159 research outputs found
Bistability in Apoptosis by Receptor Clustering
Apoptosis is a highly regulated cell death mechanism involved in many
physiological processes. A key component of extrinsically activated apoptosis
is the death receptor Fas, which, on binding to its cognate ligand FasL,
oligomerize to form the death-inducing signaling complex. Motivated by recent
experimental data, we propose a mathematical model of death ligand-receptor
dynamics where FasL acts as a clustering agent for Fas, which form locally
stable signaling platforms through proximity-induced receptor interactions.
Significantly, the model exhibits hysteresis, providing an upstream mechanism
for bistability and robustness. At low receptor concentrations, the bistability
is contingent on the trimerism of FasL. Moreover, irreversible bistability,
representing a committed cell death decision, emerges at high concentrations,
which may be achieved through receptor pre-association or localization onto
membrane lipid rafts. Thus, our model provides a novel theory for these
observed biological phenomena within the unified context of bistability.
Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our
model also suggests a mechanism by which cells may function as bistable
life/death switches independently of any such dynamics in their downstream
components. Our results highlight the role of death receptors in deciding cell
fate and add to the signal processing capabilities attributed to receptor
clustering.Comment: Accepted by PLoS Comput Bio
Long-term safety and efficacy of eculizumab in generalized myasthenia gravis
Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy.
Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients.
Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001).
Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 201
Mixing in Circular and Non-circular Jets in Crossflow
Coherent structures and mixing in the flow field of a jet in crossflow have been studied using computational (large eddy simulation) and experimental (particle image velocimetry and laser-induced fluorescence) techniques. The mean scalar fields and turbulence statistics as determined by both are compared for circular, elliptic, and square nozzles. For the latter configurations, effects of orientation are considered. The computations reveal that the distribution of a passive scalar in a cross-sectional plane can be single- or double-peaked, depending on the nozzle shape and orientation. A proper orthogonal decomposition of the transverse velocity indicates that coherent structures may be responsible for this phenomenon. Nozzles which have a single-peaked distribution have stronger modes in transverse direction. The global mixing performance is superior for these nozzle types. This is the case for the blunt square nozzle and for the elliptic nozzle with high aspect ratio. It is further demonstrated that the flow field contains large regions in which a passive scalar is transported up the mean gradient (counter-gradient transport) which implies failure of the gradient diffusion hypothesis
Broad-Spectrum Antiviral Therapeutics
Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.National Institute of Allergy and Infectious Diseases (U.S.) (grant AI057159)New England Regional Center of Excellence for Biodefense and Emerging Infectious DiseasesUnited States. Dept. of Defense (Director of Defense Research & Engineering)United States. Defense Threat Reduction AgencyUnited States. Defense Advanced Research Projects Agenc
Enzyme-Catalyzed Macrocyclization of Long Unprotected Peptides
A glutathione S-transferase (GST) catalyzed macrocyclization reaction for peptides up to 40 amino acids in length is reported. GST catalyzes the selective SNAr reaction between an N-terminal glutathione (GSH, γ-Glu-Cys-Gly) tag and a C-terminal perfluoroaryl-modified cysteine on the same polypeptide chain. Cyclic peptides ranging from 9 to 24 residues were quantitatively produced within 2 h in aqueous pH = 8 buffer at room temperature. The reaction was highly selective for cyclization at the GSH tag, enabling the combination of GST-catalyzed ligation with native chemical ligation to generate a large 40-residue peptide macrocycle.Massachusetts Institute of Technology (MIT startup funds)National Institutes of Health (U.S.) (grant GM101762)Damon Runyon Cancer Research Foundation (Award)Sontag Foundation (Distinguished Scientist Award)Amgen Inc. (Summer Graduate Research Fellowship
Targeting A20 Decreases Glioma Stem Cell Survival and Tumor Growth
The A20 protein is a known inhibitor of apoptosis that here is shown to be a novel cancer stem cell-promoting factor associated with poor glioma patient survival
Consensus guidelines for the use and interpretation of angiogenesis assays
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference
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