2,390 research outputs found
Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition
BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations
A model of membrane contraction predicting initiation and completion of bacterial cell division
Bacterial cell division involves a complex and dynamic sequence of events whereby polymers of the protein FtsZ assemble at the division plane and rearrange to achieve the goal of contracting the cell membrane at the site of cell division, thus dividing the parent cell into two daughter cells. We present a mathematical model (which we refer to as CAM-FF: Critical Accumulation of Membrane-bound FtsZ Fibres) of the assembly of the contractile ring in terms of the accumulation of short linear polymers of FtsZ that associate and dissociate from the cell membrane. In prokaryotes, the biochemical function of FtsZ is thought to underpin the assembly and at least the initial kinetic force of ring contraction. Our model extends earlier work of Surovtsev et al. [PLoS Comput. Biol., 2008, 4, e1000102] by adding (i) the kinetics of FtsZ accumulation on cell membrane anchor proteins and (ii) the physical forces required to deform the cell against its surface tension. Moreover, we provide a more rigorous treatment of intracellular diffusion and we revise some of the model parameter values in light of the experimental evidence now available. We derive a critical contraction parameter which links the chemical population dynamics of membrane-bound FtsZ molecules to the force of contraction. Using this parameter as a tool to predict the ability of the cell to initiate division, we are able to predict the division outcome in cells depleted of key FtsZ-binding proteins
Fermionic partner of Quintessence field as candidate for dark matter
Quintessence is a possible candidate for dark energy. In this paper we study
the phenomenologies of the fermionic partner of Quintessence, the Quintessino.
Our results show that, for suitable choices of the model parameters, the
Quintessino is a good candidate for cold or warm dark matter. In our scenario,
dark energy and dark matter of the Universe are connected in one chiral
superfield.Comment: 4 pages, 3 figures, version to appear in PR
A SIMULATED REDUCTION IN ANTARCTIC SEA-ICE AREA SINCE 1750: IMPLICATIONS OF THE LONG MEMORY OF THE OCEAN
Using the three-dimensional coarse-resolution climate model ECBILT-CLIO, 1000-year long ensemble simulations with natural and anthropogenic forcings have been performed to study the long-term variation of the ice cover in the Southern Ocean. Over the last 250 years, the ice area has decreased by about 1 x 10(6) km(2) in its annual mean. A comparison with experiments driven by only natural forcings suggests that this reduction is due to both natural and anthropogenic forcing, the latter playing a larger role than natural forcing over the last 150 years. Despite this contribution from anthropogenic forcing, the simulated ice area at the end of the 20th century is similar to that simulated during the 14th century because of the slow response of the Southern Ocean to radiative forcing. Sensitivity experiments performed with the model show that the model's initial conditions have a large influence on the simulated ice cover and that it is necessary to start simulations at least two centuries before the period of interest in order to remove this influence. Copyright (c) 2005 Royal Meteorological Society
Lepton Flavor Violation and the Origin of the Seesaw Mechanism
The right--handed neutrino mass matrix that is central to the understanding
of small neutrino masses via the seesaw mechanism can arise either (i) from
renormalizable operators or (ii) from nonrenormalizable or super-renormalizable
operators, depending on the symmetries and the Higgs content of the theory
beyond the Standard Model. In this paper, we study lepton flavor violating
(LFV) effects in the first class of seesaw models wherein the \nu_R Majorana
masses arise from renormalizable Yukawa couplings involving a B-L = 2 Higgs
field. We present detailed predictions for \tau -> \mu + \gamma and \mu -> e +
\gamma branching ratios in these models taking the current neutrino oscillation
data into account. Focusing on minimal supergravity models, we find that for a
large range of MSSM parameters suggested by the relic abundance of neutralino
dark matter and that is consistent with Higgs boson mass and other constraints,
these radiative decays are in the range accessible to planned experiments. We
compare these predictions with lepton flavor violation in the second class of
models arising entirely from the Dirac Yukawa couplings. We study the
dependence of the ratio r \equiv B(\mu -> e+\gamma)/B(\tau ->\mu +\gamma) on
the MSSM parameters and show that measurement of r can provide crucial insight
into the origin of the seesaw mechanism.Comment: 20 pages, Revtex, 7 figure
Statefinder diagnostic for coupled quintessence
The problem of the cosmic coincidence is a longstanding puzzle. This
conundrum may be solved by introducing a coupling between the two dark sectors.
In this Letter, we study two cases of the coupled quintessence scenario.
Assume that the mass of dark matter particles depends exponentially on the
scalar field associated to dark energy and meanwhile the scalar field evolves
in an exponential potential; Assume that the mass of dark matter
particles depends on a power law function of the scalar field and meanwhile the
scalar field evolves in a power law potential. Since the dynamics of this
system is dominated by an attractor solution, the mass of dark matter particles
is forced to change with time as to ensure that the ratio between the energy
densities of dark matter and dark energy becomes a constant at late times, and
one thus solve the cosmic coincidence problem naturally. We perform a
statefinder diagnostic to both cases of this coupled quintessence scenario. It
is shown that the evolving trajectory of this scenario in the diagram is
quite different from those of other dark energy models.Comment: 12 pages, 6 figures, to appear in Phys. Lett.
Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)
Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1α), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically
The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state
We introduce and analyze a minimal model of epigenetic silencing in budding
yeast, built upon known biomolecular interactions in the system. Doing so, we
identify the epigenetic marks essential for the bistability of epigenetic
states. The model explicitly incorporates two key chromatin marks, namely H4K16
acetylation and H3K79 methylation, and explores whether the presence of
multiple marks lead to a qualitatively different systems behavior. We find that
having both modifications is important for the robustness of epigenetic
silencing. Besides the silenced and transcriptionally active fate of chromatin,
our model leads to a novel state with bivalent (i.e., both active and
silencing) marks under certain perturbations (knock-out mutations, inhibition
or enhancement of enzymatic activity). The bivalent state appears under several
perturbations and is shown to result in patchy silencing. We also show that the
titration effect, owing to a limited supply of silencing proteins, can result
in counter-intuitive responses. The design principles of the silencing system
is systematically investigated and disparate experimental observations are
assessed within a single theoretical framework. Specifically, we discuss the
behavior of Sir protein recruitment, spreading and stability of silenced
regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the
controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page
Regenerative Medicine Therapies: lessons from the kidney
We focus on three strategies for renal regenerative medicine; administering cells to replace damaged tissue, promoting endogenous regeneration, and growing stem cell-derived organs. Mouse kidney regeneration can be promoted by stem cells injected into the circulation which do not become new kidney tissue but seem to secrete regeneration-promoting humoral factors. This argues against direct replacement but encourages developing pharmacological stimulators of endogenous regeneration. Simple 'kidneys' have been made from stem cells, but there is a large gap between what has been achieved and a useful transplantable organ. Most current work aims to stimulate endogenous regeneration or to grow new organs but much remains to be done; misplaced hype about short-term prospects of regenerative medicine helps neither researchers nor patients
Establishing Biomechanical Mechanisms in Mouse Models: Practical Guidelines for Systematically Evaluating Phenotypic Changes in the Diaphyses of Long Bones
Mice are widely used in studies of skeletal biology, and assessment of their bones by mechanical testing is a critical step when evaluating the functional effects of an experimental perturbation. For example, a gene knockout may target a pathway important in bone formation and result in a âlow bone massâ phenotype. But how well does the skeleton bear functional loads; eg, how much do bones deform during loading and how resistant are bones to fracture? By systematic evaluation of bone morphological, densitometric, and mechanical properties, investigators can establish the âbiomechanical mechanismsâ whereby an experimental perturbation alters wholeâbone mechanical function. The goal of this review is to clarify these biomechanical mechanisms and to make recommendations for systematically evaluating phenotypic changes in mouse bones, with a focus on longâbone diaphyses and cortical bone. Further, minimum reportable standards for testing conditions and outcome variables are suggested that will improve the comparison of data across studies. Basic biomechanical principles are reviewed, followed by a description of the crossâsectional morphological properties that best inform the net cellular effects of a given experimental perturbation and are most relevant to biomechanical function. Although morphology is critical, wholeâbone mechanical properties can only be determined accurately by a mechanical test. The functional importance of stiffness, maximum load, postyield displacement, and workâtoâfracture are reviewed. Because bone and body size are often strongly related, strategies to adjust wholeâbone properties for body mass are detailed. Finally, a comprehensive framework is presented using real data, and several examples from the literature are reviewed to illustrate how to synthesize morphological, tissueâlevel, and wholeâbone mechanical properties of mouse long bones. © 2015 American Society for Bone and Mineral ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111801/1/jbmr2539.pd
- âŠ