Otto G. Berg

Bio: Otto G. Berg is an academic researcher from Science for Life Laboratory. The author has contributed to research in topics: Population & Gene. The author has an hindex of 50, co-authored 105 publications receiving 10569 citations. Previous affiliations of Otto G. Berg include Uppsala University & Royal Institute of Technology.

Selection of resistant bacteria at very low antibiotic concentrations.

Abstract: The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.

Diffusion-Driven Mechanisms of Protein Translocation on Nucleic Acids. 1. Models and Theory?

Abstract: Genome regulatory proteins (e.g., repressors or polymerases) that function by binding to specific chromosomal target base pair sequences (e.g., operators or promoters) can appear to arrive at their targets at faster than diffusion-controlled rates. These proteins also exhibit appreciable affinity for nonspecific DNA, and thus this apparently facilitated binding rate must be interpreted in terms of a two-step binding mechanism. The first step involves free diffusion to any nonspecific binding site on the DNA, and the second step comprises a series of protein translocation events that are also driven by thermal fluctuations. Because of nonspecific binding, the search process in the second step is of reduced dimensionality (or volume); this results in an accelerated apparent rate of target location. In this paper we define four types of processes that may be involved in these protein translocation events between DNA sites. These are (i) "macroscopic" dissociation--reassociation processes within the domain of the DNA molecule, (ii) "microscopic" dissociation--reassociation events between closely spaced sites in the DNA molecule, (iii) "intersegment transfer" (via "ring-closure") processes between different segments of the DNA molecule, and (iv) "sliding" along the DNA molecule. We present mathematical and physical descriptions of each of these processes, and the consequences of each for the overall rate of target location are worked out as a function of both the nonspecific binding affinity between protein and DNA and the length of the DNA molecule containing the target sequence. The theory is developed in terms of the Escherichia coli lac repressor--operator interaction since data for testing these approaches are available for this system [Barkley, M. (1981) Biochemistry 20, 3833; Winter, R. B., & von Hippel, P. H. (1981) Biochemistry (second paper of three in this issue); Winter, R. B., Berg, O. G., & von Hippel, P. H. (1981) Biochemistry (third paper of three in this issue)]. However, we emphasize that this approach is general for the analysis of mechanisms of biological target location involving facilitated transfer processes via nonspecific binding to the general system of which the target forms a small part.

Diffusion-driven mechanisms of protein translocation on nucleic acids. 3. The Escherichia coli lac repressor-operator interaction: kinetic measurements and conclusions

Abstract: The association and dissociation kinetics of the Escherichia coli lac repressor--operator (RO) complex have been examined as a function of monovalent ion concentration and operator-containing DNA fragment length in order to investigate the mechanisms used by repressor in locating (and dissociating from) the operator site. Association rate constants (ka) measured with an 80- or a 203-base-pair lac operator containing DNA fragment are 3--5-fold smaller than those determined with a 6700-base-pair operator fragment or with intact lambda plac5 DNA (50000 base pairs) at all salt concentrations tested. At salt concentrations less than approximately 0.1 M KCl, association rate constants to all operator-containing DNA fragments (except lambda plac5 DNA) are insensitive to variations in salt concentration, but the limiting low salt value of ka appears to depend upon operator-containing DNA length. The value of ka for lambda plac5 DNA decreases significantly from the approximately 0.1 M KCl maximum at low salt. Above approximately 0.1 M KCl, repressor--operator association rate constants for all operator-containing DNA substrates tested show a similar decrease with increasing salt concentration, which does not appear to depend upon the length of the DNA molecule (except for the very small DNA fragments). In contrast to the association reaction, kd, the dissociation rate constant, decreases linearly (on a log kd vs. log [KCl] plot) with decreasing salt concentration over virtually the entire salt concentration range studied (0.05--0.2 M KCl). These results are consistent with the explanation of the unusually fast association kinetics for this system in terms of a two-step model in which repressor initially diffuses to a nonoperator DNA binding site (forming an RD complex) and then rapidly "scans" (in a locally correlated fashion) adjacent sites until the operator is located or the repressor dissociates from the chain. Dissociation of the RO complex follows the same two-step process in reverse. Quantitative comparisons are made between these results and the theoretical predictions of the two facilitating translocation mechanisms (one-dimensional "sliding" along the DNA double helix and direct transfer between DNA segments) developed in the first paper of this series [Berg, O. G., Winter, R. B., & von Hippel, P. H. (1981) Biochemistry (first paper of three in this issue)]. We conclude that the experimental data for the "faster-than-diffusion-controlled" interaction of repressor and operator can be quantitatively modeled by a two-step process in which sliding is the dominant transfer mechanism. Molecular models of the initial nonspecific binding event (including "hopping") as well as sliding and interchain transfer are discussed, and the possible roles of facilitated translocation mechanisms of the diffusion-driven type in this and other in vitro and in vivo protein--nucleic acid interaction processes are considered.

Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance.

Abstract: Most types of antibiotic resistance impose a biological cost on bacterial fitness. These costs can be compensated, usually without loss of resistance, by second-site mutations during the evolution of the resistant bacteria in an experimental host or in a laboratory medium. Different fitness-compensating mutations were selected depending on whether the bacteria evolved through serial passage in mice or in a laboratory medium. This difference in mutation spectra was caused by either a growth condition-specific formation or selection of the compensated mutants. These results suggest that bacterial evolution to reduce the costs of antibiotic resistance can take different trajectories within and outside a host.

Stochastic focusing: fluctuation-enhanced sensitivity of intracellular regulation.

Abstract: Many regulatory molecules are present in low copy numbers per cell so that significant random fluctuations emerge spontaneously. Because cell viability depends on precise regulation of key events, such signal noise has been thought to impose a threat that cells must carefully eliminate. However, the precision of control is also greatly affected by the regulatory mechanisms' capacity for sensitivity amplification. Here we show that even if signal noise reduces the capacity for sensitivity amplification of threshold mechanisms, the effect on realistic regulatory kinetics can be the opposite: stochastic focusing (SF). SF particularly exploits tails of probability distributions and can be formulated as conventional multistep sensitivity amplification where signal noise provides the degrees of freedom. When signal fluctuations are sufficiently rapid, effects of time correlations in signal-dependent rates are negligible and SF works just like conventional sensitivity amplification. This means that, quite counterintuitively, signal noise can reduce the uncertainty in regulated processes. SF is exemplified by standard hyperbolic inhibition, and all probability distributions for signal noise are first derived from underlying chemical master equations. The negative binomial is suggested as a paradigmatic distribution for intracellular kinetics, applicable to stochastic gene expression as well as simple systems with Michaelis–Menten degradation or positive feedback. SF resembles stochastic resonance in that noise facilitates signal detection in nonlinear systems, but stochastic resonance is related to how noise in threshold systems allows for detection of subthreshold signals and SF describes how fluctuations can make a gradual response mechanism work more like a threshold mechanism.

Stochastic Processes in Physics and Chemistry

Abstract: N G van Kampen 1981 Amsterdam: North-Holland xiv + 419 pp price Dfl 180 This is a book which, at a lower price, could be expected to become an essential part of the library of every physical scientist concerned with problems involving fluctuations and stochastic processes, as well as those who just enjoy a beautifully written book. It provides an extensive graduate-level introduction which is clear, cautious, interesting and readable.

Stochasticity in gene expression: from theories to phenotypes

Abstract: Genetically identical cells exposed to the same environmental conditions can show significant variation in molecular content and marked differences in phenotypic characteristics. This variability is linked to stochasticity in gene expression, which is generally viewed as having detrimental effects on cellular function with potential implications for disease. However, stochasticity in gene expression can also be advantageous. It can provide the flexibility needed by cells to adapt to fluctuating environments or respond to sudden stresses, and a mechanism by which population heterogeneity can be established during cellular differentiation and development.

The restaurant at the end of the random walk: recent developments in the description of anomalous transport by fractional dynamics

Abstract: Fractional dynamics has experienced a firm upswing during the past few years, having been forged into a mature framework in the theory of stochastic processes. A large number of research papers developing fractional dynamics further, or applying it to various systems have appeared since our first review article on the fractional Fokker–Planck equation (Metzler R and Klafter J 2000a, Phys. Rep. 339 1–77). It therefore appears timely to put these new works in a cohesive perspective. In this review we cover both the theoretical modelling of sub- and superdiffusive processes, placing emphasis on superdiffusion, and the discussion of applications such as the correct formulation of boundary value problems to obtain the first passage time density function. We also discuss extensively the occurrence of anomalous dynamics in various fields ranging from nanoscale over biological to geophysical and environmental systems.

Antibiotic resistance and its cost: is it possible to reverse resistance?

Abstract: Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.