haplotypes of two fragments of the Voltage-Gated Sodium Channel gene and resistance was observed suggesting that mutations in other exons may confer the knockdown resistance in this species. Biochemical assays revealed elevated levels of GSTs and cytochrome mono-oxygenases in Pahou. No G119S mutation and no altered acetylcholinesterase gene were detected in the Pahou population. qPCR analysis of five detoxification genes revealed that the GSTe2 is associated to the DDT resistance in this population with a significantly higher expression in DDT resistant samples. A significant over-expression of CYP6P9a and CYP6P9b previously associated with pyrethroid resistance was also seen but at a lower fold change than in southern Africa.

Conclusion

The multiple insecticide resistance profile of this An. funestus population in Benin shows that more attention should be paid to this important malaria vector for the implementation and management of current and future malaria vector control programs in this country.     

Central and peripheral venous lines-associated blood stream infections in the critically ill surgical patients

ABSTRACT: Critically ill surgical patients are always at increased risk of actual or potentially life-threatening health complications. Central/peripheral venous lines form a key part of their care. We review the current evidence on incidence of central and peripheral venous catheter-related bloodstream infections in critically ill surgical patients, and outline pathways for prevention and intervention. An extensive systematic electronic search was carried out on the relevant databases. Articles were considered suitable for inclusion if they investigated catheter colonisation and catheter-related bloodstream infection. Two independent reviewers were engaged in selecting appropriate articles in line with the above protocol. Our search protocol retrieved 8 articles published from 1999 to 2011. Outcomes on CVC colonisation and infections were investigated in six studies; four of which were prospective cohort studies, one prospective longitudinal study and one retrospective cohort study. Outcomes relating only to PICCs were reported in one prospective randomised trial. We identified only one study that compared CVC- and PICC-related complications in surgical intensive care units. Although our search protocol may not have yielded an exhaustive list we have identified a key deficiency in the literature, namely a paucity of studies investigating the incidence of CVC- and PICC-related bloodstream infection in exclusively critically ill surgical populations. In summary, the diverse definitions for the diagnosis of central and peripheral venous catheter-related bloodstream infections along with the vastly different sample size and extremely small PICC population size has, predictably, yielded inconsistent findings. Our current understanding is still limited; the studies we have identified do point us towards some tentative understanding that the CVC/PICC performance remains inconclusive.     

The Functional Connectivity Landscape of the Human Brain

Functional brain networks emerge and dissipate over a primarily static anatomical foundation. The dynamic basis of these networks is inter-regional communication involving local and distal regions. It is assumed that inter-regional distances play a pivotal role in modulating network dynamics. Using three different neuroimaging modalities, 6 datasets were evaluated to determine whether experimental manipulations asymmetrically affect functional relationships based on the distance between brain regions in human participants. Contrary to previous assumptions, here we show that short- and long-range connections are equally likely to strengthen or weaken in response to task demands. Additionally, connections between homotopic areas are the most stable and less likely to change compared to any other type of connection. Our results point to a functional connectivity landscape characterized by fluid transitions between local specialization and global integration. This ability to mediate functional properties irrespective of spatial distance may engender a diverse repertoire of cognitive processes when faced with a dynamic environment.     

Assessment of initiation of breastfeeding practice in Kassala,Eastern Sudan: a community-based study

Background

The World Health Organization (WHO) encourages early initiation of breastfeeding within the first hour after birth with the objective of saving children’s lives. There are few published research papers about factors associated with the initiation of breastfeeding in Sudan.The aim of this study was to investigate the prevalence of and factors associated with the timely initiation of breastfeeding among mothers with children two years and under in Kassala, Eastern Sudan.

Methods

A community-based cross-sectional study was conducted from December 2016 to March 2017. Mothers were interviewed using a structured questionnaire.

Results

A total of 250 mother-child pairs participated in the study. The mean (standard deviation) of maternal age and children’s age was 27.1 (5.68) years and 11.9 (6.9) months, respectively.Of the 250 mothers, 218 (87.2%) initiated breastfeeding within the first hour. In multivariable logistic regression analysis, factors associated with the delay of breastfeeding initiation were having a male baby (Adjusted Odds Ratio [AOR] 3.90, 95% Confidence Interval [CI]1.33, 11.47), and mothers with medical disorders (AOR 5.07, 95% CI 1.22, 21.16).

Conclusion

There was a high prevalence of early initiation of breastfeeding. An association with delayed initiation of breastfeeding was found amongst mothers who had medical disorders and those who had a male infant. Wherever possible, early initiation of breastfeeding should be promoted for all infants, regardless of gender.

     

Characterization of a highly selective inhibitor of the Aurora kinases

Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity.     

Mechanism of nicotinic acid transport in human liver cells: experiments with HepG2 cells and primary hepatocytes

This study reports on the functional expression of a specific, high-affinity carrier-mediated mechanism for the transport of niacin (nicotinic acid) in human liver cells. Both human-derived liver HepG2 cells and human primary hepatocytes were used as models in these investigations. The initial rate of transport of nicotinic acid into HepG2 cells was found to be acidic pH, temperature, and energy dependent; it was, however, Na(+) independent in nature. Evidence for the existence of a carrier-mediated system that is specific for [(3)H]nicotinic acid transport was found and included the following: 1) saturability as a function of concentration with an apparent K(m) of 0.73 +/- 0.16 microM and V(max) of 25.02 +/- 1.45 pmol.mg protein(-1).3 min(-1), 2) cis-inhibition by unlabeled nicotinic acid and nicotinamide but not by unrelated organic anions (lactate, acetate, butyrate, succinate, citrate, and valproate), and 3) trans-stimulation of [(3)H]nicotinic acid efflux by unlabeled nicotinic acid. Transport of the vitamin into human primary hepatocytes occurs similarly via an acidic pH-dependent and specific carrier-mediated process. Inhibitors of the Ca(2+)-calmodulin-mediated pathway (but not modulators of the PKC-, PKA-, and protein tyrosine kinase-mediated pathways) inhibited nicotinic acid transport into both HepG2 cells and human primary hepatocytes. Maintenance of HepG2 cells (for 48 h) in growth medium oversupplemented with nicotinic acid (or nicotinamide) did not affect the subsequent transport of [(3)H]nicotinic acid into HepG2 cells. These results show, for the first time, the existence of a specific and regulated membrane carrier-mediated system for nicotinic acid transport in human liver cells.     

Enhanced Degradation of Petroleum Hydrocarbons in Corn-Steep-Liquor-Treated Soil Microcosm

The efficiency of corn steep liquor (CSL) as a potential stimulant for remediation of hydrocarbon-contaminated soil was evaluated in soil microcosms. Chronically polluted soil samples treated with CSL, water, and un untreated control were compared over a period of 42 days. There were remarkable changes in the physicochemical status of the soil in the CSL-treated set-up with noticeable utilization of essential nutrients such as nitrogen, phosphorus, and potassium. Percentage hydrocarbon utilizers showed a concomitant increase with hydrocarbon utilization in CSL-treated (0.05–0.16%) and water-treated (0.02–0.12%) set-ups, while no significant changes occurred in the untreated control. Gas chromatographic fingerprints showed complete disappearance of the lower-fraction alkanes C₇, C₈, C₉, and C₁₁ within 21 days, as well as some higher fractions, significantly C₁₆ and C₂₉, in the CSL-treated set-up. In the CSL-treated set-up, 77.9% of hydrocarbon was degraded, while the corresponding values for the water-treated and untreated control were 40.55 and 30.6%, respectively. The percentage aliphatic components degraded differed significantly in the CSL-treated, water-treated, and untreated set-ups. The n-C₁₇/pristane and n-C₁₈/phytane ratios in the CSL-treated set-up were 1.298 and 1.153, respectively, on day 0, but at the end of the treatability period, the values had dropped drastically to 0.182 and 0.585, respectively. The results of this study show that corn steep liquor is a potential material for bioremediation of hydrocarbon-polluted sites.