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PubMed1997

The role of glutamate transporters in glutamate homeostasis in the brain.

Glutamate transporters in neurones and glia, four of which have been cloned from mammals, play a crucial role in controlling the extracellular glutamate concentration in the brain. In normal conditions, they remove glutamate from the extracellular space and thereby help to terminate glutamatergic synaptic transmission and to prevent the extracellular glutamate concentration from rising to neurotoxic values. Glutamate transport on these carriers is thought to be driven by the cotransport of Na+, the counter-transport of K+, and either the cotransport of H+ or the counter-transport of OH-. Activating the transporters also activates an anion conductance in their structure, the anion flux through which is not coupled to glutamate movement and varies widely for the different transporters. During hypoxia or ischaemia, glutamate transporters can run backwards, releasing glutamate into the extracellular space, triggering the death of neurones and thus causing mental and physical handicap. The rate of glutamate release by this process is slowed by the acid pH occurring in hypoxia/ischaemia, which may help protect the brain during transient, but not sustained, ischaemia.

ATP-Binding Cassette Transporters↗

PubMed2025

The influence of 10n and 10n+5 linker lengths on chromatin fiber topologies explored by mesoscale modeling.

The structural organization of chromatin is intricately influenced by the length of linker DNA connecting nucleosomes. Some studies have suggested preferred linker lengths of 10n and 10n+5 base pairs (bp) (n = integer). Because these lengths dictate the rotational orientation of successive nucleosomes in the fiber axis, they can markedly affect chromatin fiber compaction and topology. Using a refined mesoscale chromatin model with 5-bp resolution, we investigate the influence of linker DNA periodicity, linker histone density, salt concentration, and starting fiber topology on chromatin architecture for regular fibers versus "life-like" fibers, the latter with irregular spacing between nucleosomes. Our results reveal that regular fibers with 10n linkers exhibit compact zigzag configurations, whereas 10n+5 linkers generate more open and flexible structures. However, these effects are pronounced only for short linker lengths, as longer linkers are more heterogeneous. Moreover, increased linker histone density further enhances compaction for long linker lengths, and lower salt concentration modifies chromatin topologies, diminishing periodicity-driven effects. In addition, any periodicity effect in tightly packed solenoid configurations is much less pronounced. All these trends for regular fibers are reduced in life-like fibers with irregularly spaced nucleosomes, despite having the same average spacing. Moreover, the trend details depend highly on specific features of the fiber architecture as designed in experiments and simulations. Overall, our study highlights how reported differences depend on modeling details and emphasizes the role of linker DNA length in regulating chromatin fiber architecture and its potential implications for genome accessibility and expression.

Chromatin↗

PubMed2000

Pathogenesis of ophthalmopathy in autoimmune thyroid disease.

What causes GO is still a mystery, but the disease process results from a complex interplay of genetic and environmental factors. Genes such as those for HLA genes may determine a patient's susceptibility to the disease and its severity, but environmental factors, often unknown, may determine its course. Once established, the chronic inflammatory process within the orbital tissues appears to take on a momentum of its own. Given our current state of knowledge, the following working scheme for the pathogenesis of GO can be proposed (Fig. 1): On the background of a permissive immunogenetic milieu, circulating T cells in patients with GD, directed against certain antigens on thyroid follicular cells, recognize antigenic epitopes that are shared by tissues contained in the orbital space. Of the cell types residing in these tissues, preadipocytes and fibroblasts, most likely act as target and effector cells of the orbital immune process, respectively. This includes preadipocyte fibroblasts present in the perimysium of extraocular muscles, which do not appear to be immunologically different from those located in the orbital connective tissue. Orbital preadipocyte fibroblasts may be stimulated by unknown circulating or locally produced factors to differentiate into mature adipocytes that express increased levels of TSHr. How autoreactive T cells escape deletion and control by the immune system and come to be directed against a self-antigen presented by cells residing in the thyroid gland and extrathyroidal locations, is still unknown. Proliferation and expansion of autoreactive T cell clones may be due to mimicry of a host antigen by a microorganism, but this remains speculative. T cell recruitment into the orbital tissues is facilitated by certain chemokines and cytokines, which help to attract T cells by stimulating the expression of certain adhesion molecules (e.g., ICAM-1, VCAM-1, CD44) in vascular endothelium and connective tissue cells. These adhesion receptors are known to also play an important costimulatory role by activating T cells and facilitating antigen recognition, which amplifies the cellular immune process. Analysis of variable region genes of T cell antigen receptors in orbital T cells of patients with active GO has revealed their restricted TcR V gene usage, suggesting that antigen-driven selection and/or expansion of specific T cells may occur early in the evolution of GO. T cells and macrophages populating the orbital space are known to synthesize and release a [figure: see text] number of cytokines (most likely a Th1-type spectrum) into the surrounding tissue. Cytokines, oxygen free radicals and fibrogenic growth factors, released both from infiltrating inflammatory and residential cells, act upon orbital preadipocytes in a paracrine and autocrine manner to stimulate adipogenesis, fibroblast proliferation, glycosaminoglycan synthesis, and the expression of immunomodulatory molecules. Smoking, a well-known aggravating factor in GO, may aggravate tissue hypoxia and exert important immunomodulatory effects. The long held hypothesis of a thyroid cross-reactive antigen within the orbital tissues has recently gained significant support by an animal model of GO, and by in vitro and ex vivo studies. If confirmed in immunological studies, these data may well explain the localized infiltration of the orbital tissues by autoreactive lymphocytes that share intriguing molecular features with intrathyroidal lymphocytes. Local release of particular cytokines, TSHr-directed antibodies, or other factors might further enhance adipogenesis, glycosaminoglycan synthesis and expression of immunomodulatory proteins within the orbit. Other factors, including inflammatory cytokines, might act as counterbalancing inhibitors of these effects. However, if the net effect of these changes is to increase the volume of the fatty connective tissues within the orbit, then proptosis, extraocular muscle dysfunction, and periorbital congestion will ensue. Whether this hypothetical sequence of events will finally explain the involvement of the orbit in GD is unknown. Future studies will be aimed at identifying factors that might modulate adipogenesis in orbital cells and clarifying the link between adipogenesis and TSHr expression in the orbit. Taken together, a number of important details in the complex pathogenesis of GO have been resolved in recent years, but many challenges are still ahead. Elucidation of the primary antigen and how it is recognized by the immune system will be key issues.

Adipose Tissue↗

PubMed2001

Calculation of rigid-body conformational changes using restraint-driven Cartesian transformations.

We present an approach for calculating conformational changes in membrane proteins using limited distance information. The method, named restraint-driven Cartesian transformations, involves 1) the use of relative distance changes; 2) the systematic sampling of rigid body movements in Cartesian space; 3) a penalty evaluation; and 4) model refinement using energy minimization. As a test case, we have analyzed the structural basis of activation gating in the Streptomyces lividans potassium channel (KcsA). A total of 10 pairs of distance restraints derived from site-directed spin labeling and electron paramagnetic resonance (SDSL-EPR) spectra were used to calculate the open conformation of the second transmembrane domains of KcsA (TM2). The SDSL-EPR based structure reveals a gating mechanism consistent with a scissoring-type motion of the TM2 segments that includes a pivot point near middle of the helix. The present approach considerably reduces the amount of time and effort required to establish the overall nature of conformational changes in membrane proteins. It is expected that this approach can be implemented into restrained molecular dynamics protocol to calculate the structure and conformational changes in a variety of membrane protein systems.

Bacterial Proteins↗

PubMed2001

Biotechnology and new companies arising from academia.

20 years ago, an academic biomedical scientist or clinician who set up a company would probably have been perceived by colleagues as "on the make" and rather unacademic-"not one of us", in other words. Nowadays, academics who have started companies are commonplace, and in some universities the businessman-academic is becoming the norm, although still far more common in the USA than in Europe. At best, the opportunity to capitalise on a discovery has the potential to motivate research workers, provide greater funding for research, and ultimately create wealth. At worst, the spawning of a company from within academia has the potential to use public employees, space, and equipment for personal gain, and divert academics from the pursuit of profound scientific questions into more immediate product-driven research or even marketing dressed up as research. Here, I discuss some of the issues surrounding biotechnology and spin-off companies originating in academia.

Academies and Institutes↗

PubMed2002

Pathway evolution, structurally speaking.

Small-molecule metabolism forms the core of the metabolic processes of all living organisms. As early as 1945, possible mechanisms for the evolution of such a complex metabolic system were considered. The problem is to explain the appearance and development of a highly regulated complex network of interacting proteins and substrates from a limited structural and functional repertoire. By permitting the co-analysis of phylogeny and metabolism, the combined exploitation of pathway and structural databases, as well as the use of multiple-sequence alignment search algorithms, sheds light on this problem. Much of the current research suggests a chemistry-driven 'patchwork' model of pathway evolution, but other mechanisms may play a role. In the future, as metabolic structure and sequence space are further explored, it should become easier to trace the finer details of pathway development and understand how complexity has evolved.

Amino Acid Sequence↗

PubMed2005

Polymorphism in AB(13) nanoparticle superlattices: an example of semiconductor-metal metamaterials.

Colloidal crystallization of nanoparticles with different functionalities into multicomponent assemblies provides a route to new classes of ordered nanocomposites with novel properties tunable by the choice of the constituent building blocks. While theories based on hard sphere approximation predict crystallization of only a few stable binary phases (NaCl-, AlB(2)- and NaZn(13)-type), we find that additional polymorphs of lower packing density are possible. We demonstrate that PbSe and Pd nanoparticles can be reproducibly crystallized into two polymorphs with AB(13) stoichiometry. One polymorph is isostructural with the intermetallic compound NaZn(13) and is consistent with dense packing of hard spheres driven by entropy. The second unanticipated polymorph is of lower packing density. This observation underscores the shortcomings of applying simple space-filling principles to the crystallization of organically passivated nanocrystals and further motivates the development of models that incorporate combinations of hard-sphere, van der Waals, dipolar, and hydrophobic forces. This work demonstrates that ordered periodic structures with lower packing density are achievable and provides the first example of a binary semiconductor-metal superlattice using a combination of PbSe-Pd nanocrystals.

Journal Article↗

PubMed2005

Your highness: vertical positions as perceptual symbols of power.

Metaphorically, power equals up. Drawing on embodied theories of cognition, the author argues that thinking about power involves mental simulation of space and can be interfered with by perception of vertical differences. Study 1 assessed image schemas for power and found a shared vertical difference metaphor. Studies 2, 3, and 4 showed that the judgment of a group's power is influenced by the group's vertical position in space and motor responses implying vertical movement. Study 5 ruled out that the influence of vertical position on power judgments is driven by valence differences. Study 6 showed that vertical position also influences the power judgment result itself. The evidence suggests that the concept of power is partly represented in perceptual form as vertical difference.

Adult↗

PubMed2026

The dynamics of RAD51 foci formation and elongation in living human cells.

Homologous recombination is a DNA repair process that requires binding of RAD51 to ssDNA at the break site. This facilitates the search for a homologous repair template on the sister chromatid, or on the homologous chromosome. How broken DNA ends loaded with RAD51 filaments are brought toward their repair template in the crowded 3D genome is currently poorly understood. This is largely due to a lack of tools to visualize homology search in living human cells. Here, we show that RAD51 and MND1, two proteins operating in homology search, become visible in long, extended structures several hours after double-stranded break formation. Using GFP-MND1 we capture these elongated foci in living human cells and reveal their highly dynamic nature as they traverse the nuclear space and gradually disassemble. We show that resolution of these structures depends on RAD54L, known for its role in RAD51-driven homology search. In addition, we find that loss of cohesin inhibits their resolution, in accordance with a role for cohesin in homology search. Thus, our data suggest that these elongated foci are visible intermediates of an active DNA repair process, and that GFP-MND1 is a powerful tool to study the dynamics of homology search in living human cells.

Humans↗

PubMed2005

Chondroprotective drugs in degenerative joint diseases.

Catabolic cytokine and anabolic growth factor pathways control destruction and repair in osteoarthritis (OA). A unidirectional TNF-alpha/IL-1-driven cytokine cascade disturbs the homeostasis of the extracellular matrix of articular cartilage in OA. Although chondrocytes in OA cartilage overexpress anabolic insulin-like growth factor (IGF) and its specific receptor (IGFRI) autocrine TNF-alpha released by apoptotic articular cartilage cells sets off an auto/paracrine IL-1-driven cascade that overrules the growth factor activities that sustain repair in degenerative joint disease. Chondroprotection with reappearance of a joint space that had disappeared has been documented unmistakably in peripheral joints of patients suffering from spondyloarthropathy when treated with TNF-alpha-blocking agents that repressed the unidirectional TNF-alpha/IL-1-driven cytokine cascade. A series of connective tissue structure-modifying agents (CTSMAs) that directly affect IL-1 synthesis and release in vitro and down-modulate downstream IL-1 features, e.g. collagenase, proteoglycanase and matrix metalloproteinase activities, the expression of inducible nitric oxide synthase, the increased release of nitric oxide, and the secretion of prostaglandin E(2), IL-6 and IL-8, have been shown to possess disease-modifying OA drug (DMOAD) activities in experimental models of OA and in human subjects with finger joint and knee OA. Examples are corticosteroids, some sulphated polysaccharides, chemically modified tetracyclines, diacetylrhein/rhein, glucosamine and avocado/soybean unsaponifiables.

Antirheumatic Agents↗

PubMed1999

Theory of dust voids in plasmas.

Dusty plasmas in a gas discharge often feature a stable void, i.e., a dust-free region inside the dust cloud. This occurs under conditions relevant to both plasma processing discharges and plasma crystal experiments. The void results from a balance of the electrostatic and ion drag forces on a dust particle. The ion drag force is driven by a flow of ions outward from an ionization source and toward the surrounding dust cloud, which has a negative space charge. In equilibrium the force balance for dust particles requires that the boundary with the dust cloud be sharp, provided that the particles are cold and monodispersive. Numerical solutions of the one-dimensional nonlinear fluid equations are carried out including dust charging and dust-neutral collisions, but not ion-neutral collisions. The regions of parameter space that allow stable void equilibria are identified. There is a minimum ionization rate that can sustain a void. Spatial profiles of plasma parameters in the void are reported. In the absence of ion-neutral collisions, the ion flow enters the dust cloud's edge at Mach number M=1. Phase diagrams for expanding or contracting voids reveal a stationary point corresponding to a single stable equilibrium void size, provided the ionization rate is constant. Large voids contract and small voids expand until they attain this stationary void size. On the other hand, if the ionization rate is not constant, the void size can oscillate. Results are compared to recent laboratory and microgravity experiments.

Journal Article↗

PubMed2000

Adiabatic approximation and parametric stochastic resonance in a bistable system with periodically driven barrier

In this paper we compare the analytical adiabatic exponential approximation and exact numerical description of fluctuation-induced transitions in a "quartic" potential with periodically driven barrier. We show that the adiabatic approximation gives an adequate description of the processes in a wide region of parameter space and the accuracy of the approximation improves with increasing noise intensity. For parameter values outside this region, a different kind of resonant activation, which we call parametric stochastic resonance, is observed.

Journal Article↗

PubMed2005

Convection-driven pattern formation in phase-separating binary fluids.

Using a thermal-lattice Boltzmann model, we examine the rich phase behavior that develops when partially miscible fluids evolve in the presence of a vertical temperature gradient, which encompasses the critical temperature T(c) of the mixture. In particular, a binary AB fluid is confined between two plates in a gravitational field. The upper plate is fixed below T(c) and hence, the nearby fluid phase separates into A-rich and B-rich domains. The lower plate is fixed above the temperature T(c), and the surrounding fluid is in the homogeneous phase. A coupling between convection (driven by the temperature gradient) and phase separation gives rise to unique pattern formation. A number of regimes are identified: regularly spaced stripes, convective steady-state columns, the periodic disturbance of these columns, and finally, chaotic dripping from the upper surface. These results highlight dynamical behavior in partially miscible mixtures.

Journal Article↗

PubMed2004

Hugoniot data for carbon at megabar pressures.

We present an experimental point for the carbon equation of state (EOS) at megabar pressures, obtained by laser-driven shock waves. The rear side emissivity of "two-materials two-steps" targets (Al-C) was recorded with space and time resolution and, by applying the impedance mismatch method, allowed a direct determination of relative EOS points. Experiments were performed at the PALS and LULI laboratories using carbon samples with two different values of initial density, in order to explore a wider region of the phase diagram. Previously unreached pressures were obtained. The results are compared with previous experiments and with available theoretical models and seem to show a high compressibility of carbon at megabar pressures.

Journal Article↗

PubMed2006

The interaction of disturbances and small mammal community dynamics in a lowland forest in Belize.

1. Three floods (July 2000, August 2002, September 2003) and a hurricane (October 2001) that occurred in a lowland forest in the southern Maya Mountains of Belize presented an opportunity to evaluate the influence of these disturbances on the structure of a small mammal assemblage. 2. Four terrestrial and four primarily scansorial/arboreal species were trapped July 2000-March 2005 in six grids over 14 irregularly spaced trapping periods. 3. Community dynamics were characterized more by changes in species composition than changes in diversity. The dynamics were driven by species-specific variation in abundance, with changes in composition generally, but not exclusively, due to the occurrence or disappearance of species at low abundance. Despite the disturbances, species richness remained relatively constant. Evenness within the assemblage was consistently low, primarily as a result of dominance by one species, Heteromys desmarestianus. 4. Effects of flooding on community structure were direct but relatively brief (< 1 year), and varied with the duration and intensity of flooding. Effects from the hurricane were indirect but long-lasting and strongly related to severely reduced food resources. 5. This study suggests that long-term dynamics in the structure of many animal communities in the tropics often results from interactions between direct and indirect effects of disturbance. It also suggests that community resistance will depend on variation in disturbance type and regime, but resilience will be determined by the life-history characteristics of each species.

Animals↗

PubMed1989

Characteristics of glutamine transport in dog jejunal brush-border membrane vesicles.

The present study characterizes glutamine transport across brush-border membrane vesicles (BBMV) prepared from dog jejunum. The purity of these vesicles was demonstrated by a 20-fold enrichment of leucine aminopeptidase, a marker for BBM. Glutamine uptake was found to occur into an osmotically active space with no membrane binding and to exhibit temperature and pH dependence (optimal uptake at pH 7-7.5). Glutamine uptake was driven by an inwardly directed Na+ gradient with a distinct overshoot not observed under K+ gradient. Lithium could not substitute for Na+ as a stimulator of glutamine uptake. Na+-dependent glutamine uptake was not inhibited by methylaminoisobutyric acid, a typical substrate for system A, and was found to be electrogenic and saturable with a Km of 0.97 +/- 0.58 mM and a Vmax of 3.93 +/- 0.99 nmol.mg protein-1.10 s-1. A Na+-glutamine coupling ratio of 1:1 could be demonstrated by a plot of Hill transformation. Na+-independent glutamine uptake was found to be electroneutral and saturable with a Km of 3.70 +/- 0.66 mM and a Vmax of 2.70 +/- 1.55 nmol.mg protein-1.10 s-1. Inhibition studies confirmed the presence of a Na+-dependent as well as a Na+-independent carrier for glutamine uptake. We conclude that glutamine uptake across dog BBMV occurs via two transport systems: a Na+-dependent high-affinity system similar to the neutral brush-border system and a Na+-independent lower-affinity system similar to system L.

Amino Acids↗

PubMed2026

Phylogenetic and Functional Analyses of Wheat TaMAN Genes Responding to Salinity and Pathogens.

Endo-β-1,4-mannanases (MANs) are glycoside hydrolase family 5 (GH5) enzymes that degrade cell wall mannan polysaccharides and participate in plant growth and stress adaptation. This gene family has not been systematically characterized in common wheat (Triticum aestivum L.). Here, we identified 24 TaMAN genes (TaMAN1-TaMAN24) genome-wide and analyzed their phylogeny, gene structures, chromosomal distribution, synteny, and promoter cis-acting elements. Expression profiles under biotic and abiotic stresses were investigated using public databases, salt-stress RNA-seq, and RT-qPCR. TaMAN proteins (386-475 aa) were mainly predicted to localize in the extracellular space. Phylogenetic analysis divided them into three groups, with Groups II and III representing monocot-specific expansions. Family expansion was driven primarily by whole-genome duplication, supplemented by tandem duplication on homoeologous group 6. Promoters were enriched in hormone- and stress-responsive cis-acting elements (ABRE, as-1/CGTCA-motif, W box). TaMAN1, TaMAN5, TaMAN8, TaMAN9, TaMAN16 and TaMAN19 were significantly induced by powdery mildew, while TaMAN3, TaMAN4 and TaMAN19-TaMAN22 rapidly responded to salt stress. This study provides candidate genes for disease-resistant and salt-tolerant wheat breeding.

TaMAN gene↗

PubMed1995

Model for a pump that drives circulation of pleural fluid.

Physical and mathematical models were used to study a mechanism that could maintain the layer of pleural fluid that covers the surface of the lung. The pleural space was modeled as a thin layer of viscous fluid lying between a membrane carrying tension (T), representing the lung, and a rigid wall, representing the chest wall. Flow of the fluid was driven by sliding between the membrane and wall. The physical model consisted of a cylindrical balloon with strings stretched along its surface. When the balloon was inflated inside a vertical circular cylinder containing a viscous fluid, the strings formed narrow vertical channels between broad regions in which the balloon pressed against the outer cylinder. The channels simulated the pleural space in the regions of lobar margins. Oscillatory rotation of the outer cylinder maintained a lubricating layer of fluid between the balloon and the cylinder. The thickness of the fluid layer (h), measured by fluorescence videomicroscopy, was larger for larger fluid viscosity (mu), larger sliding velocity (U), and smaller pressure difference (delta P) between the layer and the channel. A mathematical model of the flow in a horizontal section was analyzed, and numerical solutions were obtained for parameter values of mu, U, delta P, and T that matched those of the physical model. The computed results agreed reasonably well with the experimental results. Scaling laws yield the prediction that h is approximately (T/delta P)(microU/T)2/3. For physiological values of the parameters, the predicted value of h is approximately 10(-3) cm, in good agreement with the observed thickness of the pleural space.

Body Fluids↗