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Figure 6

Simulation results: invasion of a clone with higher intrinsic fitness. Changes in the densities of the bacterial populations and concentrations of the toxin (black dashed line) and resource (black dotted line). The parameter values for this simulation are: =1.0; =1.5; =0.25; =1×10; =4×10; =0.1; =5×10; =9×10; and =0.1. In these simulations, a single cell of B (grey solid line) is introduced into the populations of (black solid line) at an initial density of 10. In ()–(), the initial concentration of the toxin is 50 units per ml. () Invasion in the absence of toxin production (=0). () Failure to invade a high-density (=1000) oscillating toxin-producing population. () Failure to invade a lower density (=300) non-oscillating toxin-producing population. () Invasion in the absence of the maintenance of toxin production because of very low resource concentration (=50). In these simulations, when the density of the invading <0.5, the simulation was set equal to zero.

4. Discussion

When we set out to use chemostat cultures to estimate the rate of transformation-mediated chromosomal gene recombination in (now a tale for another report), we did not anticipate the profound oscillations in density reported here; this study is founded on a serendipitous observation. From a population dynamic perspective, these oscillations can be accounted for by the autocatalytic production of an agent, a toxin, which either directly lyses or induces autolysis in other cells of the same clone. The results of our experiments are consistent with the predictions of this model. The concentration of this toxin appears to reach its maximum shortly after the density of the oscillating population reaches its apex and these oscillations are damped when the density of the culture is low.

We have yet to characterize the toxin responsible for these oscillations or determine the physiological and molecular mechanisms by which it acts. Our results, however, indicate that this toxin is likely to be a protein of between 30 and 50 kDa. By exclusion, our experiments suggest that this toxin is novel in the sense of not being described or characterized earlier. Using strains of deleted for the genes coding for candidates for this toxin, we have excluded the following potential toxins or genetic systems involved in its production:

The densities of strains that do not produce these peptides and proteins oscillate in a manner similar to that observed in the parental strains from which they were constructed. Moreover, using catalase and a strain that does not produce hydrogen peroxide, we have also excluded this oxidizing agent as being responsible for these density oscillations.

Although density oscillations were observed for all the strains we examined, there appears to be strain differences in the densities reached in these chemostats, with the same media and flow rates, and in the amplitude and, possibly, the period of these oscillations. For two reasons, we have not explored the variation in these dynamics systematically. First, strain variation in these dynamics is secondary to the main focus of this investigation, which is the population dynamic processes responsible for these oscillations and the ecological/evolutionary reason bacteria produce the self-killing toxins generating these oscillations. Second, the frequent sampling of viable cell density (CFU data) required for a quantitatively accurate characterization of oscillations with periods of 30 hours or so is an onerous task that we cannot justify doing given the motivation for this study.

Probably, for many readers and certainly for the authors, the most intriguing questions raised by this study are the ecological role and thereby the selection pressure responsible for the evolution of this oscillation-driving toxin. Despite the fact that this phenomenon occurs with natural isolates as well as laboratory strains of , it is conceivable that density oscillations of the amplitude observed in figure 1 are an artefact of laboratory culture. In their natural habitat within the human nasopharynx, may never reach the densities where these oscillations occur. As predicted by our model ( Blue Relaxed Crop Jeans Re/Done Best Authentic t91f3fuaeZ
) and demonstrated experimentally ( Mens Cotton Pocket Square Side View by VIDA VIDA Discount Comfortable Free Shipping 2018 Pick A Best Online hm6IKHuwNd
), oscillations in density of the amplitude observed in figure 1 are not anticipated in environments that can only support low-density populations. However, whether these oscillations are an artefact of culture conditions or not still remains necessary to account for why, evolutionarily, produce this and the other toxins that kill genetically identical bacteria.

If the killing of genetically identical members of the same population were the sole function of the toxin, the capacity to produce it or respond to its action would not be favoured by natural selection. If, however, the agent responsible for this killing provides a survival or growth advantage to the producing clone in its natural habitat, its production could be favoured by selection even if some or even many cells of the producing clone are killed. In Mens Silk Pocket Square Bleu Arachnide Square by VIDA VIDA Clearance With Credit Card niykQuo
, we briefly described three hypotheses that have been proposed to account for how the production of these suicidal agents could provide an advantage to the toxin-producing population:

Here, we propose a fourth hypothesis for the production of these clone suicidal toxins: allelopathy to prevent invasion of established populations. We find this hypothesis appealing not only because we presented it, but also because the toxin responsible for the observed oscillations kills other clones of the same species as well as closely related and thereby potentially competing species. Our theoretical analyses suggest that there are relatively broad conditions under which the production of toxins that kill bacteria of the same genotype that produce them can prevent invasion of established populations by toxin-sensitive populations that would otherwise invade because of a growth rate advantage. The necessary conditions for this to occur are that the invader is more sensitive to killing by the toxin than the resident and the concentration of the toxin in the habitat is sufficiently great for toxin-mediated killing to override the growth rate advantage of the invading population. A testable prediction of this hypothesis is that strains would be less sensitive to killing by the toxins they produce than they are to the toxins produced by other strains and species.

In this paper, we have not formally explored the other face of this allelopathy hypothesis, i.e. to facilitate the invasion of established populations of bacteria. For two reasons, we would anticipate that conditions for the invasion of a clone producing a clonal suicide toxin in mass (liquid) culture would be highly restrictive ( Statement Clutch Whimsical town by VIDA VIDA Discount Sale pDwbsrfaU
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). (i) Unlike bacteriocins, there is no evidence for immunity to this toxin by the producing clone. (ii) All of the strains and species of we have examined that are sensitive to this toxin also produce that toxin or a variant of it to which all the other strains and species are sensitive. To be sure, in physically structured habitats, where bacteria are maintained as colonies rather than planktonic cells, there are broad conditions under which bacteriocin production can facilitate invasion of established sensitive populations ( Cheap Pre Order Womens Tassel Purse Black Black New Look Discount Reliable Enjoy Online Recommend For Sale 2WddDvc
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). Whether this would also be the case for clonal suicide toxins, and how the production of these toxins would affect the population dynamics of bacteria in physically structured habitats, remains to be seen and are intriguing problems for another time.

The four hypotheses for the evolution and maintenance of self-killing toxins considered here are not mutually exclusive and, to our knowledge, none of them has been adequately tested, much less unambiguously supported experimentally. To be sure, there is good evidence that the rate of transformation-mediated recombination is greater for that produce a lysis-inducing murein hydrolase protein than for otherwise isogenic cells that do not ( Gancio embellished top handle bag Black Salvatore Ferragamo For Sale Free Shipping q0DEd2LGyT
). On the other hand, we know of no evidence that this higher rate of recombination would provide a sufficient advantage to the murein hydrolase-producing population to overcome likely fitness costs associated with synthesizing this protein and its killing isogenic cells.

Particularly intriguing from an evolutionary perspective is why pneumococcus remains susceptible to the toxins it produces. Even if the densities within natural habitats are too low for the toxin considered here to generate oscillations of the sort that motivated this study, if it is produced at all some cells would still be killed by its action. In other words, there would be continuous and, possibly, intense selection for resistance to this toxin. Nevertheless, resistance to this toxin has not been observed in chemostats maintained for three and a half months (D.E.R and O.E.C, unpublished data). Perhaps more compellingly, since clinical (wild) isolates of also oscillated in chemostats and produce the toxin, it is reasonable to assume that resistance to the toxin has not evolved even when there was plenty of time for this evolution to occur. Could it be that viable and fit mutants resistant to the toxin cannot be generated by mutation or acquired by horizontal gene transfer?

Although a largely commensal bacteria that asymptomatically colonizes many humans, is also responsible for a number of invasive infections, e.g. otitis media, bacteremias, meningitis and pneumonia. While existing antibiotics have been successful in treating invasive pneumococcus disease and resistance infrequently prevents effective chemotherapy ( Yu . 2003 ), this may not be true in the future. Anti-pneumococcus drugs with novel targets will be needed. Could the toxin responsible for the lysis reported here be developed into an effective and safe drug to treat pneumococcus infections? This would be particularly appealing if indeed viable strains of pneumococcus resistant to this toxin cannot be generated.

-acetylmuramoyl- l -alanine amidase, , which is responsible for autolysis in batch culture,

Figure 1. Efficacy of LAI against intracellular mycobacteria .

LAI, a liposome-encapsulated amikacin compound, was tested against intracellular M. avium subsp. hominissuis (MAH) and M. abscessus (Ma) in vitro . THP-1 human cells (that were first differentiated and adhered with PMA) were infected with a 10∶1 MOI of MAH strains 104 and A5, which are blood isolates (A and B, respectfully), MAH 3388, a lung isolate (C), and Ma strains 26 and 36, which are also lung isolates (D and E, respectfully) for 1 hour. Extracellular bacteria were removed and cells containing internalized bacteria were incubated at 37°C for 24 hours. Wells were either plated for CFU (day 0 control) or treated daily with HBSS (day 4 control), empty liposome, 10 µg/ml amikacin sulfate, or between 10 and 1 µg/ml of LAI for 4 days. Cells were disrupted, diluted, and plated to obtain CFUs of surviving bacteria. Bars represent means of CFU counts and error bars represent standard deviation. Statistical comparisons: 1 = p<0.05 compared to day 0 control; 2 = p<0.05 compared to day 4 control; 3 = p<0.05 compared to empty liposome; 4 = p<0.05 compared to free amikacin.


Macrophages infected with the strains Ma 36 and Ma 24 were treated with both amikacin and LAI leading to the killing of the intracellular Ma ( Panettone Spiked Metallic Suede Continental Wallet Pink Christian Louboutin Cheap Perfect Pick A Best Cheap Price TaVvR4TSQc
). LAI at 10 µg/ml was significantly more effective than free amikacin for both strains. Reductions in Ma CFUs appeared to show a linear dose dependence for LAI. Collectively, this demonstrates the effectiveness of LAI in vitro against intracellular NTM infection of macrophages.

Due to the effectiveness of LAI against intracellular mycobacteria in vitro , an established murine model was used to evaluate the efficacy of LAI for treatment of an experimental MAH respiratory infection [3] , Cheap Geniue Stockist Cheap 100% Authentic 39710934645 Womens Wallet Braun Umbra 1x10x19 cm B x H T sOliver Buy Cheap Perfect dAyO8Z
. Mice were inoculated intranasally with MAH strain 104 and infection was allowed to establish for three weeks. Three different inhaled treatment regimens of LAI were compared with inhaled saline and 100 mg/kg/day free amikacin by IP injection. The three LAI treatment groups included 76 mg/kg/day (1 hour) for 28 consecutive days, 152 mg/kg/day (2 hours) for 14 consecutive days (and then 14 days of no treatment), and 152 mg/kg/day (2 hours) every other day over 28 days. Importantly, all three groups received the same cumulative amount of LAI by the end of the 28 day period. LAI was delivered at a lower daily dose (76 mg/kg/day) compared to injected soluble amikacin (100 mg/kg/day) based on data collected throughout the treatment regimen that determined the delivered dose. After 28 days of therapy, all mice were euthanized and lungs were processed for CFU.

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