Unidirectional Processes Research Articles

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Pyrimidine and purine nucleosides and their derivatives have critical functions and pharmacological applications in the brain. Nucleosides and nucleobases are precursors of nucleotides, which serve as the energy-rich currency of intermediary metabolism and as precursors of nucleic acids. Nucleosides (e.g., adenosine) and nucleotides are key signaling molecules that modulate brain function through interaction with cell surface receptors. Brain pathologies involving nucleosides and their metabolites range from epilepsy to neurodegenerative disorders and psychiatric conditions to cerebrovascular ischemia. Nucleoside analogs are used clinically in the treatment of brain cancer and viral infections. Nucleosides are hydrophilic molecules, and transportability across cell membranes via specialized nucleoside transporter (NT) proteins is a critical determinant of their metabolism and, for nucleoside drugs, their pharmacologic actions. In mammals, there are two types of nucleoside transport process: bidirectional equilibrative processes driven by chemical gradients, and unidirectional concentrative processes driven by sodium (and proton) electrochemical gradients. In mammals, these processes, both of which are present in brain, are mediated by members of two structurally unrelated membrane protein families (ENT and CNT, respectively). In this Chapter, we review current knowledge of cellular, physiological, pathophysiological and therapeutic aspects of ENT and CNT distribution and function in the mammalian brain, including studies with NT inhibitors and new research involving NT knockout and transgenic mice. We also describe recent progress in functional and molecular studies of ENT and CNT proteins, and summarize emerging evidence of other transporter families with demonstrated or potential roles in the transport of nucleosides and their derivatives in the brain.

Baushinger’s Effect in Wear of Materials

The response of Cu–40%Zn alloy to wear during unidirectional and bidirectional abrasion processes was investigated. It was observed that the mass loss of the alloy decreased as the number of times of changing the sliding direction was increased. Corresponding to this decrease in mass loss, hardness of the worn surface increased initially and then decreased. Cracking in the surface layer was analyzed to get an insight into the mechanism involved. Results of the study suggest that Baushinger’s effect played a role when the sliding direction was alternated.

Endothelial cell plasticity: how to become and remain a lymphatic endothelial cell

Lineage commitment and differentiation into mature cell types are mostly considered to be unidirectional and irreversible processes. However, recent results have challenged this by showing that terminally differentiated cell types can be reprogrammed into other cell types, an important step towards devising strategies for gene therapy and tissue regeneration. In this Review, we summarize recent data on the earliest steps in the development of the mammalian lymphatic vasculature: the specification of lymphatic endothelial cells (LECs). We elaborate on a developmental model that integrates the different steps leading to LEC differentiation and lymphatic network formation, discuss evidence that suggests that LEC fate is plastic, and consider the potentially far-reaching implications of the ability to convert one cell type into another.

Bidirectional priming processes in the Simon task.

The Simon effect is mostly explained in terms of dual-route models, which imply unidirectional activation processes from stimulus features to response features. However, there is also evidence that these preactivated response features themselves prime corresponding stimulus features. From this perspective, the Simon effect should only occur whenever the response is unequivocally mapped to just 1 stimulus feature (one-to-one mapping). If, however, more than 1 stimulus feature is mapped to each spatial response (many-to-one mapping), priming activation should spread and thus reduce or eliminate the Simon effect. In a series of 4 Simon task experiments, the authors compared many-to-one with one-to-one mapping, holding stimulus set size constant. As was expected, the Simon effect was only present with one-to-one mapping but was eliminated with many-to-one mapping. The authors therefore suggest that the Simon effect also depends on priming from response features to stimulus features. Theoretical implications of these findings are discussed.

Elementary charge-transfer processes in mesoscopic conductors

We determine charge-transfer statistics in a quantum conductor driven by a time-dependent voltage and identify the elementary transport processes. At zero temperature unidirectional and bidirectional single-charge transfers occur. The unidirectional processes involve electrons injected from the source terminal due to excess dc bias voltage. The bidirectional processes involve electron-hole pairs created by time-dependent voltage bias. This interpretation is further supported by the charge-transfer statistics in a multiterminal beam-splitter geometry in which injected electrons and holes can be partitioned into different outgoing terminals. The probabilities of elementary processes can be probed by noise measurements: the unidirectional processes set the dc noise level, while bidirectional ones give rise to the excess noise. For ac voltage drive, the noise oscillates with increasing the driving amplitude. The decomposition of the noise into the contributions of elementary processes reveals the origin of these oscillations: the number of electron-hole pairs generated per cycle increases with increasing the amplitude. The decomposition of the noise into elementary processes is studied for different time-dependent voltages. The method we use is also suitable for systematic calculation of higher-order current correlators at finite temperature. We obtain current noise power and the third cumulant in the presence of time-dependent voltage drive. The charge-transfer statistics at finite temperature can be interpreted in terms of multiple-charge transfers with probabilities which depend on energy and temperature.

Litter decomposition promotes differential feedbacks in an oligotrophic southern Everglades wetland

The differential accumulation or loss of carbon and nutrients during decomposition can promote differentiation of wetland ecosystems, and contribute to landscape-scale heterogeneity. Tree islands are important ecosystems because they increase ecological heterogeneity in the Everglades landscape and in many tropical landscapes. Only slight differences in elevation due to peat accumulation allow the differentiation of these systems from the adjacent marsh. Hydrologic restoration of the Everglades landscape is currently underway, and increased nutrient supply that could occur with reintroduction of freshwater flow may alter these differentiation processes. In this study, we established a landscape-scale, ecosystem-level experiment to examine litter decomposition responses to increased freshwater flow in nine tree islands and adjacent marsh sites in the southern Everglades. We utilized a standard litterbag technique to quantify changes in mass loss, decay rates, and phosphorus (P), nitrogen (N) and carbon (C) dynamics of a common litter type, cocoplum (Chrysobalanus icaco L.) leaf litter over 64 weeks. Average C. icaco leaf degradation rates in tree islands were among the lowest reported for wetland ecosystems (0.23 ± 0.03 yr−1). We found lower mass loss and decay rates but higher absolute mass C, N, and P in tree islands as compared to marsh ecosystems after 64 weeks. With increased freshwater flow, we found generally greater mass loss and significantly higher P concentrations in decomposing leaf litter of tree island and marsh sites. Overall, litter accumulated N and P when decomposing in tree islands, and released P when decomposing in the marsh. However, under conditions of increased freshwater flow, tree islands accumulated more P while the marsh accumulated P rather than mineralizing P. In tree islands, water level explained significant variation in P concentration and N:P molar ratio in leaf tissue. Absolute P mass increased strongly with total P load in tree islands (r 2 = 0.81). In the marsh, we found strong, positive relationships with flow rate. Simultaneous C and P accumulation in tree island and mineralization in adjacent marsh ecosystems via leaf litter decomposition promotes landscape differentiation in this oligotrophic Everglades wetland. However, results of this study suggest that variation in flow rates, water levels and TP loads can shift differential P accumulation and loss leading to unidirectional processes among heterogeneous wetland ecosystems. Under sustained high P loading that could occur with increased freshwater flow, tree islands may shift to litter mineralization, further degrading landscape heterogeneity in this system, and signaling an altered ecosystem state.

Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors

Lineage commitment and differentiation to a mature cell type are considered to be unidirectional and irreversible processes under physiological conditions. The commitment of haematopoietic progenitors to the B-cell lineage and their development to mature B lymphocytes critically depend on the transcription factor encoded by the paired box gene 5 (Pax5). Here we show that conditional Pax5 deletion in mice allowed mature B cells from peripheral lymphoid organs to dedifferentiate in vivo back to early uncommitted progenitors in the bone marrow, which rescued T lymphopoiesis in the thymus of T-cell-deficient mice. These B-cell-derived T lymphocytes carried not only immunoglobulin heavy- and light-chain gene rearrangements but also participated as functional T cells in immune reactions. Mice lacking Pax5 in mature B cells also developed aggressive lymphomas, which were identified by their gene expression profile as progenitor cell tumours. Hence, the complete loss of Pax5 in late B cells could initiate lymphoma development and uncovered an extraordinary plasticity of mature peripheral B cells despite their advanced differentiation stage.

Feedback Loops, Reversals and Nonlinearities in Lymphocyte Development

Systems of differentiating cells are often regarded by experimental biologists as unidirectional processes, in which cells spend a fixed time at each successive developmental stage. However, mathematical modeling has in several cases revealed that differentiating cell systems are more complex than previously believed. For example, non-linear transitions, feedback effects, and even apparent reversals have been suggested by our studies on models for the development of lymphocytes and their receptor repertoires, and are reviewed in this paper. These studies have shown that cell population growth in developing lymphocyte subsets is usually nonlinear, as it depends on the density of cells in each compartment. Additionally, T cell development has been shown to be subject to feedback regulation by mature T cell subsets, and B cell development has been shown to include a phenotypic reflux from an advanced to an earlier developmental stage. The challenges we face in our efforts to understand how the repertoires of these cells are generated and regulated are also discussed here.

Higher education for sustainability by means of transdisciplinary case studies: an innovative approach for solving complex, real-world problems

Sustainable development and the interplay between its ecological, social, and economic dimensions can be regarded as a highly complex task. As a logical consequence, educating for sustainable development also has a complex character. Traditional unidirectional educational processes are only of very limited use when educating for sustainable development: Firstly, the initial state of the considered system (case) cannot be described precisely; secondly, the target state of the system is also not sufficiently known; and thirdly, the process between initial state and target state and potential barriers that might have to be passed are also not exactly known. Pure analytically based solutions are therefore, not available; a dynamic mutual learning process is required instead. Mutual learning based on real-world cases requires an interdisciplinary point of view, transdisciplinary problem-solving processes, and self-regulated and self-responsible learning. Consequently, besides analytical capabilities and deterministic process planning, dealing with the complex problem of sustainable development requires creativity, social competencies and specific communication skills in order to cope with the dynamic change that characterizes the developments in most facets of society and nature. A “vassal” that puts together all these requirements towards an educational process for sustainable development can be a transdisciplinary case study approach: In Austria this was first applied by the University of Graz within the “Erzherzog Johann case study”. In order to educate for sustainable development, the students had to work on a “real-world problem”, the development of possible ways to achieve ecologically, economically and socially sustainable development of the abandoned iron ore mining region of Eisenerz in the middle of Austria. As a core characteristic of this “real-world” case study, besides the cooperation among students, teachers and researchers of the university, the interaction with stakeholders of the region was of outstanding importance. Within transdisciplinary case studies students, teachers and researchers have to abandon the role paradigm of the teacher as provider of information and the students as “consumers” of the provided information. Knowledge and competences imparted in university classes need to be applied simultaneously within the real-world case to allow a demand-driven process of mutual learning in which students are self-responsible and decide which tools to apply in the process of attaining sustainable development. Because of the dynamics of this process, students experience the process of sustainable development instead of purely memorizing its characteristics. The process of educating for sustainable development and practical applied sustainability therefore, becomes sustainable.

Dissection of Bidirectional Synaptic Plasticity Into Saturable Unidirectional Processes

In populations of synapses, overall synaptic strength can undergo either a net strengthening (long-term potentiation) or weakening (long-term depression). These phenomena have distinct induction pathways, but the functional outcome is usually measured as a single lumped quantity. In hippocampal CA3-CA1 synapses, we took two approaches to study the activity dependence of each phenomenon in isolation. First, we selectively blocked one process by applying kinase or phosphatase inhibitors known, respectively, to block potentiation or depression. Second, we saturated depression or potentiation and examined the activity dependence of the converse process. The resulting unidirectional learning rules could be recombined to give a well-known bidirectional frequency-dependent learning rule under the assumption that when both pathways are activated kinases dominate, resulting in potentiation. Saturation experiments revealed an additional process in which potentiated synapses can be locked at high strength. Saturability of the components of plasticity implies that the amount of plasticity contributed by each pathway depends on the initial level of strength of the synapses. Variation in the distribution of initial synaptic strengths predicts a form of metaplasticity and can account for differences in learning rules observed under several physiological and genetic manipulations.

Tenascin-C regulates proliferation and migration of cultured astrocytes in a scratch wound assay

Tenascin-C (TNC), an extracellular matrix glycoprotein, is involved in tissue morphogenesis like embryogenesis, wound healing or tumorigenesis. Astrocytes are known to play major roles in wound healing in the CNS. To elucidate the roles of TNC in wound closure by astrocytes, we have examined the morphological changes of cultured astrocytes in a scratch wound assay and measured the content of soluble TNC released into the medium. We have also localized the expression of TNC mRNA, TNC, glial fibrillary acidic protein (GFAP), vimentin and integrin β1. After wounding, glial cells rapidly released the largest TNC isoform and proliferated in the border zones. Subsequently, they became polarized with unidirectional processes and finally migrated toward the denuded area. The proliferating border zone cells and pre-migratory cells intensely expressed TNC mRNA, TNC-, vimentin-, GFAP- and integrin β1-like immunoreactivity, while the migratory cells showed generally reduced expression except the front. Exogenous TNC enhanced cell proliferation and migration, while functional blocking with anti-TNC or anti-integrin β1 antibody reduced both of them. These results suggest that mechanical injury induces boundary astrocytes to produce and release TNC that promotes cell proliferation and migration via integrin β1 in an autocrine/paracrine fashion.

Targets of programmed destruction: a primer to regulatory proteolysis in yeast.

Proteasome-mediated proteolysis of defined target proteins is an important regulatory mechanism, which contributes to control of various essential pathways and programs of the eukaryotic cell. Here, I describe basic principles and mechanisms of regulatory proteolysis as observed in a prominent model cell, the yeast Saccharomyces cerevisiae. Selective proteolysis is important for balancing of a cell's proteins. It is used to directly limit or neutralize enzymes in response to defined signals. Proteasome-mediated degradation is also crucial for the regulation of gene transcription. Elimination of transcription factors as well as mobilization of transcriptional activators by limited proteolysis is involved in negative and positive control of transcription. Moreover, recent data indicate that the proteasomal degradation system may be spatially linked to the transcription machinery. Selective proteolytic destruction of regulators and structural proteins is an essential regulatory mechanism ideally designed for the regulation and correct execution of unidirectional processes as are the cell division cycle or the program of apoptotic cell death. Here the proteasomal degradation system acts on various levels.

The Privatisation Cube Paradox: Focusing on Processes or Generic Types?

This article is in response to the critique by Roger Wettenhall regarding the narrowness of conception and unidirectional processes of my proposed privatisation cube. The article attempts to highlight and elucidate the nature of generic types in a typology. It further proposes that the perception of unidirectional processes is based not on the privatisation cube itself but rather on the individualised interpretation of the concept of privatisation in the proposed model.

Modelling inter-segmental coordination of neuronal oscillators: synaptic mechanisms for uni-directional coupling during swimming in Xenopus tadpoles.

Locomotion requires longitudinal co-ordination. We have examined uni-directional synaptic coupling processes between two classes of neuronal network oscillators: autonomously active "intrinsic" oscillators, and "potential" oscillators that lack sufficient excitatory drive for autonomous activity. We model such oscillator networks in the bilaterally-symmetrical, Xenopus tadpole spinal cord circuits that co-ordinate swimming. "Glutamate" coupling EPSPs can entrain a second oscillator of lower frequency provided their strength is sufficient. Fast (AMPA) EPSPs advance spiking on each cycle, while slow (NMDA) EPSPs increase frequency over many cycles. EPSPs can also enable rhythmicity in "potential" oscillators and entrain them. IPSPs operate primarily on a cycle-by-cycle basis. They can advance or delay spiking to entrain a second "intrinsic" oscillator with higher, equal or lower frequency. Bilaterally symmetrical coupling connections operate twice per cycle: once in each half-cycle, on each side of the receiving oscillator. Excitatory and inhibitory coupling allow entrainment in complimentary areas of parameter space.

Can unidirectional influx be measured in higher plants? A mathematical approach using parameters from efflux analysis

• A comprehensive and pragmatic approach to the design of unidirectional ion transport experiments in plants is presented here, revising and simplifying classical models. • The kinetic constant for cytosolic ion exchange ( k c ) is critical to the understanding of the interrelated flux processes occurring simultaneously at the cellular level. This constant is most effectively estimated using the compartmental analysis by efflux method, which, by providing values for additional kinetic parameters (i.e. unidirectional influx and efflux) can be used to determine the extent of distortion inherent in assessments of influx at, or close to, the steady state. • Focusing on the kinetics of nitrogen exchange, with tracer efflux experiments in barley ( Hordeum vulgare ) using 13NH4+, conducted under perturbation conditions, it was demonstrated that a transitional state was rapidly established following a concentration shift, characterized by a restoration of the preperturbational (steady-state) kc value. It is concluded that a reasonably accurate estimate of unidirectional influx can be made when influx measurements are conducted subsequent to the establishment of this transitional state. • A mathematical treatment of unidirectional flux processes allows the exact determination of errors caused by ionic counterfluxes under steady-state conditions.

BIOLOGICAL TIMING AND THE CLOCK METAPHOR: OSCILLATORY AND HOURGLASS MECHANISMS

Living organisms have developed a multitude of timing mechanisms— “biological clocks.” Their mechanisms are based on either oscillations (oscillatory clocks) or unidirectional processes (hourglass clocks). Oscillatory clocks comprise circatidal, circalunidian, circadian, circalunar, and circannual oscillations—which keep time with environmental periodicities—as well as ultradian oscillations, ovarian cycles, and oscillations in development and in the brain, which keep time with biological timescales. These clocks mainly determine time points at specific phases of their oscillations. Hourglass clocks are predominantly found in development and aging and also in the brain. They determine time intervals (duration). More complex timing systems combine oscillatory and hourglass mechanisms, such as the case for cell cycle, sleep initiation, or brain clocks, whereas others combine external and internal periodicities (photoperiodism, seasonal reproduction). A definition of a biological clock may be derived from its control of functions external to its own processes and its use in determining temporal order (sequences of events) or durations. Biological and chemical oscillators are characterized by positive and negative feedback (or feedforward) mechanisms. During evolution, living organisms made use of the many existing oscillations for signal transmission, movement, and pump mechanisms, as well as for clocks. Some clocks, such as the circadian clock, that time with environmental periodicities are usually compensated (stabilized) against temperature, whereas other clocks, such as the cell cycle, that keep time with an organismic timescale are not compensated. This difference may be related to the predominance of negative feedback in the first class of clocks and a predominance of positive feedback (autocatalytic amplification) in the second class. The present knowledge of a compensated clock (the circadian oscillator) and an uncompensated clock (the cell cycle), as well as relevant models, are briefly reviewed. Hourglass clocks are based on linear or exponential unidirectional processes that trigger events mainly in the course of development and aging. An important hourglass mechanism within the aging process is the limitation of cell division capacity by the length of telomeres. The mechanism of this clock is briefly reviewed. In all clock mechanisms, thresholds at which “dependent variables” are triggered play an important role. (Chronobiology International, 18(3), 329–369, 2001)

Unidirectional infiltration in deformable porous media: mathematical modeling and self-similar solution

This study is motivated by the necessity to develop models and to obtain mathematical results which can help in improving certain industrial processes used for manufacturing composite materials. We focus on unidirectional infiltration processes in deformable porous material and on the analytical study of the related mathematical problem. A key point in developing the model is the use of a set of Lagrangian coordinates fixed on the solid. This technique allows us to simplify the mathematical problem. In the Eulerian formalism, in fact, such a problem is a free boundary problem characterized by the presence of two time-dependent interfaces. The use of material coordinates fixed on the solid allows, vice-versa, to fix one boundary and so to obtain a nonlinear one-phase Stefan problem. The latter, then, has been studied from the analytical viewpoint. In particular, we have proved the existence of a solution exhibiting a self-similar form.

6. The structure of plumes generated in unidirectional solidification processes

6. The structure of plumes generated in unidirectional solidification processes

Land-cover changes in sub-saharan Africa (1982–1991): Application of a change index based on remotely sensed surface temperature and vegetation indices at a continental scale

There is an increasing need for data on land-cover changes at broad spatial .scales. In this study, a remote sensing-based technique for land-cover-change analysis was applied to the African continent for the last decade. Ten years of daily, continental-.scale satellite remote sensing data (front the National Oceanic and Atmospheric Administration's advanced very-high resolution radiometer) were analyzed. Deviations in. the seasonal trajectory of the land surface—characterized by its brightness temperature and a vegetation index—were interpreted in terms of land-cover change on a yearly basis, from 1982 to 1991. Land-cover-change magnitudes were measured and mapped for every year. The major categories of seasonal patterns of changes were identified. Multiyear patterns of change also were categorized, and all areas affected by a continuous decrease and gain in vegetation cover over the decade were snapped. Results were related to published high-resolution remote sensing-based studies, rainfall data, and other evidence of land-cover changes. This study's results demonstrate that inte-rannual land-cover changes in Africa mostly involve erratic variations in land-corer conditions due to interannual climatic variability and temporary nwdifncations in seasonality. Continuous, unidirectional change processes (decrease or gain in vegetation cover) affected less than 4% of sub-Saharan Africa during the study period. Althongh such linear changes are just a fraction of the total land-cover changes detected, their effect on ecosystems and sustainability of livelihood might be significant. In the semiarid regions, temporary modification of the biophysical attributes of the surface driven by variations in rainfall is the dominant process. Future work will focus on finer-scale interpretation and validations of patterns of changes.

Tandem Duplication of rab Genes Followed by Sequence Divergence and Acquisition of Distinct Functions in Trypanosoma brucei

The Ras superfamily of small G proteins governs unidirectional cellular processes by virtue of GTP hydrolysis and concomitant conformational changes, which are in turn regulated by a number of accessory factors. Members of the Rab subfamily are important for correct targeting and fusion of intra-organellar vesicles loaded with trafficking proteins and lipids. During evolution from a prototype gene, novel functions may be acquired by duplicated daughter genes; for Rab proteins, this can be tested by location, which is specifically related to the function of each Rab. We have found an example of two rab genes in Trypanosoma brucei (trab genes) that clearly arose by tandem duplication, being highly related to each other and remaining juxtaposed in the genome, whose products have dramatically different subcellular locations, indicative of discrete functions. These two trab genes, isolated on a single genomic clone, are separated by a short intervening sequence and are in a head-to-tail orientation. The nucleotide sequences of the open reading frames and intervening sequence were determined and show that the genes are paralogues, probably arising from an ancient tandem duplication. Both genes are most homologous to ypt1 and sec4 in the Saccharomyces cerevisiae genome, while phylogenetic reconstruction indicates that although they have clearly diverged, the proteins are more closely related to each other than to other Rab protein sequences available in the data base. Immunofluorescence microscopy, using antibodies raised against the recombinant Trab proteins, clearly demonstrates that the native Trab proteins have completely distinct subcellular locations in the trypanosome. Trab1p is present in a widespread reticular location similar to BiP, suggesting an endoplasmic reticulum location, while Trab7p is observed in a discrete structure adjacent to the kinetoplast. Most interestingly, the Trab7p-positive compartment also appears to divide at the same time, or just prior to, the kinetoplast, i.e. early in mitosis, suggestive of association with structures in the flagellar pocket region. An estimate of the divergence time indicates that the trab1/trab7 duplication occurred approximately 100 million years ago, and therefore, the persistence of this pair suggests an essential role in the survival of T. brucei.