A varA variational principle for discrete integrable systemsiational principle for discrete integrable systems

For integrable systems in the sense of multidimensional consistency (MDC) we can consider the Lagrangian as a form, which is closed on solutions of the equations of motion. For 2-dimensional systems, described by partial difference equations with two independent variables, MDC allows us to define an action on arbitrary 2-dimensional surfaces embedded in a higher dimensional space of independent variables, where the action is not only a functional of the field variables but also the choice of surface. It is then natural to propose that the system should be derived from a variational principle which includes not only variations with respect to the dependent variables, but also with respect to variations of the surface in the space of independent variables. Here we derive the resulting system of generalized Euler-Lagrange equations arising from that principle. We treat the case where the equations are 2 dimensional (but which due to MDC can be consistently embedded in higher-dimensional space), and show that they can be integrated to yield relations of quadrilateral type. We also derive the extended set of Euler-Lagrange equations for 3-dimensional systems, i.e., those for equations with 3 independent variables. The emerging point of view from this study is that the variational principle can be considered as the set of equations not only encoding the equations of motion but as the defining equations for the Lagrangians themselves

Human Telomerase Reverse Transcriptase (hTERT) Q169 Is Essential for Telomerase Function In Vitro and In Vivo

BACKGROUND:Telomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA-binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS:To understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non-conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function. CONCLUSIONS/SIGNIFICANCE:We provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention

Regulation of Spike Timing-Dependent Plasticity of Olfactory Inputs in Mitral Cells in the Rat Olfactory Bulb

The recent history of activity input onto granule cells (GCs) in the main olfactory bulb can affect the strength of lateral inhibition, which functions to generate contrast enhancement. However, at the plasticity level, it is unknown whether and how the prior modification of lateral inhibition modulates the subsequent induction of long-lasting changes of the excitatory olfactory nerve (ON) inputs to mitral cells (MCs). Here we found that the repetitive stimulation of two distinct excitatory inputs to the GCs induced a persistent modification of lateral inhibition in MCs in opposing directions. This bidirectional modification of inhibitory inputs differentially regulated the subsequent synaptic plasticity of the excitatory ON inputs to the MCs, which was induced by the repetitive pairing of excitatory postsynaptic potentials (EPSPs) with postsynaptic bursts. The regulation of spike timing-dependent plasticity (STDP) was achieved by the regulation of the inter-spike-interval (ISI) of the postsynaptic bursts. This novel form of inhibition-dependent regulation of plasticity may contribute to the encoding or processing of olfactory information in the olfactory bulb

Interferon-β reduces proteinuria in experimental glomerulonephritis

Interferon-β (IFN-β) is a multifunctional cytokine with immunomodulatory properties. We examined the effect of IFN-β in three separate rat models of glomerular injury and in cultured human glomerular endothelial cells and podocytes. In nephrotoxic nephritis in WKY rats, recombinant rat IFN-β started either at induction or after establishment of disease significantly reduced 24-h proteinuria by up to 73% and 51%, respectively, but did not affect serum creatinine. There was a slight reduction in numbers of glomerular macrophages, but no difference in glomerular or tubulointerstitial scarring. In Thy-1 nephritis in Lewis rats, IFN-β started at induction of disease reduced proteinuria by up to 66% with no effect on numbers of glomerular macrophages, but a reduced number of proliferating cells. In puromycin nephropathy in Wistar rats, IFN-β started at induction of disease reduced proteinuria by up to 93%, but had no effect on glomerular histology. In cultured cells, human IFN-β-1a had a dramatic effect on barrier properties, increasing electrical resistance across monolayers of either glomerular endothelial cells or podocytes and decreasing trans-monolayer passage of albumin. In conclusion, these results show that IFN-β reduces proteinuria in three different rat models of glomerular injury and that its anti-proteinuric action may result from direct effects on cells that comprise the glomerular filtration barrier. These data indicate that IFN-β may have potential as a therapeutic agent in proteinuric renal disease. Copyright © 2007 by the American Society of Nephrology.link_to_subscribed_fulltex

Going above and beyond for implementation: the development and validity testing of the Implementation Citizenship Behavior Scale (ICBS)

BACKGROUND: In line with recent research on the role of the inner context of organizations in implementation effectiveness, this study extends research on organizational citizenship behavior (OCB) to the domain of evidence-based practice (EBP) implementation. OCB encompasses those behaviors that go beyond what is required for a given job that contribute to greater organizational effectiveness. The goal of this study was to develop and test a measure of implementation citizenship behavior (ICB) or those behaviors that employees perform that go above and beyond what is required in order to support EBP implementation. METHODS: The primary participants were 68 supervisors from ten mental health agencies throughout California. Items measuring ICB were developed based on past research on OCB and in consultation with experts on EBP implementation in mental health settings. Supervisors rated 357 of their subordinates on ICB and implementation success. In addition, 292 of the subordinates provided data on self-rated performance, attitudes towards EBPs, work experience, and full-time status. The supervisor sample was randomly split, with half used for exploratory factor analyses and the other half for confirmatory factor analyses. The entire sample of supervisors and subordinates was utilized for analyses assessing the reliability and construct validity of the measure. RESULTS: Exploratory factor analyses supported the proposed two-factor structure of the Implementation Citizenship Behavior Scale (ICBS): (1) Helping Others and (2) Keeping Informed. Confirmatory factor analyses with the other half of the sample supported the factor structure. Additional analyses supported the reliability and construct validity for the ICBS. CONCLUSIONS: The ICBS is a pragmatic brief measure (six items) that captures critical behaviors employees perform to go above and beyond the call of duty to support EBP implementation, including helping their fellow employees on implementation-related activities and keeping informed about issues related to EBP and implementation efforts. The ICBS can be used by researchers to better understand the outcomes of improved organizational support for implementation (i.e., implementation climate) and the proximal predictors of implementation effectiveness. The ICBS can also provide insight for organizations, practitioners, and managers by focusing on key employee behaviors that should increase the probability of implementation success. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13012-015-0255-8) contains supplementary material, which is available to authorized users