The dawn of the RNA World:toward functional complexity through ligation of random RNA oligomers

A main unsolved problem in the RNA World scenario for the origin of life is how a template-dependent RNA polymerase ribozyme emerged from short RNA oligomers obtained by random polymerization on mineral surfaces. A number of computational studies have shown that the structural repertoire yielded by that process is dominated by topologically simple structures, notably hairpin-like ones. A fraction of these could display RNA ligase activity and catalyze the assembly of larger, eventually functional RNA molecules retaining their previous modular structure: molecular complexity increases but template replication is absent. This allows us to build up a stepwise model of ligation- based, modular evolution that could pave the way to the emergence of a ribozyme with RNA replicase activity, step at which information-driven Darwinian evolution would be triggered. Copyright © 2009 RNA Society.

Reasoning Methods for Designing and Surveying Relationships Described by Sets of Functional Constraints

This work is supported by the Hungarian Scientific Research Fund (OTKA), grant T042706.

A Semantic-Oriented Architecture of a Functional Module for Personalized and Adaptive Access to the Knowledge in a Multimedia Digital Library

This article presents the principal results of the doctoral thesis “Semantic-oriented Architecture and Models for Personalized and Adaptive Access to the Knowledge in Multimedia Digital Library” by Desislava Ivanova Paneva-Marinova (Institute of Mathematics and Informatics), successfully defended before the Specialised Academic Council for Informatics and Mathematical Modelling on 27 October, 2008.

Optimum Trajectory of Dynamic Input-Output Balance Model for Open Economy

When export and import is connected with output of basic production, and criterion functional represents a final state of economy, the generalization of classical qualitative results of the main-line theory on a case of dynamic input-output balance optimization model for open economy is given.

Analysis of Dermatoglyphic Signs for Definition Psychic Functional State of Human's Organism

Relation between dermatoglyphic signs and temperaments types is considered. An algorithm for papillary patterns classification and Izenk’s two factors model are used for establishment relationship asymmetry signs with psychic functional state of human’s organism.

JSONYA/FN: Functional Computation in JSON

Functional programming has a lot to offer to the developers of global Internet-centric applications, but is often applicable only to a small part of the system or requires major architectural changes. The data model used for functional computation is often simply considered a consequence of the chosen programming style, although inappropriate choice of such model can make integration with imperative parts much harder. In this paper we do the opposite: we start from a data model based on JSON and then derive the functional approach from it. We outline the identified principles and present Jsonya/fn — a low-level functional language that is defined in and operates with the selected data model. We use several Jsonya/fn implementations and the architecture of a recently developed application to show that our approach can improve interoperability and can achieve additional reuse of representations and operations at relatively low cost. ACM Computing Classification System (1998): D.3.2, D.3.4.

Brain-derived neurotrophic factor as an indicator of chemical neurotoxicity:an animal-free CNS cell culture model

Recent changes to the legislation on chemicals and cosmetics testing call for a change in the paradigm regarding the current 'whole animal' approach for identifying chemical hazards, including the assessment of potential neurotoxins. Accordingly, since 2004, we have worked on the development of the integrated co-culture of post-mitotic, human-derived neurons and astrocytes (NT2.N/A), for use as an in vitro functional central nervous system (CNS) model. We have used it successfully to investigate indicators of neurotoxicity. For this purpose, we used NT2.N/A cells to examine the effects of acute exposure to a range of test chemicals on the cellular release of brain-derived neurotrophic factor (BDNF). It was demonstrated that the release of this protective neurotrophin into the culture medium (above that of control levels) occurred consistently in response to sub-cytotoxic levels of known neurotoxic, but not non-neurotoxic, chemicals. These increases in BDNF release were quantifiable, statistically significant, and occurred at concentrations below those at which cell death was measureable, which potentially indicates specific neurotoxicity, as opposed to general cytotoxicity. The fact that the BDNF immunoassay is non-invasive, and that NT2.N/A cells retain their functionality for a period of months, may make this system useful for repeated-dose toxicity testing, which is of particular relevance to cosmetics testing without the use of laboratory animals. In addition, the production of NT2.N/A cells without the use of animal products, such as fetal bovine serum, is being explored, to produce a fully-humanised cellular model.

Functional astrocyte-neuron lactate shuttle in a human stem cell derived neuronal network

The development of stem cell-derived neuronal networks will promote experimental system development for drug screening, toxicological testing and disease modelling, providing that they mirror closely the functional competencies of their in vivo counterparts. The NT2 cell line is one of the best documented embryocarcinoma cell lines, and can be differentiated into neurons and astrocytes. Great focus has also been placed on defining the electrophysiological properties of these cells, and more recently we have investigated the functional properties of their associated astrocytes. We now show for the first time in a human stem cell derived co-culture model that these cultures are also metabolically competent and demonstrate a functional astrocyte neuron lactate shuttle (ANLS). The ANLS hypothesis proposes that during neuronal activity, glutamate released into the synaptic cleft is taken up by astrocytes and triggers glucose uptake which is converted into lactate and released via monocarboxylate transporters for neuronal use. Using mixed cultures of NT2 derived neurons and astrocytes we have shown that these cells modulate their glucose uptake in response to glutamate, an effect that was blocked by cytochalasin B and ouabain. Additionally we demonstrate that in response to increased neuronal activity and under hypoglycaemic conditions, co-cultures modulate glycogen turnover and increase lactate production. Similar results were also shown following treatment with glutamate, potassium, Isoproterenol and dbcAMP. Together these results demonstrate for the first time a functional ANLS in a human stem cell derived co-culture.

The development of functional astrocyte-neuron networks derived from stem cells

There is currently great scientific and medical interest in the potential of tissue grown from stem cells. These cells present opportunities for generating model systems for drug screening and toxicological testing which would be expected to be more relevant to human outcomes than animal based tissue preparations. Newly realised astrocytic roles in the brain have fundamental implications within the context of stem cell derived neuronal networks. If the aim of stem cell neuroscience is to generate functional neuronal networks that behave as networks do in the brain, then it becomes clear that we must include and understand all the cellular components that comprise that network, and which are important to support synaptic integrity and cell to cell signalling. We have shown that stem cell derived neurons exhibit spontaneous and coordinated calcium elevations in clusters and in extended processes, indicating local and long distance signalling (1). Tetrodotoxin sensitive network activity could also be evoked by electrical stimulation. Similarly, astrocytes exhibit morphology and functional properties consistent with this glial cell type. Astrocytes also respond to neuronal activity and to exogenously applied neurotransmitters with calcium elevations, and in contrast to neurons, also exhibited spontaneous rhythmic calcium oscillations. Astroctyes also generate propagating calcium waves that are gap junction and purinergic signalling dependent. Our results show that stem cell derived astrocytes exhibit appropriate functionality and that stem cell neuronal networks interact with astrocytic networks in co-culture. Using mixed cultures of stem cell derived neurons and astrocytes, we have also shown both cell types also modulate their glucose uptake, glycogen turnover and lactate production in response to glutamate as well as increased neuronal activity (2). This finding is consistent with their neuron-astrocyte metabolic coupling thus demonstrating a tractable human model, which will facilitate the study of the metabolic coupling between neurons and astrocytes and its relationship with CNS functional issues ranging from plasticity to neurodegeneration. Indeed, cultures treated with oligomers of amyloid beta 1-42 (Aβ1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose (3). Both co-cultures of neurons and astrocytes and purified cultures of astrocytes showed a significant decrease in glucose uptake after treatment with 2 and 0.2 μmol/L Aβ at all time points investigated (p <0.01). In addition, a significant increase in the glycogen content of cells was also measured. Mixed neuron and astrocyte co-cultures as well as pure astrocyte cultures showed an initial decrease in glycogen levels at 6 hours compared with control at 0.2 μmol/L and 2 μmol/L P <0.01. These changes were accompanied by changes in NAD+/NADH (P<0.05), ATP (P<0.05), and glutathione levels (P<0.05), suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism. As numerous cell types interact in the brain it is important that any in vitro model developed reflects this arrangement. Our findings indicate that stem cell derived neuron and astrocyte networks can communicate, and so have the potential to interact in a tripartite manner as is seen in vivo. This study therefore lays the foundation for further development of stem cell derived neurons and astrocytes into therapeutic cell replacement and human toxicology/disease models. More recently our data provides evidence for a detrimental effect of Aβ on carbohydrate metabolism in both neurons and astrocytes. As a purely in vitro system, human stem cell models can be readily manipulated and maintained in culture for a period of months without the use of animals. In our laboratory cultures can be maintained in culture for up to 12 months months thus providing the opportunity to study the consequences of these changes over extended periods of time relevant to aspects of the disease progression time frame in vivo. In addition, their human origin provides a more realistic in vitro model as well as informing other human in vitro models such as patient-derived iPSC.

An integrated functional mapping and source localization platform for brain research

The premise of this dissertation is to create a highly integrated platform that combines the most current recording technologies for brain research through the development of new algorithms for three-dimensional (3D) functional mapping and 3D source localization. The recording modalities that were integrated include: Electroencephalography (EEG), Optical Topographic Maps (OTM), Magnetic Resonance Imaging (MRI), and Diffusion Tensor Imaging (DTI). This work can be divided into two parts: The first part involves the integration of OTM with MRI, where the topographic maps are mapped to both the skull and cortical surface of the brain. This integration process is made possible through the development of new algorithms that determine the probes location on the MRI head model and warping the 2D topographic maps onto the 3D MRI head/brain model. Dynamic changes of the brain activation can be visualized on the MRI head model through a graphical user interface. The second part of this research involves augmenting a fiber tracking system, by adding the ability to integrate the source localization results generated by commercial software named Curry. This task involved registering the EEG electrodes and the dipole results to the MRI data. Such Integration will allow the visualization of fiber tracts, along with the source of the EEG, in a 3D transparent brain structure. The research findings of this dissertation were tested and validated through the participation of patients from Miami Children Hospital (MCH). Such an integrated platform presented to the medical professionals in the form of a user-friendly graphical interface is viewed as a major contribution of this dissertation. It should be emphasized that there are two main aspects to this research endeavor: (1) if a dipole could be situated in time at its different positions, its trajectory may reveal additional information on the extent and nature of the brain malfunction; (2) situating such a dipole trajectory with respect to the fiber tracks could ensure the preservation of these fiber tracks (axons) during surgical interventions, preserving as a consequence these parts of the brain that are responsible for information transmission.

Reduced-parameter model of head-related transfer functions for synthesized spatial audio

Digital systems can generate left and right audio channels that create the effect of virtual sound source placement (spatialization) by processing an audio signal through pairs of Head-Related Transfer Functions (HRTFs) or, equivalently, Head-Related Impulse Responses (HRIRs). The spatialization effect is better when individually-measured HRTFs or HRIRs are used than when generic ones (e.g., from a mannequin) are used. However, the measurement process is not available to the majority of users. There is ongoing interest to find mechanisms to customize HRTFs or HRIRs to a specific user, in order to achieve an improved spatialization effect for that subject. Unfortunately, the current models used for HRTFs and HRIRs contain over a hundred parameters and none of those parameters can be easily related to the characteristics of the subject. This dissertation proposes an alternative model for the representation of HRTFs, which contains at most 30 parameters, all of which have a defined functional significance. It also presents methods to obtain the value of parameters in the model to make it approximately equivalent to an individually-measured HRTF. This conversion is achieved by the systematic deconstruction of HRIR sequences through an augmented version of the Hankel Total Least Squares (HTLS) decomposition approach. An average 95% match (fit) was observed between the original HRIRs and those re-constructed from the Damped and Delayed Sinusoids (DDSs) found by the decomposition process, for ipsilateral source locations. The dissertation also introduces and evaluates an HRIR customization procedure, based on a multilinear model implemented through a 3-mode tensor, for mapping of anatomical data from the subjects to the HRIR sequences at different sound source locations. This model uses the Higher-Order Singular Value Decomposition (HOSVD) method to represent the HRIRs and is capable of generating customized HRIRs from easily attainable anatomical measurements of a new intended user of the system. Listening tests were performed to compare the spatialization performance of customized, generic and individually-measured HRIRs when they are used for synthesized spatial audio. Statistical analysis of the results confirms that the type of HRIRs used for spatialization is a significant factor in the spatialization success, with the customized HRIRs yielding better results than generic HRIRs.

Spatiotemporal variation of the abundance of calcareous green macroalgae in the Florida Keys: A study of synchrony within a macroalgal functional-form group

The abundance of calcareous green algae was recorded quarterly at 28 sites within the Florida Keys National Marine Sanctuary (FKNMS) for a period of 7 years as part of a sea grass monitoring program. To evaluate the validity of using the functional-form group approach, we designed a sampling method that included the functional-form group and the component genera. This strategy enabled us to analyze the spatiotemporal patterns in the abundance of calcareous green algae as a group and to describe synchronous behavior among its genera through the application of a nonlinear regression model to both categories of data. Spatial analyses revealed that, in general, all genera displayed long-term trends of increasing abundance at most sites; however, at some sites the long-term trends for genera opposed one another. Strong synchrony in the timing of seasonal changes was found among all genera, possibly reflecting similar reproductive and seasonal growth pattern, but the variability in the magnitude of seasonal changes was very high among genera and sites. No spatial patterns were found in long-term or seasonal changes; the only significant relation detected was for slope, with sites closer to land showing higher values, suggesting that some factors associated with land proximity are affecting this increase. We conclude that the abundances of genera behaved differently from the functional-form group, indicating that the use of the functionalform group approach may be unsuitable to detect changes in sea grass community structure in the FKNMS at the existing temporal and spatial scale of the monitoring program.

A conceptual model of ecological interactions in the mangrove estuaries of the Florida Everglades

A brackish water ecotone of coastal bays and lakes, mangrove forests, salt marshes, tidal creeks, and upland hammocks separates Florida Bay, Biscayne Bay, and the Gulf of Mexico from the freshwater Everglades. The Everglades mangrove estuaries are characterized by salinity gradients that vary spatially with topography and vary seasonally and inter-annually with rainfall, tide, and freshwater flow from the Everglades. Because of their location at the lower end of the Everglades drainage basin, Everglades mangrove estuaries have been affected by upstream water management practices that have altered the freshwater heads and flows and that affect salinity gradients. Additionally, interannual variation in precipitation patterns, particularly those caused to El Nin˜o events, control freshwater inputs and salinity dynamics in these estuaries. Two major external drivers on this system are water management activities and global climate change. These drivers lead to two major ecosystem stressors: reduced freshwater flow volume and duration, and sea-level rise. Major ecological attributes include mangrove forest production, soil accretion, and resilience; coastal lake submerged aquatic vegetation; resident mangrove fish populations; wood stork (Mycteria americana) and roseate spoonbill (Platelea ajaja) nesting colonies; and estuarine crocodilian populations. Causal linkages between stressors and attributes include coastal transgression, hydroperiods, salinity gradients, and the ‘‘white zone’’ freshwater/estuarine interface. The functional estuary and its ecological attributes, as influenced by sea level and freshwater flow, must be viewed as spatially dynamic, with a possible near-term balancing of transgression but ultimately a long-term continuation of inland movement. Regardless of the spatio-temporal timing of this transgression, a salinity gradient supportive of ecologically functional Everglades mangrove estuaries will be required to maintain the integrity of the South Florida ecosystem.

Functional near infrared spectroscopy study of language, joint attention and motor skills

Near infrared spectroscopy (NIRS) is an emerging non-invasive optical neuro imaging technique that monitors the hemodynamic response to brain activation with ms-scale temporal resolution and sub-cm spatial resolution. The overall goal of my dissertation was to develop and apply NIRS towards investigation of neurological response to language, joint attention and planning and execution of motor skills in healthy adults. Language studies were performed to investigate the hemodynamic response, synchrony and dominance feature of the frontal and fronto-temporal cortex of healthy adults in response to language reception and expression. The mathematical model developed based on granger causality explicated the directional flow of information during the processing of language stimuli by the fronto-temporal cortex. Joint attention and planning/ execution of motor skill studies were performed to investigate the hemodynamic response, synchrony and dominance feature of the frontal cortex of healthy adults and in children (5-8 years old) with autism (for joint attention studies) and individuals with cerebral palsy (for planning/execution of motor skills studies). The joint attention studies on healthy adults showed differences in activation as well as intensity and phase dependent connectivity in the frontal cortex during joint attention in comparison to rest. The joint attention studies on typically developing children showed differences in frontal cortical activation in comparison to that in children with autism. The planning and execution of motor skills studies on healthy adults and individuals with cerebral palsy (CP) showed difference in the frontal cortical dominance, that is, bilateral and ipsilateral dominance, respectively. The planning and execution of motor skills studies also demonstrated the plastic and learning behavior of brain wherein correlation was found between the relative change in total hemoglobin in the frontal cortex and the kinematics of the activity performed by the participants. Thus, during my dissertation the NIRS neuroimaging technique was successfully implemented to investigate the neurological response of language, joint attention and planning and execution of motor skills in healthy adults as well as preliminarily on children with autism and individuals with cerebral palsy. These NIRS studies have long-term potential for the design of early stage interventions in children with autism and customized rehabilitation in individuals with cerebral palsy.

Trait Contributions to Fish Community Assembly Emerge From Trophic Interactions in an Individual-Based Model

Community ecology seeks to understand and predict the characteristics of communities that can develop under different environmental conditions, but most theory has been built on analytical models that are limited in the diversity of species traits that can be considered simultaneously. We address that limitation with an individual-based model to simulate assembly of fish communities characterized by life history and trophic interactions with multiple physiological tradeoffs as constraints on species performance. Simulation experiments were carried out to evaluate the distribution of 6 life history and 4 feeding traits along gradients of resource productivity and prey accessibility. These experiments revealed that traits differ greatly in importance for species sorting along the gradients. Body growth rate emerged as a key factor distinguishing community types and defining patterns of community stability and coexistence, followed by egg size and maximum body size. Dominance by fast-growing, relatively large, and fecund species occurred more frequently in cases where functional responses were saturated (i.e. high productivity and/or prey accessibility). Such dominance was associated with large biomass fluctuations and priority effects, which prevented richness from increasing with productivity and may have limited selection on secondary traits, such as spawning strategies and relative size at maturation. Our results illustrate that the distribution of species traits and the consequences for community dynamics are intimately linked and strictly dependent on how the benefits and costs of these traits are balanced across different conditions.