Quantitative Biology
Colloquium
Spring 2008
Schedule 4:15-5:15 Tuesdays
|
February 5 |
Department of Epidemiology & Biostatistics, College of Public Health Survival
Analysis via Multiple Imputation |
|
Keating 103 |
In survival analysis, censored observations can be regarded as
missing event time data. We develop a direct approach, multiple imputation,
which shares common ideas with the redistribute to the right algorithm to
recover information for censored observations. This approach can handle both
interval-censored and right-censored data. In one sample situations, we show
that with a large number of imputes the imputation method will reproduce the
Kaplan-Meier estimates. In interval-censored data situations, we propose a
nonparametric multiple imputation scheme, NPMLE imputation. The imputation
methods convert interval-censored data problems to completed data problems,
which enables estimates of measures of uncertainty to be more easily
obtained. In a situation with auxiliary variables, we incorporate auxiliary
variables into imputation through two working Cox proportional hazards models
and show that the imputation method can reduce bias due to dependent
censoring and improve the efficiency. These findings of improved efficiency
and reduced bias can be seen in both interval-censored and right-censored
data. The methods are applied to AIDS data sets. |
|
February 12 |
Departments of Biomedical Engineering and Radiology
and BIO5 Institute Noninvasive Measurement of Tissue Properties with
MRI |
|
MRB 102 |
Magnetic resonance imaging (MRI) is a common and useful tool in
medicine and biology. Typically,
when MRI images are used by radiologist to make a clinical diagnosis, the analysis
of the images is carried out qualitatively, and relies heavily on the
experience of the radiologist. Although quantitative information is available
in MRI, it is typically not obtained because of the increased data
acquisition time required, and the ability of radiologists to make decisions
without it. However, in some
circumstances, quantitative information can be very valuable in the diagnosis
and evaluation of disease and in critical evaluation of therapy. A description of quantitative parameters
available from MRI experiments will be presented and research projects in
which they are being used will be discussed Magnetic resonance imaging (MRI)
is a common and useful tool in medicine and biology. Typically, when MRI images are used
by radiologist to make a clinical diagnosis, the analysis of the images is
carried out qualitatively, and relies heavily on the experience of the
radiologist. Although quantitative information is available in MRI, it is
typically not obtained because of the increased data acquisition time
required, and the ability of radiologists to make decisions without it. However, in some circumstances,
quantitative information can be very valuable in the diagnosis and evaluation
of disease and in critical evaluation of therapy. A description of quantitative parameters available from MRI
experiments will be presented and research projects in which they are being
used will be discussed |
|
February 19 |
Department of Physics Mechanical
Tension within DNA Controls Gene Transcription Initiation |
|
MRB 102 |
We have investigated the effect of DNA tension upon the
association and dissociation of the T7 RNA polymerase/promoter DNA Interaction.
Using two optically trapped beads, we suspended a single DNA molecule
containing the T7-phi13 promoter above a 3rd surface-immobilized bead that
bears active molecules of T7 RNAP. The DNA was brought into contact with the
surface bead, while applying a 50 Hz triangle oscillation to the bead upstream of the promoter.
Binding of T7 RNAP at the promoter was detected as the decoupling of motion
of the two optically trapped beads: oscillations of the downstream bead are
reduced or cease altogether upon binding. The DNA tension upon binding is
directly proportional to the displacement of the downstream bead from the
center of the optical trap. By altering both the mean tension in the DNA -
changing trap stiffness or the mean bead-to-bead distance - we have been able
to observe promoter binding across the range of force 1-12 pN. From these
data we find clear evidence that the mean lifetime of the promoter/T7 RNAP
complex decreases with increasing tension as indicated by an increasing
dissociation rate constant, koff, from 3.5 s-1 at 1.5 pN up to 73 s-1 at
>8 pN. From these observations, we propose that tension within a DNA
molecule is able to regulate gene expression, at least in the case of the
bacteriophage T7 enzyme. Based on the recent structural data of the T7 RNAP
initiation complex we speculate on the mechanism by which force may affect
the dissociation kinetics. |
|
February 26 |
Department of Ecology and Evolutionary Biology and BIO5 Institute Who's
Your Great-great-great Granddaddy?
Estimation of Time to Most Recent Common Ancestor Given Molecular
Genealogical Data |
|
Keating 103 |
Molecular marker data is exceptional at determining if a
biological sample (suchas blood or an offspring!) came from a specified
individual. Genealogists have
become very interested in using molecular data to assess slightly more
distant relationships, those within 3-20 generations. I'll review why this is done using
collections of completely linked markers (such as the Y chromosome) and
discuss various statistical models for estimating the time to the most recent
common ancestor given two such sequences. We start with a simple maximum likelihood approach,
discover its flaws, and then develop a fully Bayesian estimator that
addresses these concerns. |
|
March 4 |
Institute for the Study of Planet Earth Departments of Geosciences and Atmospheric Sciences Climate Change, Sea Level, and Western Drought:
Dangerous Anthropogenic Interference? |
|
Keating 103 |
The
reality of global warming, reflected in a broad spectrum of climate system
change, is now unequivocal. Moreover, human complicity in global warming has
also been established beyond a reasonable doubt. With these and other
advances embodied in the Intergovernmental Panel on Climate Change Fourth
Assessment Report (IPCC AR4) has come a shift in scientific focus toward
efforts designed to improve our understanding of what will happen in the
future, and to what can be done to deal with the reality of global to
regional climate change. Major efforts are now needed to develop strategies
for adapting to climate change that is already in the pipeline, and also to
identify climate changes that may be deemed unacceptable, and thus worthy
drivers of mitigation strategies designed to reduce the rate of atmospheric
greenhouse gas increases to ÒsafeÓ levels. There
may be many aspects of future global climate change that will ultimately be
deemed undesirable and worthy of mitigation efforts, but two major issues are
already coming into focus. The first is global sea level rise coupled with
increasing tropical storm intensities. There is no doubt that global sea
level is rising, and little doubt that the rates of sea level rise are likely
to increase. In contrast to what some biased media and individuals are
saying, the IPCC AR4 did not lower estimates of future sea level rise. Indeed, the
most recent estimates suggest that 1m or more of sea level rise could occur
by 2100, as well as a commitment to a much larger sea level rise over subsequent
centuries. The wildcard will be the future behavior of the large polar ice
sheets, and there is growing evidence that the ice sheets are more vulnerable
to global warming than widely thought. Although
coastal areas could thus be big losers in the face of continued climate
change, recent climate change coupled with climate change projections
indicate that the American West – including the alpine West - could be
a more near-term casualty. Surface air temperatures are already rising faster
than elsewhere in the coterminous United States, and will likely continue to
rise steadily. These temperature increases are already causing snow to fall
increasingly as rain, and also to melt earlier in the year. Thus, even in the
absence of a precipitation decrease, there will be less snow-related run-off and
related surface water flow. This trend is also being exacerbated in some
parts of the West by human-caused increases in atmospheric dust loading.
Unfortunately, nearly all state-of-the-art climate models being forced with
increasing greenhouse gases (and other human-caused pollution) are also
simulating a steady decline in average wintertime precipitation in the
Southwest. More troubling is the fact that these simulated changes are also
in accord with what has been happening in the real world – there is a
growing scientific consensus that winters will become much hotter and
significantly drier due to the greenhouse-gas climate forcing. On top of
these trends in average condition is the likelihood that multi-year, even
multi-decade, drought will also become more common. Thus, the recent western drought – already the worst
of the instrumental era – could be a harbinger of greater aridity to
come, and also a significant threat to the West as we know it. Fortunately,
there are solutions if we choose to act aggressively. |
|
March 11 |
Department of Plant Sciences and BIO5 Institute Genome-wide Analyses of Tandem Repeats in Humans |
|
Keating 103 |
Using the compiled human genome sequence, we systematically
catalogued all tandem repeats with periods between 20 and 2,000 bp and
defined two subsets whose pattern sequences were found at either single
(slTRs) or multiple loci (mlTRs).
Parameters compiled for these subsets are consistent with a two step
model for their evolution beginning with an initial duplication event
insensitive to the unique or repetitive nature of the nascent sequence. Subsequent amplification steps via
gene conversion are infrequent and can create new alleles varying in both
repeat number and internal sequence.
Tandem repeats are non-randomly distributed in the genome; both
subsets are found at higher frequency at many but not all chromosome ends and
internal clusters of mlTRs are also seen. Despite the integral role of recombination in the biology
of tandem repeats, recombination hotspots co-localized only with shorter
microsatellites and not the longer repeats examined here. An increased frequency of slTRs was
observed near imprinted genes, consistent with a functional role, while both
slTRs and mlTRs were found more frequently near genes implicated in triplet
expansion diseases, suggesting a general instability of these regions. Using
our collated parameters, we identified 2,230 slTRs as candidates for highly
informative molecular markers. |
|
March 18 |
Spring
Break |
|
March 28 – Al Scott Lecture |
Program in Applied Mathematics Theoretical model of metabolic blood flow regulation |
|
4:00 Math 501 |
The ability of the circulatory system to adequately match blood
supply to tissue demand implies the existence of regulatory mechanisms that
communicate tissue status to blood vessels. For example, red blood cells have been shown to respond to
low tissue oxygen levels by releasing ATP. The ATP triggers a conducted
response signal to travel upstream and cause arterioles to dilate so that
more blood is delivered to the region of demand. A theoretical model focusing on the role of this mechanism
in blood flow regulation is presented here. In the model, arterioles control blood flow by dilating or
constricting in response to changes inmetabolism as well as to changes in
pressure and wall shear stress.
The model predicts that responses to these three stimuli can account
for the increase in blood flow that occurs with increased oxygen demand. |
|
April 1 |
Postponed to April 29 |
|
April 8 |
Program in Neuroscience Visual
Speedometers in the Honeybee Brain |
|
Keating 103 |
In 1973 Karl von Frisch was awarded the Nobel Prize in
Physiology for his work decoding the "language" of bees. The language of bees, also known as
the "waggle dance", is used by foraging honeybees to indicate the
distance and direction of a food source to other bees in the hive. Since then we have learned from
numerous behavioral studies that a honeybee's judgment of distance is based on a visual estimate of speed. This estimate is relatively
independent of spatial frequency, contrast and direction of motion and can
even be made with only monocular input. Despite our thorough understanding of the many behaviors that
rely on visual speed estimation, we still lack a solid understanding of the
underlying neural processes responsible for the estimate. My research has focused on evaluating
various models of visual speed estimation based on their effectiveness for
replicating, in simulation, the behaviors observed in honeybees. I then use the results from the simulations to generate hypotheses and
experiments to further refine the models. In addition, I have recently begun
my own behavioral work to gather more detailed information on the properties
of the honeybee speedometer.. |
|
April 15 |
Department of Biochemistry and Molecular Biophysics Department of Mathematics Coils,
Coiled-coils, and Coiled-coiled-coils: Unraveling the Hierarchical Structure
of Adiponectin |
|
Keating 103 |
Adiponectin is a signalling hormone which stimulates the body's response
to insulin and is of interest as a possible therapeutic for diabetes.
Detailed knowledge of adiponectin's three-dimensional structure is
prerequisite to a mechanistic understanding of its physiological role.
However, its biochemical properties preclude the use of conventional
experimental structure-determination methods. In this talk we will show how
to develop new methods, based on the differential geometry of curves to model
the structure and mechanics of proteins. These methods are particularly well-suited
to explore the properties of helical assembly. Starting with simple helical
structure (coils) we will show how we can construct higher order assembly
such as the ubiquitous coiled-coils, a protein motif found in many fibrous
proteins. The mechanical properties of such assembly can be determined by
developing a multiscale theory. The next higher order assembly is the
coiled-coiled-coil, which we believe is applicable to adiponectin, since
it exists in serum in three
distinct oligomeric states with 3, 6, and 18 protein subunits. |
|
April 22 |
Departments of Cell Biology and Anatomy and Molecular
and Cellular Biology Department of Systems and Industrial Engineering Network
Modeling of Gene Regulatory Pathways in Vertebrate Development |
|
Keating 103 |
We are developing methods for defining transcriptional
regulatory networks underlying fundamental processes during embryonic
development. Our general approach is to create a preliminary structure
network (PSN) using a variety of biological information stores, to iteratively
sample this and modified networks across parameter space, and then to test successful
networks in vivo. A primary limitation for generation and modification of the
PSN is the relative lack of interaction data in most model organisms, including
chicken. To overcome this problem, we have created integrated interolog
(interaction homolog) networks for all organisms represented in NCBIÕs
HomoloGene database using all available interaction data. This has greatly
increased the amount of interaction data available for the twenty organisms
presently in HomoloGene. We have also developed new algorithms for more
rapidly sampling networks in topology space and for measuring their
robustness with respect to changes in reaction rates. To measure robustness
efficiently, we use approximations to the ODE systems that are valid in a
neighborhood, and use the fact that re-optimizing is much less expensive than
optimizing from scratch. Our methods are related to Markov Chain Monte Carlo
sampling and Trust Regions. Preliminary results indicate an improvement of an
order of magnitude in terms of computing time, with only a marginal increase
in variance. |
|
April 29 |
Departments of Cell Biology and Anatomy and Molecular
and Cellular Biology Multiple
Models of Molecular Assembly at Synapses |
|
Keating 103 |
Assembly of molecular specializations in cell membranes clearly
involves signaling. Examples include neural synapses, immunological synapses,
and cell surface adhesion structures.
But HOW does the signaling get translated into the formation of large
scale molecular structures?
Also, the resulting structures must be quasi-stable, accommodating the
incessant turnover of cell surface molecules while retaining characteristic
sizes and substructure over potentially years. I present multiple models that generate molecular assemblies
with remarkable similarities to those seen in biological systems. Successful models are self-organizing
and involve coupled state transitions.
Rich structures result even from the self-organization of a single
type of molecule. The use of
multiple models helps to identify specific properties that underly aspects of
the biology. For example, the
perforation of synapses from central and peripheral nervous systems and even
including immunological synapses can result from the selective turnover of
anchored molecules within the synapses. |