Monotone and near-monotone biochemical networks

Monotone subsystems have appealing properties as components of larger networks, since they exhibit robust dynamical stability and predictability of responses to perturbations. This suggests that natural biological systems may have evolved to be, if not monotone, at least close to monotone in the sense of being decomposable into a “small” number of monotone components, In addition, recent research has shown that much insight can be attained from decomposing networks into monotone subsystems and the analysis of the resulting interconnections using tools from control theory. This paper provides an expository introduction to monotone systems and their interconnections, describing the basic concepts and some of the main mathematical results in a largely informal fashion. Supported in part by NSF Grants DMS-0504557 and DMS-0614371.     

Three catalytic sites in mitochondrial ATPase

Kinetic data obtained after determining the hydrolytic activity of ATPase from rat liver in preparations where the enzyme had been purified, or in mitochondria, strongly suggest the existence of three different catalytic sites with different affinity for the substrate. The results obtained when measuring the ATPase activity at different substrate concentrations, and in the presence of the inhibitors KOCN or KSCN, or of the activators dinitrophenol and bicarbonate, show that the binding of these compounds to a regulatory site or sites affects in a different degree the hydrolytic activity of each catalytic site.     

Improvement of catalytic antibody activity by protease processing

An immunoglobulin L chain (HIR) was treated with lysyl-endopeptidase. Gel filtration chromatography of the digestion mix identified a peak displaying a significantly higher specific catalytic activity than that of the original sample. The protein in the peak was 11 kDa in size and constituted the VL fragment of HIR. The Km and Kcat values of Chromozym TRY hydrolysis for HIR were 1.5 x 10(-4) M and 6.2 min(-1), and for the VL fragment 7.3 x 10(-4) M and 4.8 x 10(2) min(-1), respectively. Three out of the five BJPs studied in this paper displayed elevated catalytic activity after processing with lysyl-endopeptidase. Similar results were also obtained for the complete antibody.     

A mathematical model for progression and heterogeneity in colorectal cancer dynamics

This paper deals with the development of a mathematical model that describes cancer dynamics at the cellular scale.The selected case study concerns colon and rectum cancer, which originates in colorectal crypts. Cells inside the crypts are assumed to be organized according to a compartmental-like arrangement and to be homogeneously mixing. A mathematical model for cancer progression is proposed here. This model describes the generation of multiple clonal sub-populations of cells at different progression stages in a single crypt.Asymptotic analysis and simulations are developed with an exploratory aim. The obtained results offer some insights into the role played by mutation, proliferation and differentiation phenomena on cancer dynamics. In particular, the acquisition of an additional growing power and a reduction for cellular differentiation seem more likely to be the driving force behind carcinogenesis rather than an increase in the mutation rate. The mutation rate instead seems to affect progression dynamics and intra-tumor heterogeneity. The role played by cells, at different differentiation stages, in the onset and progression of colorectal cancer is highlighted. The results support the fact that stem cells play a key role in cancer development and the idea that transit-amplifying cells could also take on an active role in carcinogenesis.     

Sam Karlin and multi-locus population genetics

Between 1967 and 1982, Sam Karlin made fundamental contributions to many areas of deterministic population genetic theory. This remembrance focuses on his work in multi-locus population genetics, primarily on the interaction between genotypic selection and the rate of recombination.     

Co-existent activity patterns in inhibitory neuronal networks with short-term synaptic depression

A network of two neurons mutually coupled through inhibitory synapses that display short-term synaptic depression is considered. We show that synaptic depression expands the number of possible activity patterns that the network can display and allows for co-existence of different patterns. Specifically, the network supports different types of n-m anti-phase firing patterns, where one neuron fires n spikes followed by the other neuron firing m spikes. When maximal synaptic conductances are identical, n-n anti-phase firing patterns are obtained and there are conductance intervals over which different pairs of these solutions co-exist. The multitude of n-m anti-phase patterns and their co-existence are not found when the synapses are non-depressing. Geometric singular perturbation methods for dynamical systems are applied to the original eight-dimensional model system to derive a set of one-dimensional conditions for the existence and co-existence of different anti-phase solutions. The generality and validity of these conditions are demonstrated through numerical simulations utilizing the Hodgkin-Huxley and Morris-Lecar neuronal models.     

Kin recognition: Competition and cooperation in Impatiens (Balsaminaceae)

The ability to recognize kin is an important element in social behavior and can lead to the evolution of altruism. Recently, it has been shown that plants are capable of kin recognition through root interactions. Here we tested for kin recognition in a North American species of Impatiens that has a high opportunity of growing with kin and responds strongly to aboveground competition. We measured how the plants responded to the aboveground light quality cues of competition and to the presence of root neighbors and determined whether the responses depended on whether the neighbors were siblings or strangers. The study families were identified by DNA sequencing as members of the same species, provisionally identified as Impatiens pallida (hereafter I. cf. pallida). We found that I. cf. pallida plants were capable of kin recognition, but only in the presence of another plant's roots. Several traits responded to relatedness in shared pots, including increased leaf to root allocation with strangers and increased stem elongation and branchiness in response to kin, potentially indicating both increased competition toward strangers and reduced interference (cooperation) toward kin. Impatiens cf. pallida responded to both competition cues simultaneously, with the responses to the aboveground competition cue dependent on the presence of the belowground competition cue.     

Naturally occurring catalytic antibodies: evidence for preferred development of the catalytic function in IgA class antibodies

IgG class antibodies express catalytic activities rarely and at very low levels. Here, we studied polyclonal IgA and IgG preparations from healthy human sera and saliva for the ability to hydrolyze model peptidyl-aminomethylcoumarin (peptide-AMC) substrates. These substrates permit objective evaluation of the catalytic potential of the antibody classes with minimal effects of noncovalent interactions occurring at sites remote from the reaction center. The IgA preparations hydrolyzed Glu-Ala-Arg-AMC at rates 3-orders of magnitude greater than IgG preparations from the same individuals. The cleavage occurred preferentially on the C terminal side of a basic residue. The activity was confirmed using monoclonal IgAs isolated from patients with multiple myeloma. Active site-directed inhibitors of serine proteases inhibited the catalytic activity and were bound irreversibly by the IgA, suggesting the involvement of a serine protease-like mechanism similar to that utilized by previously described IgM antibodies. These observations suggest that mechanisms underlying B cell clonal selection favor the retention and improvement of catalytic activity in the IgA, but not the IgG compartment of the immune response.     

Temperature and the catalytic activity of enzymes: A fresh understanding

The discovery of an additional step in the progression of an enzyme from the active to inactive state under the influence of temperature has led to a better match with experimental data for all enzymes that follow Michaelis–Menten kinetics, and to an increased understanding of the process. The new model of the process, the Equilibrium Model, describes an additional mechanism by which temperature affects the activity of enzymes, with implications for ecological, metabolic, structural, and applied studies of enzymes.     

Redundancy in ribonucleotide excision repair: Competition,compensation, and cooperation

The survival of all living organisms is determined by their ability to reproduce, which in turn depends on accurate duplication of chromosomal DNA. In order to ensure the integrity of genome duplication, DNA polymerases are equipped with stringent mechanisms by which they select and insert correctly paired nucleotides with a deoxyribose sugar ring. However, this process is never 100% accurate. To fix occasional mistakes, cells have evolved highly sophisticated and often redundant mechanisms. A good example is mismatch repair (MMR), which corrects the majority of mispaired bases and which has been extensively studied for many years. On the contrary, pathways leading to the replacement of nucleotides with an incorrect sugar that is embedded in chromosomal DNA have only recently attracted significant attention. This review describes progress made during the last few years in understanding such pathways in both prokaryotes and eukaryotes. Genetic studies in Escherichia coli and Saccharomyces cerevisiae demonstrated that MMR has the capacity to replace errant ribonucleotides, but only when the base is mispaired. In contrast, the major evolutionarily conserved ribonucleotide repair pathway initiated by the ribonuclease activity of type 2 Rnase H has broad specificity. In yeast, this pathway also requires the concerted action of Fen1 and pol δ, while in bacteria it can be successfully completed by DNA polymerase I. Besides these main players, all organisms contain alternative enzymes able to accomplish the same tasks, although with differing efficiency and fidelity. Studies in bacteria have very recently demonstrated that isolated rNMPs can be removed from genomic DNA by error-free nucleotide excision repair (NER), while studies in yeast suggest the involvement of topoisomerase 1 in alternative mutagenic ribonucleotide processing. This review summarizes the most recent progress in understanding the ribonucleotide repair mechanisms in prokaryotes and eukaryotes.     

Resident-invader dynamics and the coexistence of similar strategies

We study the resident-invader dynamics for a given class of models of unstructured populations of finite-dimensional strategies. We prove various results on the existence and uniqueness of -limit sets in the interior of the resident-invader population state space, and we classify the generically possible types of dynamics in terms of the invasion conditions when the resident and invader strategies are similar to one another.This work was supported by the Academy of Finland     

Phenol and phenolics from lignocellulosic biomass by catalytic microwave pyrolysis

Catalytic microwave pyrolysis of biomass using activated carbon was investigated to determine the effects of pyrolytic conditions on the yields of phenol and phenolics. The high concentrations of phenol (38.9%) and phenolics (66.9%) were obtained at the temperature of 589 K, catalyst-to-biomass ratio of 3:1 and retention time of 8 min. The increase of phenol and its derivatives compared to pyrolysis without catalysts has a close relationship with the decomposition of lignin under the performance of activated carbon. The concentration of esters was also increased using activated carbon as a catalyst. The high content of phenols obtained in this study can be used either directly as fuel after upgrading or as feedstock of bio-based phenols for chemical industry.     

Mixed-ligand thiosemicarbazone complexes of nickel: Synthesis, structure and catalytic activity

Reaction of thiosemicarbazones of salicylaldehyde, 2-hydroxyacetophenone and 2-hydroxynaphthaldehyde with Ni(ClO₄)₂·6H₂O, using 2,2′-bipyridine as coligand, afforded three dinuclear complexes (1a, 1b and 1c). Similar reactions using 2,2′:6′2″-terpyridine as coligand yielded three mononuclear complexes (2a, 2b and 2c). Crystal structures of 1b and 2a have been determined. In the dinuclear complexes, one nickel center is surrounded octahedrally by a dianionic O,N,S-donor thiosemicarbazone, a bipyridine and the bridging phenolate oxygen of the other thiosemicarbazone. The second nickel center adopts a square-planar geometry created by the second O,N,S-coordinated thiosemicarbazone and the bridging sulfur of the first thiosemicarbazone. In the mononuclear complexes nickel is complexed by a monoanionic O,N,S-coordinated thiosemicarbazone and a terpyridine, and the cationic species are isolated as perchlorate salts. All these six complexes are paramagnetic (μ_eff = 2.63-2.92 B.M.) and in dimethylsulfoxide solution they show intense absorptions in the visible and ultraviolet region, origin of which has been probed through DFT calculations. Cyclic voltammetry on the complexes shows one irreversible oxidation of coordinated thiosemicarbazone on the positive side of SCE, and one irreversible reduction of the coordinated polypyridine ligand on the negative side. These nickel complexes are found to be efficient catalysts for Suzuki cross-coupling reactions.     

Implication of pH in the catalytic properties of anthrax lethal factor

The anthrax lethal factor (LF) is a Zn(2+)-endopeptidase specific for mitogen-activated protein kinase kinases (MAPKKs), which are cleaved within their N-terminal region. Much line of effort was carried out to elucidate the catalytic activity of LF for designing the inhibitor and to understand the cellular mechanism of its cytotoxicity. Current assay methods to analyze the LF activity have been based on a synthetic peptide, consisting of 15-20 residues around being cleaved. However, there are accumulating reports that the region distal to cleavage site is required for the LF-mediated proteolysis of substrate. In this study, we demonstrate the catalytic properties of LF, using the full-length native substrate, MEK. We described the catalytic properties of LF focused on the effects of the pH alteration, which was encountered during the endocytosis of lethal toxin, and of the requirement for metal ions. We present the first evidence that additional metal ions are required for the LF catalyzed hydrolysis of native substrate, and that the pH alteration causes a significant change of catalytic properties of LF.     

The nature of the coupling between segmental oscillators of the lamprey spinal generator for locomotion: A mathematical model

We present a theoretical model which is used to explain the intersegmental coordination of the neural networks responsible for generating locomotion in the isolated spinal cord of lamprey.A simplified mathematical model of a limit cycle oscillator is presented which consists of only a single dependent variable, the phase (t). By coupling N such oscillators together we are able to generate stable phase locked motions which correspond to traveling waves in the spinal cord, thus simulating fictive swimming. We are also able to generate irregular drifting motions which are compared to the experimental data obtained from cords with selective surgical lesions.     

Ribozymes: the characteristics and properties of catalytic RNAs

Ribozymes, or catalytic RNAs, were discovered a little more than 15 years ago. They are found in the organelles of plants and lower eukaryotes, in amphibians, in prokaryotes, in bacteriophages, and in viroids and satellite viruses that infect plants. An example is also known of a ribozyme in hepatitis delta virus, a serious human pathogen. Additional ribozymes are bound to be found in the future, and it is tempting to regard the RNA component(s) of various ribonucleoprotein complexes as the catalytic engine, while the proteins serve as mere scaffolding--an unheard-of notion 15 years ago! In nature, ribozymes are involved in the processing of RNA precursors. However, all the characterized ribozymes have been converted, with some clever engineering, into RNA enzymes that can cleave or modify targeted RNAs (or even DNAs) without becoming altered themselves. While their success in vitro is unquestioned, ribozymes are increasingly used in vivo as valuable tools for studying and regulating gene expression. This review is intended as a brief introduction to the characteristics of the different identified ribozymes and their properties.     

Development of a supported tri-metallic catalyst and evaluation of the catalytic activity in biomass steam gasification

A supported tri-metallic catalyst (nano-Ni–La–Fe/γ-Al₂O₃) was developed for tar reduction and enhanced hydrogen production in biomass steam gasification, with focuses on preventing coke deposition and sintering effects to lengthen the lifetime of developed catalysts. The catalyst was prepared by deposition–precipitation method and characterized by various analytical approaches. Following that, the activity of catalysts in biomass steam gasification was investigated in a bench-scale combined fixed bed reactor. With presence of the catalyst, the content of hydrogen in gas products was increased to over 10 vol.%, the tar removal efficiency reached 99% at 1073 K, and more importantly the coke deposition on the catalyst surfaces and sintering effects were avoided, leading to a long lifetime of catalysts.     

A modified Zeeman model for producing HRV signals and its application to ECG signal generation

Developing a mathematical model for the artificial generation of electrocardiogram (ECG) signals is a subject that has been widely investigated. One of the challenges is to generate ECG signals with a wide range of waveforms, power spectra and variations in heart rate variability (HRV)--all of which are important indexes of human heart functions. In this paper we present a comprehensive model for generating such artificial ECG signals. We incorporate into our model the effects of respiratory sinus arrhythmia, Mayer waves and the important very low-frequency component in the power spectrum of HRV. We use a new modified Zeeman model for generating the time series for HRV, and a single cycle of ECG is produced by using a simple neural network. The importance of the work is the model's ability to produce artificial ECG signals that resemble experimental recordings under various physiological conditions. As such the model provides a useful tool to simulate and analyse the main characteristics of ECG, such as its power spectrum and HRV under different conditions. Potential applications of this model include using the generated ECG as a flexible signal source to assess the effectiveness of a diagnostic ECG signal-processing device.     

Characterization of the two catalytic domains in histone deacetylase 6

Histone deacetylase 6 (HDAC6) is the only known HDAC with two potentially functional catalytic domains, yet the role towards substrate played by these two domains remains ambiguous. Most studies report HDAC6 activities measured using either immune complexes or in vitro translated products. Here, we characterize the activity of highly purified recombinant HDAC6, mutants with active site histidine mutations in each domain (H216A and H611A), and individual catalytic domains. The deacetylase activities of these proteins, as well as their kinetic parameters, were measured using histone, alpha-tubulin, and fluorogenic acetylated lysine as substrates. Mutant H216A only slightly lowers the catalytic rate. However, mutant H611A decreases the catalytic rate more than 5000-fold. The first domain expressed alone is not catalytically active. In contrast, the second domain shows only a modest decrease in substrate binding and product formation rate. Our results indicate that the in vitro deacetylase activity of HDAC6 resides in the C-terminal second catalytic domain.