Modelling bioactivities of combinations of whole extracts of edibles with a simplified theoretical framework reveals the statistical role of molecular diversity and system complexity in their mode of action and their nearly certain safety.

Network pharmacology and polypharmacology are emerging as novel drug discovery paradigms. The many discovery, safety and regulatory issues they raise may become tractable with polypharmacological combinations of natural compounds found in whole extracts of edible and mixes thereof. The primary goal of this work is to get general insights underlying the innocuity and the emergence of beneficial and toxic activities of combinations of many compounds in general and of edibles in particular. A simplified model of compounds' interactions with an organism and of their desired and undesired effects is constructed by considering the departure from equilibrium of interconnected biological features. This model allows to compute the scaling of the probability of significant effects relative to nutritional diversity, organism complexity and synergy resulting from mixing compounds and edibles. It allows also to characterize massive indirect perturbation mode of action drugs as a potential novel multi-compound-multi-target pharmaceutical class, coined Ediceuticals when based on edibles. Their mode of action may readily target differentially organisms' system robustness as such based on differential complexity for discovering nearly certainly safe novel antimicrobials, antiviral and anti-cancer treatments. This very general model provides also a theoretical framework to several pharmaceutical and nutritional observations. In particular, it characterizes two classes of undesirable effects of drugs, and may question the interpretation of undesirable effects in healthy subjects. It also formalizes nutritional diversity as such as a novel statistical supra-chemical parameter that may contribute to guide nutritional health intervention. Finally, it is to be noted that a similar formalism may be further applicable to model whole ecosystems in general.

Increased biofilm formation by nontypeable Haemophilus influenzae isolates from patients with invasive disease or otitis media versus strains recovered from cases of respiratory infections.

Biofilm formation by nontypeable (NT) Haemophilus influenzae remains a controversial topic. Nevertheless, biofilm-like structures have been observed in the middle-ear mucosa of experimental chinchilla models of otitis media (OM). To date, there have been no studies of biofilm formation in large collections of clinical isolates. This study aimed to investigate the initial adhesion to a solid surface and biofilm formation by NT H. influenzae by comparing isolates from healthy carriers, those with noninvasive respiratory disease, and those with invasive respiratory disease. We used 352 isolates from patients with nonbacteremic community-acquired pneumonia (NB-CAP), chronic obstructive pulmonary disease (COPD), OM, and invasive disease and a group of healthy colonized children. We then determined the speed of initial adhesion to a solid surface by the BioFilm ring test and quantified biofilm formation by crystal violet staining. Isolates from different clinical sources displayed high levels of biofilm formation on a static solid support after growth for 24 h. We observed clear differences in initial attachment and biofilm formation depending on the pathology associated with NT H. influenzae isolation, with significantly increased biofilm formation for NT H. influenzae isolates collected from patients with invasive disease and OM compared with NT H. influenzae isolates from patients with NB-CAP or COPD and healthy colonized subjects. In all cases, biofilm structures were detached by proteinase K treatment, suggesting an important role for proteins in the initial adhesion and static biofilm formation measured by crystal violet staining.

High-throughput screening of metal-N-heterocyclic carbene complexes against biofilm formation by pathogenic bacteria.

A set of molecules including a majority of metal-N-heterocyclic carbene (NHC) complexes (metal=Ag, Cu, and Au) and azolium salts were evaluated by high-throughput screening of their activity against biofilm formation associated with pathogenic bacteria. The anti-planktonic effects were compared in parallel. Representative biofilm-forming strains of various genera were selected (Listeria, Pseudomonas, Staphylococcus, and Escherichia). All the compounds were tested at 1 mg L(-1) by using the BioFilm Ring Test. An information score (IS, sum of the activities) and an activity score (AS, difference between anti-biofilm and anti-planktonic activity) were determined from normalized experimental values to classify the most active molecules against the panel of bacterial strains. With this method we identified lipophilic Ag(I) and Cu(I) complexes possessing aromatic groups on the NHC ligand as the most efficient at inhibiting biofilm formation.

Solid phase DNA amplification: a simple Monte Carlo Lattice model.

Recently, a new way to amplify DNA, called solid phase amplification (SPA), has been introduced. SPA differs from the traditional polymerase chain reaction (PCR) in the use of surface-bound instead of freely-diffusing primers to amplify DNA. This limits the amplification to two-dimensional surfaces and therefore allows the easy parallelization of DNA amplification in a single system. Furthermore, SPA could provide an alternate route to DNA target implantation on DNA chips for genomic studies. Standard PCR processes are usually characterized (at least initially) by an exponential growth and a broad population distribution, and they are well described by the theory of branching processes, wherein a generating function can be used to obtain the probability distribution function for the population of offspring. This theoretical approach is not appropriate for SPA because it cannot properly take into account the many-body (steric) and geometric effects in a quenched two-dimensional environment. In this article, we propose a simple Lattice Monte Carlo technique to model SPA. We study the growth, stability, and morphology of isolated DNA colonies under various conditions. Our results indicate that, in most cases, SPA is characterized by a geometric growth and a rather sharp size distribution. Various non-ideal effects are studied, and we demonstrate that such effects do not generally change the nature of the process, except in extreme cases.