350 research outputs found
Neutral Evolution of Mutational Robustness
We introduce and analyze a general model of a population evolving over a
network of selectively neutral genotypes. We show that the population's limit
distribution on the neutral network is solely determined by the network
topology and given by the principal eigenvector of the network's adjacency
matrix. Moreover, the average number of neutral mutant neighbors per individual
is given by the matrix spectral radius. This quantifies the extent to which
populations evolve mutational robustness: the insensitivity of the phenotype to
mutations. Since the average neutrality is independent of evolutionary
parameters---such as, mutation rate, population size, and selective
advantage---one can infer global statistics of neutral network topology using
simple population data available from {\it in vitro} or {\it in vivo}
evolution. Populations evolving on neutral networks of RNA secondary structures
show excellent agreement with our theoretical predictions.Comment: 7 pages, 3 figure
Man versus Machine versus Ribozyme
A microfluidic device has been constructed to carry out the automated, continuous evolution of ribozymes. A comparison with manual efforts reveals that both are capable of far flung forays into sequence space
Optimal replication of random vectors by ordinary integrals
We consider a problem of replication of random vectors by ordinary integrals
in the setting when a underlying random variable is generated by a Wiener
process. The goal is to find an optimal adapted process such that its
cumulative integral at a fixed terminal time matches this variable. The optimal
process has to be minimal in an integral norm
T-entropy and Variational Principle for the spectral radius of transfer and weighted shift operators
The paper deals with the variational principles for evaluation of the
spectral radii of transfer and weighted shift operators associated with a
dynamical system. These variational principles have been the matter of numerous
investigations and the principal results have been achieved in the situation
when the dynamical system is either reversible or it is a topological Markov
chain. As the main summands these principles contain the integrals over
invariant measures and the Kolmogorov--Sinai entropy. In the article we derive
the Variational Principle for an arbitrary dynamical system. It gives the
explicit description of the Legendre dual object to the spectral potential. It
is shown that in general this principle contains not the Kolmogorov--Sinai
entropy but a new invariant of entropy type -- the t-entropy.Comment: 51 pages, v.2: editorial correction
Chemokine Requirements for B Cell Entry to Lymph Nodes and Peyer's Patches
B cell entry to lymph nodes and Peyer's patches depends on chemokine receptor signaling, but the principal chemokine involved has not been defined. Here we show that the homing of CXCR4−/− B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice. We also find that CXCR4 can contribute to T cell homing. Using intravital microscopy, we find that B cell adhesion to high endothelial venules (HEVs) is disrupted when CCR7 and CXCR4 are predesensitized. In Peyer's patches, B cell entry is dependent on CXCR5 in addition to CCR7/CXCR4. CXCL12 (SDF1) is displayed broadly on HEVs, whereas CXCL13 (BLC) is found selectively on Peyer's patch follicular HEVs. These findings establish the principal chemokine and chemokine receptor requirements for B cell entry to lymph nodes and Peyer's patches
Regulation of lymph node vascular growth by dendritic cells
Lymph nodes grow rapidly and robustly at the initiation of an immune response, and this growth is accompanied by growth of the blood vessels. Although the vessels are critical for supplying nutrients and for controlling cell trafficking, the regulation of lymph node vascular growth is not well understood. We show that lymph node endothelial cells begin to proliferate within 2 d of immunization and undergo a corresponding expansion in cell numbers. Endothelial cell proliferation is dependent on CD11c+ dendritic cells (DCs), and the subcutaneous injection of DCs is sufficient to trigger endothelial cell proliferation and growth. Lymph node endothelial cell proliferation is dependent on vascular endothelial growth factor (VEGF), and DCs are associated with increased lymph node VEGF levels. DC-induced endothelial cell proliferation and increased VEGF levels are mediated by DC-induced recruitment of blood-borne cells. Vascular growth in the draining lymph node includes the growth of high endothelial venule endothelial cells and is functionally associated with increased cell entry into the lymph node. Collectively, our results suggest a scenario whereby endothelial cell expansion in the draining lymph node is induced by DCs as part of a program that optimizes the microenvironment for the ensuing immune response
Chance and Necessity in Evolution: Lessons from RNA
The relationship between sequences and secondary structures or shapes in RNA
exhibits robust statistical properties summarized by three notions: (1) the
notion of a typical shape (that among all sequences of fixed length certain
shapes are realized much more frequently than others), (2) the notion of shape
space covering (that all typical shapes are realized in a small neighborhood of
any random sequence), and (3) the notion of a neutral network (that sequences
folding into the same typical shape form networks that percolate through
sequence space). Neutral networks loosen the requirements on the mutation rate
for selection to remain effective. The original (genotypic) error threshold has
to be reformulated in terms of a phenotypic error threshold. With regard to
adaptation, neutrality has two seemingly contradictory effects: It acts as a
buffer against mutations ensuring that a phenotype is preserved. Yet it is
deeply enabling, because it permits evolutionary change to occur by allowing
the sequence context to vary silently until a single point mutation can become
phenotypically consequential. Neutrality also influences predictability of
adaptive trajectories in seemingly contradictory ways. On the one hand it
increases the uncertainty of their genotypic trace. At the same time neutrality
structures the access from one shape to another, thereby inducing a topology
among RNA shapes which permits a distinction between continuous and
discontinuous shape transformations. To the extent that adaptive trajectories
must undergo such transformations, their phenotypic trace becomes more
predictable.Comment: 37 pages, 14 figures; 1998 CNLS conference; high quality figures at
http://www.santafe.edu/~walte
Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum
Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents. © 2009 Elsevier Ltd. All rights reserved
Profiling the Essential Nature of Lipid Metabolism in Asexual Blood and Gametocyte Stages of Plasmodium falciparum
SummaryDuring its life cycle, Plasmodium falciparum undergoes rapid proliferation fueled by de novo synthesis and acquisition of host cell lipids. Consistent with this essential role, Plasmodium lipid synthesis enzymes are emerging as potential drug targets. To explore their broader potential for therapeutic interventions, we assayed the global lipid landscape during P. falciparum sexual and asexual blood stage (ABS) development. Using liquid chromatography-mass spectrometry, we analyzed 304 lipids constituting 24 classes in ABS parasites, infected red blood cell (RBC)-derived microvesicles, gametocytes, and uninfected RBCs. Ten lipid classes were previously uncharacterized in P. falciparum, and 70%–75% of the lipid classes exhibited changes in abundance during ABS and gametocyte development. Utilizing compounds that target lipid metabolism, we affirmed the essentiality of major classes, including triacylglycerols. These studies highlight the interplay between host and parasite lipid metabolism and provide a comprehensive analysis of P. falciparum lipids with candidate pathways for drug discovery efforts
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