15 research outputs found
The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in <i>Plasmodium</i> asexual blood stages
Glycosylation is an important posttranslational protein
modification in all eukaryotes. Besides
glycosylphosphatidylinositol (GPI) anchors and N-glycosylation,
O-fucosylation has been recently reported in key sporozoite
proteins of the malaria parasite. Previous analyses showed the
presence of GDP-fucose (GDP-Fuc), the precursor for all
fucosylation reactions, in the blood stages of Plasmodium
falciparum. The GDP-Fuc de novo pathway, which requires the
action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose
synthase (FS), is conserved in the parasite genome, but the
importance of fucose metabolism for the parasite is unknown. To
functionally characterize the pathway we generated a PfGMD
mutant and analyzed its phenotype. Although the labelling by the
fucose-binding Ulex europaeus agglutinin I (UEA-I) was
completely abrogated, GDP-Fuc was still detected in the mutant.
This unexpected result suggests the presence of an alternative
mechanism for maintaining GDP-Fuc in the parasite. Furthermore,
PfGMD null mutant exhibited normal growth and invasion rates,
revealing that the GDP-Fuc de novo metabolic pathway is not
essential for the development in culture of the malaria parasite
during the asexual blood stages. Nonetheless, the function of
this metabolic route and the GDP-Fuc pool that is generated
during this stage may be important for gametocytogenesis and
sporogonic development in the mosquito
SIMS: A Hybrid Method for Rapid Conformational Analysis
Proteins are at the root of many biological functions, often performing complex tasks as the result of large changes in their
structure. Describing the exact details of these conformational changes, however, remains a central challenge for
computational biology due the enormous computational requirements of the problem. This has engendered the
development of a rich variety of useful methods designed to answer specific questions at different levels of spatial,
temporal, and energetic resolution. These methods fall largely into two classes: physically accurate, but computationally
demanding methods and fast, approximate methods. We introduce here a new hybrid modeling tool, the Structured
Intuitive Move Selector (SIMS), designed to bridge the divide between these two classes, while allowing the benefits of both
to be seamlessly integrated into a single framework. This is achieved by applying a modern motion planning algorithm,
borrowed from the field of robotics, in tandem with a well-established protein modeling library. SIMS can combine precise
energy calculations with approximate or specialized conformational sampling routines to produce rapid, yet accurate,
analysis of the large-scale conformational variability of protein systems. Several key advancements are shown, including the
abstract use of generically defined moves (conformational sampling methods) and an expansive probabilistic
conformational exploration. We present three example problems that SIMS is applied to and demonstrate a rapid solution
for each. These include the automatic determination of ムムactiveメメ residues for the hinge-based system Cyanovirin-N,
exploring conformational changes involving long-range coordinated motion between non-sequential residues in Ribose-
Binding Protein, and the rapid discovery of a transient conformational state of Maltose-Binding Protein, previously only
determined by Molecular Dynamics. For all cases we provide energetic validations using well-established energy fields,
demonstrating this framework as a fast and accurate tool for the analysis of a wide range of protein flexibility problems
Approachability in Stackelberg Stochastic Games with Vector Costs
The notion of approachability was introduced by Blackwell [1] in the context
of vector-valued repeated games. The famous Blackwell's approachability theorem
prescribes a strategy for approachability, i.e., for `steering' the average
cost of a given agent towards a given target set, irrespective of the
strategies of the other agents. In this paper, motivated by the multi-objective
optimization/decision making problems in dynamically changing environments, we
address the approachability problem in Stackelberg stochastic games with vector
valued cost functions. We make two main contributions. Firstly, we give a
simple and computationally tractable strategy for approachability for
Stackelberg stochastic games along the lines of Blackwell's. Secondly, we give
a reinforcement learning algorithm for learning the approachable strategy when
the transition kernel is unknown. We also recover as a by-product Blackwell's
necessary and sufficient condition for approachability for convex sets in this
set up and thus a complete characterization. We also give sufficient conditions
for non-convex sets.Comment: 18 Pages, Submitted to Dynamic Games and Application