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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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. $(a)$ 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; $(b)$ 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 $s-r$ 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 “low bone mass” 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 “biomechanical mechanisms” whereby an experimental perturbation alters whole‐bone 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 long‐bone 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 cross‐sectional 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, whole‐bone mechanical properties can only be determined accurately by a mechanical test. The functional importance of stiffness, maximum load, postyield displacement, and work‐to‐fracture are reviewed. Because bone and body size are often strongly related, strategies to adjust whole‐bone 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, tissue‐level, and whole‐bone 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