Pore-forming toxins (PFTs) are the most common class of bacterial protein toxins and constitute important bacterial virulence factors. The mode of action of PFT is starting to be better understood. ...In contrast, little is known about the cellular response to this threat. Recent studies reveal that cells do not just swell and lyse, but are able to sense and react to pore formation, mount a defense, even repair the damaged membrane and thus survive. These responses involve a variety of signal-transduction pathways and sophisticated cellular mechanisms such as the pathway regulating lipid metabolism. In this review we discuss the different classes of bacterial PFTs and their modes of action, and provide examples of how the different bacteria use PFTs. Finally, we address the more recent field dealing with the eukaryotic cell response to PFT-induced damage.
We introduce a generalization of the one-dimensional accelerated failure time model allowing the covariate effect to be any positive function of the covariate. This function and the baseline hazard ...rate are estimated nonparametrically via an iterative algorithm. In an application in non-life reserving, the survival time models the settlement delay of a claim and the covariate effect is often called operational time. The accident date of a claim serves as covariate. The estimated hazard rate is a nonparametric continuous-time alternative to chain-ladder development factors in reserving and is used to forecast outstanding liabilities. Hence, we provide an extension of the chain-ladder framework for claim numbers without the assumption of independence between settlement delay and accident date. Our proposed algorithm is an unsupervised learning approach to reserving that detects operational time in the data and adjusts for it in the estimation process. Advantages of the new estimation method are illustrated in a data set consisting of paid claims from a motor insurance business line on which we forecast the number of outstanding claims.
Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when ...parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.
ABSTRACT
With rising antibiotic resistance, alternative treatments for communicable diseases are increasingly relevant. One possible alternative for some types of infections is honey, used in wound ...care since before 2000 BCE and more recently in licensed, medical‐grade products. However, it is unclear whether medical application of honey results in the evolution of bacterial honey resistance and whether this has collateral effects on other bacterial traits such as antibiotic resistance. Here, we used single‐step screening assays and serial transfer at increasing concentrations to isolate honey‐resistant mutants of Escherichia coli. We only detected bacteria with consistently increased resistance to the honey they evolved in for two of the four tested honey products, and the observed increases were small (maximum twofold increase in IC90). Genomic sequencing and experiments with single‐gene knockouts showed a key mechanism by which bacteria increased their honey resistance was by mutating genes involved in detoxifying methylglyoxal, which contributes to the antibacterial activity of Leptospermum honeys. Crucially, we found no evidence that honey adaptation conferred cross‐resistance or collateral sensitivity against nine antibiotics from six different classes. These results reveal constraints on bacterial adaptation to different types of honey, improving our ability to predict downstream consequences of wider honey application in medicine.
Humans interact constantly with surfaces and associated microbial communities in the environment. The factors shaping the composition of these communities are poorly understood: some proposed ...explanations emphasize the influence of local habitat conditions (niche‐based explanations), while others point to geographic structure and the distance among sampled locations (dispersal‐based explanations). However, the relative roles of these different drivers for microbial community assembly on human‐associated surfaces are not clear. Here, we used a combination of sampling, sequencing (16S rRNA) and culturing to show that the composition of banknote‐associated bacterial communities varies depending on the local collection environment. Using banknotes collected from various locations and types of shops across Switzerland, we found taxonomic diversity dominated by families such as Pseudomonadaceae and Staphylococcaceae, but with banknote samples from particular types of shops (especially butcher shops) having distinct community structure. By contrast, we found no evidence of geographic structure: similarity of community composition did not decrease with increasing distance among sampled locations. These results show that microbial communities associated with banknotes, one of the most commonly encountered and exchanged human‐associated surfaces, can reflect the local environmental conditions (in this case, the type of shop), and the signal for this type of variation was stronger than that for geographic structure among the locations sampled here.
Continuous chain-ladder with paid data Bischofberger, Stephan M.; Hiabu, Munir; Isakson, Alex
Scandinavian actuarial journal,
07/2020, Letnik:
2020, Številka:
6
Journal Article
Recenzirano
Odprti dostop
We introduce a continuous-time framework for the prediction of outstanding liabilities, in which chain-ladder development factors arise as a histogram estimator of a cost-weighted hazard function ...running in reversed development time. We use this formulation to show that under our assumptions on the individual data chain-ladder is consistent. Consistency is understood in the sense that both the number of observed claims grows to infinity and the level of aggregation tends to zero. We propose alternatives to chain-ladder development factors by replacing the histogram estimator with kernel smoothers and by estimating a cost-weighted density instead of a cost-weighted hazard. Finally, we provide a real-data example and a simulation study confirming the strengths of the proposed alternatives.
Abstract
Although experiments indicate that the abiotic environment plays an important role in bacterial interactions with their parasitic viruses (bacteriophages or phages), it is not yet clear how ...exposure to compounds present in nature alters the impact of phages on bacterial growth and evolution. To address this question, we exposed Escherichia coli K12 MG1655, in combination with three lytic phages, to various substances that natural and clinical microbial populations are likely to encounter: bile salts (present in mammalian gastrointestinal tracts), sodium dodecyl sulfate (SDS, a common surfactant in cleaning and hygiene products) and four antibiotics (present at variable concentrations in natural and clinical environments). Our results show that bile salts and SDS can reduce the detrimental effect of phages on bacterial growth. In some cases these compounds completely mitigated any negative effects of phages on bacterial growth and consequently bacteria did not evolve resistance to phages in these conditions. The proportional effects of phages were unaffected by antibiotics in most combinations, excepting three cases of phage-drug synergy. These results suggest that accounting for interactions between phages and environmental factors such as surfactants and antibiotics will improve understanding of both bacterial growth and resistance evolution to phages in vivo and in nature.
Parasitism of bacteria (Escherichia coli) by viruses can be prevented by compounds present in the natural environment of this species, but antibiotics do not show the same effects.
Summary
Bacteria in nature often encounter non‐antibiotic antibacterials (NAAs), such as disinfectants and heavy metals, and they can evolve resistance via mechanisms that are also involved in ...antibiotic resistance. Understanding whether susceptibility to different types of antibacterials is non‐randomly associated across natural and clinical bacteria is therefore important for predicting the spread of resistance, yet there is no consensus about the extent of such associations or underlying mechanisms. We tested for associations between susceptibility phenotypes of 93 natural and clinical Escherichia coli isolates to various NAAs and antibiotics. Across all compound combinations, we detected a small number of non‐random associations, including a trio of positive associations among chloramphenicol, triclosan and benzalkonium chloride. We investigated genetic mechanisms that can explain such associations using genomic information, genetic knockouts and experimental evolution. This revealed some mutations that are selected for by experimental exposure to one compound and confer cross‐resistance to other compounds. Surprisingly, these interactions were asymmetric: selection for chloramphenicol resistance conferred cross‐resistance to triclosan and benzalkonium chloride, but selection for triclosan resistance did not confer cross‐resistance to other compounds. These results identify genetic changes involved in variable cross‐resistance across antibiotics and NAAs, potentially contributing to associations in natural and clinical bacteria.
A comparison of in-sample forecasting methods Bischofberger, Stephan M.; Hiabu, Munir; Mammen, Enno ...
Computational statistics & data analysis,
September 2019, 2019-09-00, Letnik:
137
Journal Article
Recenzirano
Odprti dostop
In-sample forecasting is a recent continuous modification of well-known forecasting methods based on aggregated data. These aggregated methods are known as age-cohort methods in demography, ...economics, epidemiology and sociology and as chain ladder in non-life insurance. Data is organized in a two-way table with age and cohort as indices, but without measures of exposure. It has recently been established that such structured forecasting methods based on aggregated data can be interpreted as structured histogram estimators. Continuous in-sample forecasting transfers these classical forecasting models into a modern statistical world including smoothing methodology that is more efficient than smoothing via histograms. All in-sample forecasting estimators are collected and their performance is compared via a finite sample simulation study. All methods are extended via multiplicative bias correction. Asymptotic theory is being developed for the histogram-type method of sieves and for the multiplicatively corrected estimators. The multiplicative bias corrected estimators improve all other known in-sample forecasters in the simulation study. The density projection approach seems to have the best performance with forecasting based on survival densities being the runner-up.
Design, construction and tests of the ICARUS T600 detector Amerio, S.; Amoruso, S.; Antonello, M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
07/2004, Letnik:
527, Številka:
3
Journal Article
Recenzirano
We have constructed and operated the ICARUS T600 liquid argon (LAr) time projection chamber (TPC). The ICARUS T600 detector is the largest LAr TPC ever built, with a size of about
500
tons
of fully ...imaging mass. The design and assembly of the detector relied on industrial support and represents the applications of concepts matured in laboratory tests to the kton scale.
The ICARUS T600 was commissioned for a technical run that lasted about 3 months. During this period all the detector features were extensively tested with an exposure to cosmic-rays at surface with a resulting data collection of about 30
000 events.
The detector was developed as the first element of a modular design. Thanks to the concept of modularity, it will be possible to realize a detector with several ktons active mass, to act as an observatory for astroparticle and neutrino physics at the Gran Sasso Underground Laboratory and a second-generation nucleon decay experiment.
In this paper a description of the ICARUS T600 is given, detailing its design specifications, assembly procedures and acceptance tests. Commissioning procedures and results of the technical run are also reported, as well as results from the off-line event reconstruction.
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