Potential Model Systems Research Articles

Research highlights for issue 6: the applicability of model system research.

Research highlights for issue 6: the applicability of model system research.

Towards an integrated understanding of gut microbiota using insects as model systems

Metazoans form symbioses with microorganisms that synthesize essential nutritional compounds and increase their efficiency to digest and absorb nutrients. Despite the growing awareness that microbes within the gut play key roles in metabolism, health and development of metazoans, symbiotic relationships within the gut are far from fully understood. Insects, which generally harbor a lower microbial diversity than vertebrates, have recently emerged as potential model systems to study these interactions. In this review, we give a brief overview of the characteristics of the gut microbiota in insects in terms of low diversity but high variability at intra- and interspecific levels and we investigate some of the ecological and methodological factors that might explain such variability. We then emphasize how studies integrating an array of techniques and disciplines have the potential to provide new understanding of the biology of this micro eco-system.

Where to from here?

It is a plain fact that we are doing research in a need-to-cure-world. When our understanding of a disease pathology is a work in progress, it is often wise to focus on specific aspects of the disorder, gain an understanding of its components that will be assembled in a conceptual framework, and proceed to a therapy based approach [1]. Thus, before envisioning a cure for addiction, let us critically analyze whether our attempts to understand this exceedingly complex phenomenon using animal model systems atleast nearly reflect the human condition. To study a given scientific hypothesis, choices of model/model organisms are essential and options can be many. The model setting is complex. Frequently, responses connected to drug/addiction do not occur equally between humans (intraspecies variability) and variation in such responses between species can be even more diverse (interspecies variability). Additionally, when addressing “addiction” we have a multifactorial setting of intricate, imperfectly understood human behavior mechanisms e.g. craving, executive control that ideally would be mimicked in animal models. Realistically, the latter may only be possible in part. Thus, there exists a plethora of real and potential model systems and experimental approaches attempting to essentially address the same questions. The following thoughts (both scientific and opinions) are largely, inspired by Dr. Andrey Ryabinin’s talk entitled “New hopes from evolutionary approaches to animal models of alcoholism and addiction” in the First International Conference and Exhibition on Addiction Research & Therapy in Las Vegas, USA (Aug 20-22, 2012).

Microbial life associated with low‐temperature alteration of ultramafic rocks in the Leka ophiolite complex

Water-rock interactions in ultramafic lithosphere generate reduced chemical species such as hydrogen that can fuel subsurface microbial communities. Sampling of this environment is expensive and technically demanding. However, highly accessible, uplifted oceanic lithospheres emplaced onto continental margins (ophiolites) are potential model systems for studies of the subsurface biosphere in ultramafic rocks. Here, we describe a microbiological investigation of partially serpentinized dunite from the Leka ophiolite (Norway). We analysed samples of mineral coatings on subsurface fracture surfaces from different depths (10-160 cm) and groundwater from a 50-m-deep borehole that penetrates several major fracture zones in the rock. The samples are suggested to represent subsurface habitats ranging from highly anaerobic to aerobic conditions. Water from a surface pond was analysed for comparison. To explore the microbial diversity and to make assessments about potential metabolisms, the samples were analysed by microscopy, construction of small subunit ribosomal RNA gene clone libraries, culturing and quantitative-PCR. Different microbial communities were observed in the groundwater, the fracture-coating material and the surface water, indicating that distinct microbial ecosystems exist in the rock. Close relatives of hydrogen-oxidizing Hydrogenophaga dominated (30% of the bacterial clones) in the oxic groundwater, indicating that microbial communities in ultramafic rocks at Leka could partially be driven by H2 produced by low-temperature water-rock reactions. Heterotrophic organisms, including close relatives of hydrocarbon degraders possibly feeding on products from Fischer-Tropsch-type reactions, dominated in the fracture-coating material. Putative hydrogen-, ammonia-, manganese- and iron-oxidizers were also detected in fracture coatings and the groundwater. The microbial communities reflect the existence of different subsurface redox conditions generated by differences in fracture size and distribution, and mixing of fluids. The particularly dense microbial communities in the shallow fracture coatings seem to be fuelled by both photosynthesis and oxidation of reduced chemical species produced by water-rock reactions.

Integrating Materials and Life Sciences Toward the Engineering of Biomimetic Materials

Research in the field of biological and biomimetic materials constitutes a case study of how traditional research boundaries are becoming increasingly obsolete. Positioned at the intersection of life and physical sciences, it is becoming more and more evident that future development in this area will require extensive interaction between materials and life scientists. To highlight this cross-talking, we provide a brief overview of the field, intended to illustrate how these disciplines can be integrated. We start with a short historical perspective, emphasizing the role of biologists in initiating early studies in the field. In the second part of the paper, a summary of important biochemical concepts and techniques relevant to biological materials is presented, with the goal of guiding nonspecialists towards the relevant techniques and knowledge required to investigate potential model systems. In the third part, we describe two case studies that emphasize the critical role of biosynthesis in understanding structure–function–property relationships in biological materials. We conclude with some remarks related to our own perception of how integration of materials and life sciences will lead to future developments in the field.

Review: Experimental models for Barrett's esophagus and esophageal adenocarcinoma

Several different cell culture systems and laboratory animal models have been used over the years to study Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Most of the existing models have key differences with the human esophagus and complex pathogenesis of disease. None of the models offers an ideal system for the complex study of environmental exposure, genetic risk, and prevention strategies. In fact, different model systems may be required to answer different specific research questions about the pathogenesis of BE and EAC. Given the high mortality associated with EAC and the fact that current screening strategies miss most cases of EAC, advances in basic and translational science related to esophageal injury, repair, and carcinogenesis are clearly needed. This review describes several of the existing and potential model systems for BE and EAC with their benefits and disadvantages.

Improving the Prediction of Response to Therapy in Autism

Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.

Not a simple case – A first comprehensive phylogenetic hypothesis for the Midas cichlid complex in Nicaragua (Teleostei: Cichlidae: Amphilophus)

Nicaraguan Midas cichlids from crater lakes have recently attracted attention as potential model systems for speciation research, but no attempt has been made to comprehensively reconstruct phylogenetic relationships of this highly diverse and recently evolved species complex. We present a first AFLP (2793 loci) and mtDNA based phylogenetic hypothesis including all described and several undescribed species from six crater lakes (Apoyeque, Apoyo, Asososca Leon, Masaya, Tiscapa and Xiloá), the two great Lakes Managua and Nicaragua and the San Juan River. Our analyses demonstrate that the relationships between the Midas cichlid members are complex, and that phylogenetic information from different markers and methods do not always yield congruent results. Nevertheless, monophyly support for crater lake assemblages from Lakes Apoyeque, Apoyo, A. Leon is high as compared to those from L. Xiloá indicating occurrence of sympatric speciation. Further, we demonstrate that a ‘three species’ concept for the Midas cichlid complex is inapplicable and consequently that an individualized and voucher based approach in speciation research of the Midas cichlid complex is necessary at least as long as there is no comprehensive revision of the species complex available.

Time-Resolved EPR Investigation of Potential Model Systems for Acrylate Polymer Main Chain Radicals Based on Esters of Kemp’s Tri-Acid

Methyl esters of Kemp's tri-acid and cyclohexanetricarboxylic acid are structurally similar to acrylate polymers, having the same functionalities and stereoregularities as poly(methylmethacrylate) and poly(methylacrylate), respectively. The photochemistry and free radicals from these model systems have been studied using time-resolved electron paramagnetic resonance spectroscopy with laser flash photolysis at 248 nm. Chemically induced electron spin polarization from the triplet mechanism (net emission) is observed. Well-resolved spectra are obtained at all temperatures for the model system radicals, which are determined to be in the slow motion condition, that is, there is no interconversion of chair conformations. The temperature dependence of the spectra is minimal; some hyperfine lines shift as the temperature increases, but without much broadening. Density functional theory calculations are presented and discussed in support of the experimental data.

2H Solid-State NMR of Ruthenium Complexes

The (2)H solid-state NMR spectra of the transition metal complexes Tp*RuD(THT)(2) (1a), Tp*RuD(D(2))(THT) (1b), Tp*RuD(D(2))(2) (1c), Cp*RuD(3)(PPh(3)) (2) and RuD(2)(eta(2)-D(2))(2)(PCy(3))(2) (3) have been measured in a wide temperature range. These compounds were chosen as potential model systems for hydrogen surface species in Ru-nanoparticles. The deuterium quadrupolar coupling constants Q(cc) and asymmetry parameters were extracted by (2)H NMR line-shape analysis. The Q(cc) values of the deuterons bound to the metal vary between 13 kHz and 76 kHz. In addition all spectra show that some of the deuterium is incorporated into carbon positions exhibiting quadrupolar coupling constants in the range of 134 kHz to 192 kHz. The room temperature spectra contain an additional weak very narrow line which was assigned to deuterons exhibiting a high mobility. These deuterons are attributed to crystallographic impurity and partially to D(2) molecules which lost by the complexes. The temperature where their motion is quenched and the types of these motions depend on the chemical structure. We propose to use the values of the quadrupolar coupling constants measured in order to characterize different hydrogen species on the surface of Ru-nanoparticles.

Phase and Glass Transitions in Short-Range Central Potential Model Systems: The Case of C60

Extensive molecular dynamics simulations show that a short-range central potential, suited to model C60, undergoes a high temperature transition to a glassy phase characterized by the positional disorder of the constituent particles. Crystallization, melting, and sublimation, which also take place during the simulation runs, are illustrated in detail. It turns out that vitrification and the mentioned phase transitions occur when the packing fraction of the system-defined in terms of an effective hard-core diameter-equals that of hard spheres at their own glass and melting transition, respectively. A close analogy also emerges between our findings and recent mode coupling theory calculations of structural arrest lines in a similar model of protein solutions. We argue that the conclusions of the present study might hold for a wide class of potentials currently employed to mimic interactions in complex fluids (some of which are of biological interest), suggesting how to achieve at least qualitative predictions of vitrification and crystallization in those systems.

Preface to Pachyonychia Congenita Symposium Proceedings

Preface to Pachyonychia Congenita Symposium Proceedings

Crystal Structures and Electron Micrographs of Fungal Volvatoxin A2

Membrane adhesion and insertion of protein are essential to all organisms, but the underlying mechanisms remain largely unknown. Membrane pore-forming toxins (PFTs) are potential model systems for studying these mechanisms. We have determined the crystal structures of volvatoxin A2 (VVA2), a fungal PFT from Volvariella volvacea, using Br-multiple-wavelength anomalous diffraction (MAD). The VVA2 structures obtained at pH 4.6, pH 5.5 and pH 6.5 were refined to resolutions of 1.42 A, 2.6 A and 3.2 A, respectively. The structures reveal that the VVA2 monomer contains a single alpha/beta domain. Most of the VVA2 surface is occupied by its oligomerization motif and two putative heparin-binding motifs. Residues Ala91 to Ala101 display several conformations at different pH values, which might be under the control of His87. We also found that the shape of one putative heparin-binding motif in VVA2 appears similar to those found in fibroblast growth factors, and the other one displays a linear polypeptide. Our results suggest several possible intermediates of protein assembly in solution and protein adhering to cell membranes before conformational changes. The electron micrographs of VVA2 molecules in solution, at a protein concentration of 1 microg ml(-1), show that they can assemble into filament-like or braid-like oligomers in a pH-dependent way. In addition, the arc-shaped VVA2 structure obtained at pH 6.5 suggests that VVA2 could form a two-layered helical oligomer with 18 subunits per turn. The structures presented here could be used to elucidate the pore-formation mechanisms of VVA2 and its structural neighbors, Cyt toxins from Bacillus thuringiensis.

Immortalized human keratinocytes: A model system to study the efficacy of therapeutic drugs in response to the chemical warfare agent sulfur mustard (HD)

Cytokines have been established as biomarkers to detect exposure of cells to chemical warfare agents such as sulfur mustard (2,2'-dichlorodiethyl sulfide, HD). In this study cultured normal and SV40 immortalized human epidermal keratinocyte (NHEK/IHEK) cells were compared as potential model systems to measure the efficacy of therapeutic drugs against HD. Immortalized human epidermal keratinocytes resemble their primary cell counterparts but have the advantage of being carried through long-term culture. Immortalized cells also provide consistency and durability and are less costly than primary keratinocytes. Immunoassay studies were performed to examine the response of these two cell lines to HD. We found that both normal and immortalized NHEKs secreted the pro-inflammatory mediator interleukin-8 (IL-8) when exposed to HD. However, a major difference was observed between the NHEK cell line 6207 and IHEK cell line 425. IHEK cell line 425 produced higher levels of Interleuken-8 then those of its normal counterpart cell line 6207. This observation is significant since therapeutic drugs such as ibuprofen, which depress cytokine production, may not allow these biomarkers to be detected efficiently in experimental analysis of certain NHEK cell lines. The fact that Il-8 production higher in cell line 425 cell makes this in vitro model a potential screening tool to study the efficacy of drugs that suppress production of cytokine markers.

Evolution of Cannabinoid Receptors in Vertebrates: Identification of a CB2Gene in the Puffer FishFugu rubripes

9 -tetrahydrocannabinol, the psychoactive ingredient of cannabis, exerts effects in humans by binding to the Gprotein-coupled cannabinoid receptors CB 1 and CB2, which are expressed in the nervous and immune systems, respectively. Genes encoding CB 1 receptors have also been discovered in non-mammalian vertebrates, including the puffer fish Fugu rubripes. Here the identification of aFugu gene that encodes an ortholog of mammalian CB 2 receptors is reported. This is the first CB 2 gene to be identified in a non-mammalian vertebrate, and it indicates that the gene duplication event that gave rise to CB 1 and CB2 receptors occurred before the divergence of teleosts and tetrapods. Moreover, non-mammalian vertebrate species can now be considered as potential model systems in which the physi

Apoptosis and chemoresistance in transgenic cancer models.

Multidrug resistance remains an unresolved problem in clinical oncology. Over a decade ago genes encoding cellular efflux pumps were shown to confer resistance to a broad spectrum of biochemically unrelated anticancer drugs even before the compounds reached their intracellular targets. More recently it has become apparent that many drugs induce a common apoptotic program, such that mutations in this program can also produce multidrug resistance. However, a thorough evaluation of the contribution of apoptotic defects to this "postdamage" drug resistant phenotype is technically complicated, and this has led to uncertainty about the overall significance of apoptosis in therapy-induced cell death. For example, correlative analyses using patient specimens are limited by unknown background mutations in the biopsy material, and assays using cancer cell lines can be biased by unphysiological conditions. We sought to circumvent these restrictions by utilizing a tractable transgenic cancer model to examine the impact of apoptosis on treatment outcome. Here we discuss potential caveats of cell culture based assays, highlight features of genetically engineered mice as potential model systems, and describe a tractable transgenic mouse model to study drug responses in a series of primary lymphomas with genetically defined lesions treated at their natural site.

The [Re, O 8] + potential energy surface: fourier transform ion cyclotron resonance collision induced dissociation studies and density functional calculations

As potential model systems for organometallic oxidation reaction, ions of the composition [Re, O n ] +, n = 2–6, 8, are produced using a standard laser vaporization source and examined by Fourier transform ion cyclotron resonance collision induced dissociation mass spectrometry. Energy resolved collision induced dissociation (CID) in combination with density functional theory calculations is used to characterize the species and extract thermochemical properties. For the first time in FT-ICR, relative intensity data are converted to absolute cross sections, which are used for quantitative threshold evaluation. It is shown that [Re, O 5] + and [Re, O 6] + contain at least one, and [Re, O 8] + at least two dioxygen ligands, bound with an energy of 50–90 kJ/mol. Threshold energies in combination with the theoretical results indicate that all even-numbered species [Re, O 2 m ] + consist of O 2 ligands and can thus be written as Re(O 2) m +. [Re, O 5] + is identified as ReO 3(O 2) +, the calculation yielding an end-on coordinated ligand, whereas in the Re(O 2) m + species all ligands are side-on coordinated.

ChemInform Abstract: The Synthesis of Copper(II) Complexes of 2‐((2‐Mercaptophenyl)iminomethyl)phenols by the Electrochemical Cleavage of a Disulfide Bond.

AbstractThe electrochemical cleavage of (I) leads to Schiff base ligands (II) which might act as potential model systems for low symmetry type I copper sites of copper‐bearing metalloproteins.

The potential of bacterial photosynthesis in recycling of human wastes.

(1) Potential uses of photosynthetie bacteria in the recycling of human wastes have been considered. It is concluded that systems using photosynthetic bacteria may have advantages over purely algal systems under conditions where total recycling is needed and energy is not abundant. (2) Two systems are proposed in which the metabolic potential of the photosynthetic bacteria might be realized. Both systems include an anaerobic recycling stage in which fermented wastes are converted to biomass by bacterial photosynthesis. In one system gaseous recycling is accomplished by a secondary algal reactor acting under aerobic conditions. In the other, oxygen is regenerated by electrolysis of water, and hydrogen and carbon dioxide are assimilated autotrophically under anaerobic conditions in the same bacterial photosynthesis reactor used for anaerobic recycling. (3) Advantages and disadvantages arising from the use of photosynthetic bacteria in recycling are discussed, and some potential model systems are proposed.

Potential model systems for the nitrogenase enzyme

Potential model systems for the nitrogenase enzyme