Instabilities in complex mixtures with a large number of components

Inside living cells are complex mixtures of thousands of components. It is hopeless to try to characterise all the individual interactions in these mixtures. Thus, we develop a statistical approach to approximating them, and examine the conditions under which the mixtures phase separate. The approach approximates the matrix of second virial coefficients of the mixture by a random matrix, and determines the stability of the mixture from the spectrum of such random matrices.Comment: 4 pages, uses RevTeX 4.

A Markov Chain based method for generating long-range dependence

This paper describes a model for generating time series which exhibit the statistical phenomenon known as long-range dependence (LRD). A Markov Modulated Process based upon an infinite Markov chain is described. The work described is motivated by applications in telecommunications where LRD is a known property of time-series measured on the internet. The process can generate a time series exhibiting LRD with known parameters and is particularly suitable for modelling internet traffic since the time series is in terms of ones and zeros which can be interpreted as data packets and inter-packet gaps. The method is extremely simple computationally and analytically and could prove more tractable than other methods described in the literatureComment: 8 pages, 2 figure

Thermodynamics of Heat Shock Response

Production of heat shock proteins are induced when a living cell is exposed to a rise in temperature. The heat shock response of protein DnaK synthesis in E.coli for temperature shifts from temperature T to T plus 7 degrees, respectively to T minus 7 degrees is measured as function of the initial temperature T. We observe a reversed heat shock at low T. The magnitude of the shock increases when one increase the distance to the temperature $T_0 \approx 23^o$, thereby mimicking the non monotous stability of proteins at low temperature. Further we found that the variation of the heat shock with T quantitatively follows the thermodynamic stability of proteins with temperature. This suggest that stability related to hot as well as cold unfolding of proteins is directly implemented in the biological control of protein folding. We demonstrate that such an implementation is possible in a minimalistic chemical network.Comment: To be published in Physical Review Letter

Non-equilibrium states of a photon cavity pumped by an atomic beam

We consider a beam of two-level randomly excited atoms that pass one-by-one through a one-mode cavity. We show that in the case of an ideal cavity, i.e. no leaking of photons from the cavity, the pumping by the beam leads to an unlimited increase in the photon number in the cavity. We derive an expression for the mean photon number for all times. Taking into account leaking of the cavity, we prove that the mean photon number in the cavity stabilizes in time. The limiting state of the cavity in this case exists and it is independent of the initial state. We calculate the characteristic functional of this non-quasi-free non-equilibrium state. We also calculate the energy flux in both the ideal and open cavity and the entropy production for the ideal cavity.Comment: Corrected energy production calculations and made some changes to ease the readin

Antisense oligonucleotide-based splicing correction in individuals with leber congenital amaurosis due to compound heterozygosity for the c.2991+1655A>G mutation in CEP290

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant

Strong negative self regulation of Prokaryotic transcription factors increases the intrinsic noise of protein expression

Background Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. Results We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Conclusions Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic models with strong repressors

Ionization Probabilities through ultra-intense Fields in the extreme Limit

We continue our investigation concerning the question of whether atomic bound states begin to stabilize in the ultra-intense field limit. The pulses considered are essentially arbitrary, but we distinguish between three situations. First the total classical momentum transfer is non-vanishing, second not both the total classical momentum transfer and the total classical displacement are vanishing together with the requirement that the potential has a finite number of bound states and third both the total classical momentum transfer and the total classical displacement are vanishing. For the first two cases we rigorously prove, that the ionization probability tends to one when the amplitude of the pulse tends to infinity and the pulse shape remains fixed. In the third case the limit is strictly smaller than one. This case is also related to the high frequency limit considered by Gavrila et al.Comment: 16 pages LateX, 2 figure

A manganese photosensitive tricarbonyl molecule [Mn(CO)3(tpa-κ(3)N)]Br enhances antibiotic efficacy in a multi-drug-resistant Escherichia coli

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ(3)N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ(3)N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ(3)N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ(3)N)]Br

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure