34 research outputs found
On the Complexity of an Unregulated Traffic Crossing
The steady development of motor vehicle technology will enable cars of the
near future to assume an ever increasing role in the decision making and
control of the vehicle itself. In the foreseeable future, cars will have the
ability to communicate with one another in order to better coordinate their
motion. This motivates a number of interesting algorithmic problems. One of the
most challenging aspects of traffic coordination involves traffic
intersections. In this paper we consider two formulations of a simple and
fundamental geometric optimization problem involving coordinating the motion of
vehicles through an intersection.
We are given a set of vehicles in the plane, each modeled as a unit
length line segment that moves monotonically, either horizontally or
vertically, subject to a maximum speed limit. Each vehicle is described by a
start and goal position and a start time and deadline. The question is whether,
subject to the speed limit, there exists a collision-free motion plan so that
each vehicle travels from its start position to its goal position prior to its
deadline.
We present three results. We begin by showing that this problem is
NP-complete with a reduction from 3-SAT. Second, we consider a constrained
version in which cars traveling horizontally can alter their speeds while cars
traveling vertically cannot. We present a simple algorithm that solves this
problem in time. Finally, we provide a solution to the discrete
version of the problem and prove its asymptotic optimality in terms of the
maximum delay of a vehicle
Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor β on mRNA stability and translatability
Estrogen signaling is mediated by estrogen receptors (ERs), ERα and ERβ. Aberrant
estrogen signaling is involved in breast cancer development. ERα is one of the key
biomarkers for diagnosis and treatment of breast cancer. Unlike ERα, ERβ is still not
introduced as a marker for diagnosis and established as a target of therapy. Numerous
studies suggest antiproliferative effects of ERβ, however its role remains to be fully
explored. Albeit important, ERα is not a perfect marker, and some aspects of ERα
function are still unclear. This thesis aims to characterize distinct molecular facets of
ER action relevant for breast cancer and provide valuable information for ER-based
diagnosis and treatment design.
In PAPER I, we analyzed the functionality of two common single
nucleotide polymorphisms in the 3’ untranslated regions of ERβ, rs4986938 and
rs928554, which have been extensively investigated for association with various
diseases. A significant difference in allelic expression was observed for rs4986938 in
breast tumor samples from heterozygous individuals. However, no difference in mRNA
stability or translatability between the alleles was observed.
In PAPER II, we provided a more comprehensive understanding of ERβ
function independent of ERα. A global gene expression analysis in a HEK293/ERβ cell
model identified a set of ERβ-regulated genes. Gene Ontology (GO) analysis showed
that they are involved in cell-cell signaling, morphogenesis and cell proliferation.
Moreover, ERβ expression resulted in a significant decrease in cell proliferation.
In PAPER III, using the human breast cancer MCF-7/ERβ cell model,
we demonstrated, for the first time, the binding of ERα/β heterodimers to various
DNA-binding regions in intact chromatin.
In PAPER IV, we investigated a potential cross-talk between estrogen
signaling and DNA methylation by identifying their common target genes in MCF-7
cells. Gene expression profiling identified around 150 genes regulated by both 17β-
estradiol (E2) and a hypomethylating agent 5-aza-2’-deoxycytidine. Based on GO
analysis, CpG island prediction analysis and previously reported ER binding regions,
we selected six genes for further analysis. We identified BTG3 and FHL2 as direct
target genes of both pathways. However, our data did not support a direct molecular
interplay of mediators of estrogen and epigenetic signaling at promoters of regulated
genes.
In PAPER V, we further explored the interactions between estrogen
signaling and DNA methylation, with focus on DNA methyltransferases (DNMT1,
DNMT3a and DNMT3b). E2, via ERα, up-regulated DNMT1 and down-regulated
DNMT3a and DNMT3b mRNA expression. Furthermore, DNMT3b interacted with
ERα. siRNA-mediated DNMT3b depletion increased the expression of two genes,
CDKN1A and FHL2. We proposed that the molecular mechanism underlying
regulation of FHL2 and CDKN1A gene expression involves interplay of DNMT3b and
ERα.
In conclusion, the studies presented in this thesis contribute to the knowledge of ERβ
function, and give additional insight into the cross-talk mechanisms underlying ERα
signaling with ERβ and with DNA methylation pathways