Regulation Of Plasma Von Willebrand Factor (Vwf) By Modifier Genes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106136/1/jth01723.pd

Admit your weakness: Verifying correctness on TSO architectures

“The final publication is available at http://link.springer.com/chapter/10.1007%2F978-3-319-15317-9_22 ”.Linearizability has become the standard correctness criterion for fine-grained non-atomic concurrent algorithms, however, most approaches assume a sequentially consistent memory model, which is not always realised in practice. In this paper we study the correctness of concurrent algorithms on a weak memory model: the TSO (Total Store Order) memory model, which is commonly implemented by multicore architectures. Here, linearizability is often too strict, and hence, we prove a weaker criterion, quiescent consistency instead. Like linearizability, quiescent consistency is compositional making it an ideal correctness criterion in a component-based context. We demonstrate how to model a typical concurrent algorithm, seqlock, and prove it quiescent consistent using a simulation-based approach. Previous approaches to proving correctness on TSO architectures have been based on linearizabilty which makes it necessary to modify the algorithm’s high-level requirements. Our approach is the first, to our knowledge, for proving correctness without the need for such a modification

Correctness of an STM Haskell implementation

A concurrent implementation of software transactional memory in Concurrent Haskell using a call-by-need functional language with processes and futures is given. The description of the small-step operational semantics is precise and explicit, and employs an early abort of conflicting transactions. A proof of correctness of the implementation is given for a contextual semantics with may- and should-convergence. This implies that our implementation is a correct evaluator for an abstract specification equipped with a big-step semantics

Quiescent consistency: Defining and verifying relaxed linearizability

Concurrent data structures like stacks, sets or queues need to be highly optimized to provide large degrees of parallelism with reduced contention. Linearizability, a key consistency condition for concurrent objects, sometimes limits the potential for optimization. Hence algorithm designers have started to build concurrent data structures that are not linearizable but only satisfy relaxed consistency requirements. In this paper, we study quiescent consistency as proposed by Shavit and Herlihy, which is one such relaxed condition. More precisely, we give the first formal definition of quiescent consistency, investigate its relationship with linearizability, and provide a proof technique for it based on (coupled) simulations. We demonstrate our proof technique by verifying quiescent consistency of a (non-linearizable) FIFO queue built using a diffraction tree. © 2014 Springer International Publishing Switzerland

Plasticity of the cis-Regulatory Input Function of a Gene

The transcription rate of a gene is often controlled by several regulators that bind specific sites in the gene's cis-regulatory region. The combined effect of these regulators is described by a cis-regulatory input function. What determines the form of an input function, and how variable is it with respect to mutations? To address this, we employ the well-characterized lac operon of Escherichia coli, which has an elaborate input function, intermediate between Boolean AND-gate and OR-gate logic. We mapped in detail the input function of 12 variants of the lac promoter, each with different point mutations in the regulator binding sites, by means of accurate expression measurements from living cells. We find that even a few mutations can significantly change the input function, resulting in functions that resemble Pure AND gates, OR gates, or single-input switches. Other types of gates were not found. The variant input functions can be described in a unified manner by a mathematical model. The model also lets us predict which functions cannot be reached by point mutations. The input function that we studied thus appears to be plastic, in the sense that many of the mutations do not ruin the regulation completely but rather result in new ways to integrate the inputs

Differential Regulation of Primitive Myelopoiesis in the Zebrafish by Spi-1/Pu.1 and C/ebp1

The zebrafish has become a powerful tool for analysis of vertebrate hematopoiesis. Zebrafish, unlike mammals, have a robust primitive myeloid pathway that generates both granulocytes and macrophages. It is not clear how this unique primitive myeloid pathway relates to mammalian definitive hematopoiesis. In this study, we show that the two myeloid subsets can be distinguished using RNA in situ hybridization. Using a morpholino-antisense gene knockdown approach, we have characterized the hematopoietic defects resulting from knockdown of the myeloid transcription factor gene pu.1 and the unique zebrafish gene c/ebp1. Severe reduction of pu.1 resulted in complete loss of primitive macrophage development, with effects on granulocyte development only with maximal knockdown. Reduction of c/ebp1 did not ablate initial macrophage or granulocyte development, but resulted in loss of expression of the secondary granule gene lys C. These data reveal strong functional conservation of pu.1 between zebrafish primitive myelopoiesis and mammalian definitive myelopoiesis. Further, these results are consistent with a conserved role between c/ebp1 and mammalian C/EBPE, whose ortholog in zebrafish has not been identified. These studies validate the examination of zebrafish primitive myeloid development as a model for human myelopoiesis, and form a framework for identification and analysis of myeloid mutants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63190/1/zeb.2007.0505.pd

Phylogenetic Tree Reconstruction Accuracy and Model Fit when Proportions of Variable Sites Change across the Tree

Commonly used phylogenetic models assume a homogeneous process through time in all parts of the tree. However, it is known that these models can be too simplistic as they do not account for nonhomogeneous lineage-specific properties. In particular, it is now widely recognized that as constraints on sequences evolve, the proportion and positions of variable sites can vary between lineages causing heterotachy. The extent to which this model misspecification affects tree reconstruction is still unknown. Here, we evaluate the effect of changes in the proportions and positions of variable sites on model fit and tree estimation. We consider 5 current models of nucleotide sequence evolution in a Bayesian Markov chain Monte Carlo framework as well as maximum parsimony (MP). We show that for a tree with 4 lineages where 2 nonsister taxa undergo a change in the proportion of variable sites tree reconstruction under the best-fitting model, which is chosen using a relative test, often results in the wrong tree. In this case, we found that an absolute test of model fit is a better predictor of tree estimation accuracy. We also found further evidence that MP is not immune to heterotachy. In addition, we show that increased sampling of taxa that have undergone a change in proportion and positions of variable sites is critical for accurate tree reconstruction