Experimental Evidence for Efimov Quantum States

Three interacting particles form a system which is well known for its complex physical behavior. A landmark theoretical result in few-body quantum physics is Efimov's prediction of a universal set of weakly bound trimer states appearing for three identical bosons with a resonant two-body interaction. Surprisingly, these states even exist in the absence of a corresponding two-body bound state and their precise nature is largely independent of the particular type of the two-body interaction potential. Efimov's scenario has attracted great interest in many areas of physics; an experimental test however has not been achieved. We report the observation of an Efimov resonance in an ultracold thermal gas of cesium atoms. The resonance occurs in the range of large negative two-body scattering lengths and arises from the coupling of three free atoms to an Efimov trimer. We observe its signature as a giant three-body recombination loss when the strength of the two-body interaction is varied near a Feshbach resonance. This resonance develops into a continuum resonance at non-zero collision energies, and we observe a shift of the resonance position as a function of temperature. We also report on a minimum in the recombination loss for positive scattering lengths, indicating destructive interference of decay pathways. Our results confirm central theoretical predictions of Efimov physics and represent a starting point from which to explore the universal properties of resonantly interacting few-body systems.Comment: 8 pages, 4 figures, Proceedings of ICAP-2006 (Innsbruck

Viscosity Dependence of the Folding Rates of Proteins

The viscosity dependence of the folding rates for four sequences (the native state of three sequences is a beta-sheet, while the fourth forms an alpha-helix) is calculated for off-lattice models of proteins. Assuming that the dynamics is given by the Langevin equation we show that the folding rates increase linearly at low viscosities \eta, decrease as 1/\eta at large \eta and have a maximum at intermediate values. The Kramers theory of barrier crossing provides a quantitative fit of the numerical results. By mapping the simulation results to real proteins we estimate that for optimized sequences the time scale for forming a four turn \alpha-helix topology is about 500 nanoseconds, whereas the time scale for forming a beta-sheet topology is about 10 microseconds.Comment: 14 pages, Latex, 3 figures. One figure is also available at http://www.glue.umd.edu/~klimov/seq_I_H.html, to be published in Physical Review Letter

Evidence for Efimov quantum states in an ultracold gas of cesium atoms

Systems of three interacting particles are notorious for their complex physical behavior. A landmark theoretical result in few-body quantum physics is Efimov's prediction of a universal set of bound trimer states appearing for three identical bosons with a resonant two-body interaction. Counterintuitively, these states even exist in the absence of a corresponding two-body bound state. Since the formulation of Efimov's problem in the context of nuclear physics 35 years ago, it has attracted great interest in many areas of physics. However, the observation of Efimov quantum states has remained an elusive goal. Here we report the observation of an Efimov resonance in an ultracold gas of cesium atoms. The resonance occurs in the range of large negative two-body scattering lengths, arising from the coupling of three free atoms to an Efimov trimer. Experimentally, we observe its signature as a giant three-body recombination loss when the strength of the two-body interaction is varied. We also detect a minimum in the recombination loss for positive scattering lengths, indicating destructive interference of decay pathways. Our results confirm central theoretical predictions of Efimov physics and represent a starting point with which to explore the universal properties of resonantly interacting few-body systems. While Feshbach resonances have provided the key to control quantum-mechanical interactions on the two-body level, Efimov resonances connect ultracold matter to the world of few-body quantum phenomena.Comment: 18 pages, 3 figure

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Does gamma-aminobutyric acid (GABA) influence the development of chronic inflammation in rheumatoid arthritis?

<p>Abstract</p> <p>Background</p> <p>Recent studies have demonstrated a role for spinal p38 MAP kinase (MAPK) in the development of chronic inflammation and peripheral arthritis and a role for GABA in the inhibition of p38 MAPK mediated effects. Integrating these data suggests that GABA may play a role in downregulating mechanisms that lead to the production of proinflammatory agents such as interleukin-1, interleukin-6, and matrix metalloproteinase 3 – agents implicated in the pathogenesis of rheumatoid arthritis (RA). Genetic studies have also associated RA with members of the p38 MAPK pathway.</p> <p>Hypothesis</p> <p>We propose a hypothesis for an inefficient GABA signaling system that results in unchecked proinflammatory cytokine production via the p38 MAPK pathway. This model also supports the need for increasing research in the integration of immunology and neuroscience.</p

Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide

The PhoQ/PhoP signaling system responds to low magnesium and the presence of certain cationic antimicrobial peptides. It regulates genes important for growth under these conditions, as well as additional genes important for virulence in many gram-negative pathogens. PhoQ is a sensor kinase that phosphorylates and activates the transcription factor PhoP. Since feedback inhibition is a common theme in stress-response circuits, we hypothesized that some members of the PhoP regulon may play such a role in the PhoQ/PhoP pathway. We therefore screened for PhoP-regulated genes that mediate feedback in this system. We found that deletion of mgrB (yobG), which encodes a 47 amino acid peptide, results in a potent increase in PhoP-regulated transcription. In addition, over-expression of mgrB decreased transcription at both high and low concentrations of magnesium. Localization and bacterial two-hybrid studies suggest that MgrB resides in the inner-membrane and interacts directly with PhoQ. We further show that MgrB homologs from Salmonella typhimurium and Yersinia pestis also repress PhoP-regulated transcription in these organisms. In cell regulatory circuits, feedback has been associated with modulating the induction kinetics and/or the cell-to-cell variability in response to stimulus. Interestingly, we found that elimination of MgrB-mediated feedback did not have a significant effect on the kinetics of reporter protein production and did not decrease the variability in expression among cells. Our results indicate MgrB is a broadly conserved membrane peptide that is a critical mediator of negative feedback in the PhoQ/PhoP circuit. This new regulator may function as a point of control that integrates additional input signals to modulate the activity of this important signaling system

Stabilizing Salt-Bridge Enhances Protein Thermostability by Reducing the Heat Capacity Change of Unfolding

Most thermophilic proteins tend to have more salt bridges, and achieve higher thermostability by up-shifting and broadening their protein stability curves. While the stabilizing effect of salt-bridge has been extensively studied, experimental data on how salt-bridge influences protein stability curves are scarce. Here, we used double mutant cycles to determine the temperature-dependency of the pair-wise interaction energy and the contribution of salt-bridges to ΔCp in a thermophilic ribosomal protein L30e. Our results showed that the pair-wise interaction energies for the salt-bridges E6/R92 and E62/K46 were stabilizing and insensitive to temperature changes from 298 to 348 K. On the other hand, the pair-wise interaction energies between the control long-range ion-pair of E90/R92 were negligible. The ΔCp of all single and double mutants were determined by Gibbs-Helmholtz and Kirchhoff analyses. We showed that the two stabilizing salt-bridges contributed to a reduction of ΔCp by 0.8–1.0 kJ mol−1 K−1. Taken together, our results suggest that the extra salt-bridges found in thermophilic proteins enhance the thermostability of proteins by reducing ΔCp, leading to the up-shifting and broadening of the protein stability curves

The Transcription Factor AmrZ Utilizes Multiple DNA Binding Modes to Recognize Activator and Repressor Sequences of Pseudomonas aeruginosa Virulence Genes

AmrZ, a member of the Ribbon-Helix-Helix family of DNA binding proteins, functions as both a transcriptional activator and repressor of multiple genes encoding Pseudomonas aeruginosa virulence factors. The expression of these virulence factors leads to chronic and sustained infections associated with worsening prognosis. In this study, we present the X-ray crystal structure of AmrZ in complex with DNA containing the repressor site, amrZ1. Binding of AmrZ to this site leads to auto-repression. AmrZ binds this DNA sequence as a dimer-of-dimers, and makes specific base contacts to two half sites, separated by a five base pair linker region. Analysis of the linker region shows a narrowing of the minor groove, causing significant distortions. AmrZ binding assays utilizing sequences containing variations in this linker region reveals that secondary structure of the DNA, conferred by the sequence of this region, is an important determinant in binding affinity. The results from these experiments allow for the creation of a model where both intrinsic structure of the DNA and specific nucleotide recognition are absolutely necessary for binding of the protein. We also examined AmrZ binding to the algD promoter, which results in activation of the alginate exopolysaccharide biosynthetic operon, and found the protein utilizes different interactions with this site. Finally, we tested the in vivo effects of this differential binding by switching the AmrZ binding site at algD, where it acts as an activator, for a repressor binding sequence and show that differences in binding alone do not affect transcriptional regulation

Targeting neuroinflammation for therapeutic intervention in neurodegenerative pathologies: A role for the peptide analogue of thymulin (PAT)

Introduction: Inflammation has a vital task in protecting the organism, but when deregulated, it can have serious pathological consequences. The central nervous system (CNS) is capable of mounting immune and inflammatory responses, albeit different from that observed in the periphery. Neuroinflammation, however, can be a major contributor to neurodegenerative diseases and constitute a major challenge for medicine and basic research. Areas covered: Both innate and adaptive immune responses normally play an important role in homeostasis within the CNS. Microglia, astrocytes and neuronal cells express a wide array of toll-like receptors (TLR) that can be upregulated by infection, trauma, injuries and various exogenic or endogenic factors. Chronic hyper activation of brain immune cells can result in neurotoxic actions due to excessive production of several pro-inflammatory mediators. Several studies have recently described an important role for targeting receptors such as nicotinic receptors located on cells in the CNS or in other tissues for the control of inflammation. Expert opinion: Thymulin and its synthetic peptide analogue (PAT) appear to exert potent anti-inflammatory effects at the level of peripheral tissues as well as at the level of the brain. This effect involves, at least partially, the activation of cholinergic mechanisms. © 2012 Informa UK, Ltd