Phenotypic plasticity and longevity in plants and animals: cause and effect?

Immobile plants and immobile modular animals outlive unitary animals. This paper discusses competing but not necessarily mutually exclusive theories to explain this extreme longevity, especially from the perspective of phenotypic plasticity. Stem cell immortality, vascular autonomy, and epicormic branching are some important features of the phenotypic plasticity of plants that contribute to their longevity. Monocarpy versus polycarpy can also influence the kind of senescent processes experienced by plants. How density-dependent phenomena affecting the establishment of juveniles in these immobile organisms can influence the evolution of senescence, and consequently longevity, is reviewed and discussed. Whether climate change scenarios will favour long-lived or short-lived organisms, with their attendant levels of plasticity, is also presented.

Ion-regulatory proreins in neuronal development and communication

Brain function is critically dependent on the ionic homeostasis in both the extra- and intracellular compartment. The regulation of brain extracellular ionic composition mainly relies on active transport at blood brain and at blood cerebrospinal fluid interfaces whereas intracellular ion regulation is based on plasmalemmal transporters of neurons and glia. In addition, the latter mechanisms can generate physiologically as well as pathophysiologically significant extracellular ion transients. In this work I have studied molecular mechanisms and development of ion regulation and how these factors alter neuronal excitability and affect synaptic and non-synaptic transmission with a particular emphasis on intracellular pH and chloride (Cl-) regulation. Why is the regulation of acid-base equivalents (H+ and HCO3-) and Cl- of such interest and importance? First of all, GABAA-receptors are permeable to both HCO3- and Cl-. In the adult mammalian central nervous system (CNS) fast postsynaptic inhibition relies on GABAA-receptor mediated transmission. Today, excitatory effects of GABAA-receptors, both in mature neurons and during the early development, have been recognized and the significance of the dual actions of GABA on neuronal communication has become an interesting field of research. The transmembrane gradients of Cl- and HCO3- determine the reversal potential of GABAA-receptor mediated postsynaptic potentials and hence, the function of pH and Cl- regulatory proteins have profound consequences on GABAergic signaling and neuronal excitability. Secondly, perturbations in pH can cause a variety of changes in cellular function, many of them resulting from the interaction of protons with ionizable side chains of proteins. pH-mediated alterations of protein conformation in e.g. ion channels, transporters, and enzymes can powerfully modulate neurotransmission. In the context of pH homeostasis, the enzyme carbonic anhydrase (CA) needs to be taken into account in parallel with ion transporters: for CO2/HCO3- buffering to act in a fast manner, CO2 (de)hydration must be catalyzed by this enzyme. The acid-base equivalents that serve as substrates in the CO2 dehydration-hydration reaction are also engaged in many carrier and channel mediated ion movements. In such processes, CA activity is in key position to modulate transmembrane solute fluxes and their consequences. The bicarbonate transporters (BTs; SLC4) and the electroneutral cation-chloride cotransporters (CCCs; SLC12) belong the to large gene family of solute carriers (SLCs). In my work I have studied the physiological roles of the K+-Cl- cotransporter KCC2 (Slc12a5) and the Na+-driven Cl--HCO3- exchanger NCBE (Slc4a10) and the roles of these two ion transporters in the modualtion of neuronal communication and excitability in the rodent hippocampus. I have also examined the cellular localization and molecular basis of intracellular CA that has been shown to be essential for the generation of prolonged GABAergic excitation in the mature hippocampus. The results in my Thesis provide direct evidence for the view that the postnatal up-regulation of KCC2 accounts for the developmental shift from depolarizing to hyperpolarizing postsynaptic EGABA-A responses in rat hippocampal pyramidal neurons. The results also indicate that after KCC2 expression the developmental onset of excitatory GABAergic transmission upon intense GABAA-receptor stimulation depend on the expression of intrapyramidal CA, identified as the CA isoform VII. Studies on mice with targeted Slc4a10 gene disruption revealed an important role for NCBE in neuronal pH regulation and in pH-dependent modulation of neuronal excitability. Furthermore, this ion transporter is involved in the basolateral Na+ and HCO3- uptake in choroid plexus epithelial cells, and is thus likely to contribute to cerebrospinal fluid production.

Inferring neuronal network connectivity from spike data: A temporal data mining approach

Understanding the functioning of a neural system in terms of its underlying circuitry is an important problem in neuroscience. Recent d evelopments in electrophysiology and imaging allow one to simultaneously record activities of hundreds of neurons. Inferring the underlying neuronal connectivity patterns from such multi-neuronal spike train data streams is a challenging statistical and computational problem. This task involves finding significant temporal patterns from vast amounts of symbolic time series data. In this paper we show that the frequent episode mining methods from the field of temporal data mining can be very useful in this context. In the frequent episode discovery framework, the data is viewed as a sequence of events, each of which is characterized by an event type and its time of occurrence and episodes are certain types of temporal patterns in such data. Here we show that, using the set of discovered frequent episodes from multi-neuronal data, one can infer different types of connectivity patterns in the neural system that generated it. For this purpose, we introduce the notion of mining for frequent episodes under certain temporal constraints; the structure of these temporal constraints is motivated by the application. We present algorithms for discovering serial and parallel episodes under these temporal constraints. Through extensive simulation studies we demonstrate that these methods are useful for unearthing patterns of neuronal network connectivity.

Juvenile neuronal ceroid lipofuscinosis; psychiatric symptoms, GAD-autoantibodies, and response to medication

Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative diseases in childhood. Its clinical onset, with visual failure as the first sign, is between the ages of 4 to 8 years. During the disease progress, epilepsy, motor symptoms, cognitive decline, and psychiatric symptoms become apparent. It leads to premature death between ages 15 and 30. Treatment consists of symptomatic drug administration and various forms of rehabilitation, but to date, no curative treatment exists. To gain a more comprehensive picture of psychiatric problems, symptoms were evaluated by the Child Behavior Checklist, the Teacher Report Form, and the Children s Depression Inventory. The JNCL patients had a great number of severe psychiatric symptoms, with wide inter-individual variability. The most common symptoms were social, thought, attention, and sleep problems, somatic complaints, and aggressive behaviour. Patients with psychotropic treatment had more problems than did those without psychotropic treatment, and female patients had more problems than did males. Between 10 and 20% of the patients reported depressive symptoms. In a 5-year follow-up, [123I]β-CIT SPECT and MRI revealed a tendency of decreasing serotonin transporter (SERT) availability and progressive brain atrophy. The correlation between changes in midbrain SERT and total brain volume was positive; no correlation appeared between SERT or brain atrophy and depressive symptoms. Thus, it seems likely that the low SERT availability is associated with progressive brain atrophy; it may also predispose towards depression, however. An open survey of psychotropic drugs and their efficacy was performed on JNCL patients in Finland. The most commonly used psychotropic drugs were the antidepressant citalopram and the antipsychotic risperidone. Their efficacy was good or satisfactory in the majority of cases and they seemed well tolerated. Quetiapine had a marked effect on one patient with a history of severe psychotic symptoms. Glutamate decarboxylase 65 autoantibodies (GAD65ab), found in JNCL patients, indicate that an immunomediated reaction against GAD or GABAergic neurons may play a part in the underlying pathogenetic mechanism. GAD65ab s also appeared in the serum of all eight JNCL patients included and intermittent corticosteroid therapy was initiated in all cases. After one year, the GAD65ab s had disappeared in the two oldest patients, who experienced an improvement in motor symptoms and alertness associated with their prednisolone therapy. Two younger patients experienced a significant IQ increase, but no change in GADab s. A randomized study with longer follow-up time is needed, however, to clarify the effect of prednisolone on disease progression.

Nano-meter scale plasticity in KBr studied by nanoindenter and force microscopy

The early stages of plasticity in KBr single crystals have been studied by means of nano-meter-scale indentation in complementary experiments using both a nanoindenter and an atomic force microscope. Nanoindentafion experiments precisely correlate indentation depth and forces, while force microscopy provides high-resolution force measurements and images of the surface revealing dislocation activity. The two methods provide very similar results for the onset of plasticity in KBr. Upon loading we observe yield of the surface in atomic layer units which we attribute to the nucleation of single dislocations. Unloading is accompanied by plastic recovery as evident from a non-linear force distance unloading curve and delayed discrete plasticity events.

High-strength bulk Al-based bimodal ultrafine eutectic composite with enhanced plasticity

An in situ bulk ultrafine bimodal eutectic Al-Cu-Si composite was synthesized by solidification. This heterostructured composite with microstructural length scale hierarchy in the eutectic microstructure, which combines an ultrafine-scale binary cellular eutectic (alpha-Al + Al2Cu) and a nanometer-sized anomalous ternary eutectic (alpha-Al + Al2Cu + Si), exhibits high fracture strength (1.1 +/- 0.1 GPa) and large compressive plastic strain (11 +/- 2%) at room temperature. The improved compressive plasticity of the bimodal-nanoeutectic composite originates from homogeneous and uniform distribution of inhomogeneous plastic deformation (localized shear bands), together with strong interaction between shear bands in the spatially heterogeneous structure.

Characterization of mouse neuronal Ca2+/calmodulin kinase II inhibitor alpha

We have overexpressed an 8.5-kDa mouse Ca2+/calmodulin kinase II inhibitor a protein (mCaMKIIN alpha) in Escherichia coli and demonstrate that the recombinant protein is a potent inhibitor of Ca2+/calmodulin kinase 11 (CaMKII) in vitro. However, antibodies raised against recombinant mCaMKIIN alpha. react with an similar to 37-kDa protein present in mouse brain. The pattern of expression of the similar to 37-kDa protein is similar to that of mCaMKIIN alpha mRNA as both are expressed in normal but not Japanese encephalitis virus (JEV)-infected mouse brain. Subcellular localization studies indicate that the similar to 37-kDa protein is present in the post-synaptic density (PSD) where mCaMKII alpha is known to perform key regulatory functions. We conclude that the similar to 37-kDa protein identified in this study is mCaMKIIN alpha. and its localization in the PSD indicates a novel role for this protein in the regulation of neuronal CaMKII alpha. (c) 2007 Elsevier B.V. All rights reserved.

Structural plasticity and enzyme action: Crystal structures of Mycobacterium tuberculosis peptidyl-tRNA hydrolase

Peptidyl-tRNA hydrolase cleaves the ester bond between tRNA and the attached peptide in peptidyl-tRNA in order to avoid the toxicity resulting from its accumulation and to free the tRNA available for further rounds in protein synthesis. The structure of the enzyme from Mycobacteritan tuberculosis has been determined in three crystal forms. This structure and the structure of the enzyme frorn Escherichia coli in its crystal differ substantially on account of the binding of the C terminus of the E. coli enzyme to the peptide-binding site of a neighboring molecule in the crystal. A detailed examination of this difference led to an elucidation of the plasticity of the binding site of the enzyme. The peptide-binding site of the enzyme is a cleft between the body, of the molecule and a polypepticle Y stretch involving a loop and a helix. This stretch is in the open conformation when the enzyme is in the free state as in the crystals of M. tuberculosis peptidyl-tRNA hydrolase. Furthermore, there is no physical continuity between the tRNA and the peptide-binding sites. The molecule in the E. coli crystal mimics the peptide-bound enzyme molecule. The peptide stretch referred to earlier now closes on the bound peptide. Concurrently, a channel connecting the tRNA and the peptide-binding site opens primarily through the concerted movement of two residues. Thus, the crystal structure of M. tuberculosis peptidyl-tRNA hydrolase when compared with the crystal structure of the E. coli enzyme, leads to a model of structural changes associated with enzyme action on the basis of the plasticity of the molecule. (c) 2007 Elsevier Ltd. All rights reserved.

Characterisation of head-hardened rail steel in terms of cyclic plasticity response and microstructure for improved material modelling

Stress- and strain-controlled tests of heat treated high-strength rail steel (Australian Standard AS1085.1) have been performed in order to improve the characterisation of the said material׳s ratcheting and fatigue wear behaviour. The hardness of the rail head material has also been studied and it has been found that hardness reduces considerably below four-millimetres from the rail top surface. Historically, researchers have used test coupons with circular cross-sections to conduct cyclic load tests. Such test coupons, typically five-millimetres in gauge diameter and ten‐millimetres in grip diameter, are usually taken from the rail head sample. When there is considerable variation of material properties over the cross-section it becomes likely that localised properties of the rail material will be missed. In another case from the literature, disks 47 mm in diameter for a twin-disk rolling contact test machine were obtained directly from the rail sample and used to validate ratcheting and rolling contact fatigue wear models. The question arises: How accurate are such tests, especially when large material property gradients exist? In this research paper, the effects of rail sampling location on the ratcheting behaviour of AS1085.1 rail steel were investigated using rectangular-shaped specimens obtained at four different depths to observe their respective cyclic plasticity behaviour. The microstructural features of the test coupons were also analysed, especially the pearlite inter-lamellar spacing which showed strong correlation with both hardness and cyclic plasticity behaviour of the material. This work ultimately provides new data and testing methodology to aid the selection of valid parameters for material constitutive models to better understand rail surface ratcheting and wear.

Structural plasticity and enzyme action: Crystal structures of Mycobacterium tuberculosis peptidyl-tRNA hydrolase

Peptidyl-tRNA hydrolase cleaves the ester bond between tRNA and the attached peptide in peptidyl-tRNA in order to avoid the toxicity resulting from its accumulation and to free the tRNA available for further rounds in protein synthesis. The structure of the enzyme from Mycobacteritan tuberculosis has been determined in three crystal forms. This structure and the structure of the enzyme frorn Escherichia coli in its crystal differ substantially on account of the binding of the C terminus of the E. coli enzyme to the peptide-binding site of a neighboring molecule in the crystal. A detailed examination of this difference led to an elucidation of the plasticity of the binding site of the enzyme. The peptide-binding site of the enzyme is a cleft between the body, of the molecule and a polypepticle Y stretch involving a loop and a helix. This stretch is in the open conformation when the enzyme is in the free state as in the crystals of M. tuberculosis peptidyl-tRNA hydrolase. Furthermore, there is no physical continuity between the tRNA and the peptide-binding sites. The molecule in the E. coli crystal mimics the peptide-bound enzyme molecule. The peptide stretch referred to earlier now closes on the bound peptide. Concurrently, a channel connecting the tRNA and the peptide-binding site opens primarily through the concerted movement of two residues. Thus, the crystal structure of M. tuberculosis peptidyl-tRNA hydrolase when compared with the crystal structure of the E. coli enzyme, leads to a model of structural changes associated with enzyme action on the basis of the plasticity of the molecule. (c) 2007 Elsevier Ltd. All rights reserved.

Analysis of connectivity map: Control to glutamate injured and phenobarbital treated neuronal network

We study the responses of a cultured neural network when it is exposed to epileptogenesis glutamate injury causing epilepsy and subsequent treatment with phenobarbital by constructing connectivity map of neurons using correlation matrix. This study is particularly useful in understanding the pharmaceutical drug induced changes in the neuronal network properties with insights into changes at the systems biology level. (C) 2010 American Institute of Physics. [doi:10.1063/1.3398025]

Three-Dimensional simulation of deformation fields underneath vickers indenter:Effects of power-law Plasticity

The effects of power-law plasticity (yield strength and strain hardening exponent) on the plastic strain distribution underneath a Vickers indenter was systematically investigated by recourse to three-dimensional finite element analysis, motivated by the experimental macro-and micro-indentation on heat-treated Al-Zn-Mg alloy. For meaningful comparison between simulated and experimental results, the experimental heat treatment was carefully designed such that Al alloy achieve similar yield strength with different strain hardening exponent, and vice versa. On the other hand, full 3D simulation of Vickers indentation was conducted to capture subsurface strain distribution. Subtle differences and similarities were discussed based on the strain field shape, size and magnitude for the isolated effect of yield strength and strain hardening exponent.