212 research outputs found
Garden of therapeutic delights: new targets in rheumatic diseases
Advances in our understanding of the cellular and molecular mechanisms in rheumatic disease fostered the advent of the targeted therapeutics era. Intense research activity continues to increase the number of potential targets at an accelerated pace. In this review, examples of promising targets and agents that are at various stages of clinical development are described. Cytokine inhibition remains at the forefront with the success of tumor necrosis factor blockers, and biologics that block interleukin-6 (IL-6), IL-17, IL-12, and IL-23 and other cytokines are on the horizon. After the success of rituximab and abatacept, other cell-targeted approaches that inhibit or deplete lymphocytes have moved forward, such as blocking BAFF/BLyS (B-cell activation factor of the tumor necrosis factor family/B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) or suppressing T-cell activation with costimulation molecule blockers. Small-molecule inhibitors might eventually challenge the dominance of biologics in the future. In addition to plasma membrane G protein-coupled chemokine receptors, small molecules can be designed to block intracellular enzymes that control signaling pathways. Inhibitors of tyrosine kinases expressed in lymphocytes, such as spleen tyrosine kinase and Janus kinase, are being tested in autoimmune diseases. Inactivation of the more broadly expressed mitogen-activated protein kinases could suppress inflammation driven by macrophages and mesenchymal cells. Targeting tyrosine kinases downstream of growth factor receptors might also reduce fibrosis in conditions like systemic sclerosis. The abundance of potential targets suggests that new and creative ways of evaluating safety and efficacy are needed
Observation of Feshbach-like resonances in collisions between ultracold molecules
We observe magnetically tuned collision resonances for ultracold Cs2
molecules stored in a CO2-laser trap. By magnetically levitating the molecules
against gravity, we precisely measure their magnetic moment. We find an avoided
level crossing which allows us to transfer the molecules into another state. In
the new state, two Feshbach-like collision resonances show up as strong
inelastic loss features. We interpret these resonances as being induced by Cs4
bound states near the molecular scattering continuum. The tunability of the
interactions between molecules opens up novel applications such as controlled
chemical reactions and synthesis of ultracold complex molecules
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
`St\"uckelberg interferometry' with ultracold molecules
We report on the realization of a time-domain `St\"uckelberg interferometer',
which is based on the internal state structure of ultracold Feshbach molecules.
Two subsequent passages through a weak avoided crossing between two different
orbital angular momentum states in combination with a variable hold time lead
to high-contrast population oscillations. This allows for a precise
determination of the energy difference between the two molecular states. We
demonstrate a high degree of control over the interferometer dynamics. The
interferometric scheme provides new possibilities for precision measurements
with ultracold molecules.Comment: 4 pages, 5 figure
Transport Coefficients from Large Deviation Functions
We describe a method for computing transport coefficients from the direct
evaluation of large deviation function. This method is general, relying on only
equilibrium fluctuations, and is statistically efficient, employing trajectory
based importance sampling. Equilibrium fluctuations of molecular currents are
characterized by their large deviation functions, which is a scaled cumulant
generating function analogous to the free energy. A diffusion Monte Carlo
algorithm is used to evaluate the large deviation functions, from which
arbitrary transport coefficients are derivable. We find significant statistical
improvement over traditional Green-Kubo based calculations. The systematic and
statistical errors of this method are analyzed in the context of specific
transport coefficient calculations, including the shear viscosity, interfacial
friction coefficient, and thermal conductivity.Comment: 11 pages, 5 figure
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
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