Progress and the individual

An address delivered at the twentieth commencement convocation of the Rice Institute by Ralph Budd, President of the Burlington Lines

Reactive oxygen species induce virus-independent MAVS-oligomerization in systemic lupus erythematosus

The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)–like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress–induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome

Towards Symbolic Model-Based Mutation Testing: Combining Reachability and Refinement Checking

Model-based mutation testing uses altered test models to derive test cases that are able to reveal whether a modelled fault has been implemented. This requires conformance checking between the original and the mutated model. This paper presents an approach for symbolic conformance checking of action systems, which are well-suited to specify reactive systems. We also consider nondeterminism in our models. Hence, we do not check for equivalence, but for refinement. We encode the transition relation as well as the conformance relation as a constraint satisfaction problem and use a constraint solver in our reachability and refinement checking algorithms. Explicit conformance checking techniques often face state space explosion. First experimental evaluations show that our approach has potential to outperform explicit conformance checkers.Comment: In Proceedings MBT 2012, arXiv:1202.582

Caspase Activation Is Required for T Cell Proliferation

Triggering of Fas (CD95) by its ligand (FasL) rapidly induces cell death via recruitment of the adaptor protein Fas-associated death domain (FADD), resulting in activation of a caspase cascade. It was thus surprising that T lymphocytes deficient in FADD were reported recently to be not only resistant to FasL-mediated apoptosis, but also defective in their proliferative capacity. This finding suggested potentially dual roles of cell growth and death for Fas and possibly other death receptors. We report here that CD3-induced proliferation and interleukin 2 production by human T cells are blocked by inhibitors of caspase activity. This is paralleled by rapid cleavage of caspase-8 after CD3 stimulation, but no detectable processing of caspase-3 during the same interval. The caspase contribution to T cell activation may occur via TCR-mediated upregulation of FasL, as Fas-Fc blocked T cell proliferation, whereas soluble FasL augmented CD3-induced proliferation. These findings extend the role of death receptors to the promotion of T cell growth in a caspase-dependent manner

Prognostic modeling studies of the Keweenaw Current in Lake Superior. Part II: Simulation,

ABSTRACT The formation and evolution of the Keweenaw Current in Lake Superior were examined using a nonorthogonalcoordinate primitive equation numerical model. The model was initialized by the monthly averaged temperature field observed in June and September 1973 and run prognostically under different forcing conditions with and without winds. As a Rossby adjustment problem, the model predicted the formation of a well-defined coastal current jet within an inertial period of 16.4 h after the current field adjusted to the initial temperature field. The magnitude and direction of this current jet varied with the cross-shelf temperature gradient and wind velocity. It tended to intensify during northeastward (downwelling favorable) winds, and to lessen, or even reverse, during southwestward to northwestward (upwelling favorable) or southeastward (downwelling favorable) winds. In a case with strong stratification and without external atmospheric forcings, a well-defined clockwise warm-core eddy formed near the northeastern coast of the Keweenaw Peninsula as a result of baroclinic instability. A warmcore eddy was detected recently from satellite surface temperature images, the shape and location of which were very similar to those of the model-predicted eddy. The energy budget analysis suggested that the eddy kinetic energy grew exponentially over a timescale of 7 days. Growth was due to a rapid energy transfer from available eddy potential energy. The subsequent decline of the eddy kinetic energy was the result of turbulent diffusion, transfer from the eddy kinetic energy to mean kinetic energy, and outward net energy flux

Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice.

OBJECTIVES: Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants. METHODS: Lupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function. RESULTS: MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody . CONCLUSIONS: These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus

Iron Age and Anglo-Saxon genomes from East England reveal British migration history

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain

The CD95 Receptor: Apoptosis Revisited

CD95 is the quintessential death receptor and, when it is bound by ligand, cells undergo apoptosis. Recent evidence suggests, however, that CD95 mediates not only apoptosis but also diverse nonapoptotic functions depending on the tissue and the conditions