264 research outputs found
A statistical method for revealing form-function relations in biological networks
Over the past decade, a number of researchers in systems biology have sought
to relate the function of biological systems to their network-level
descriptions -- lists of the most important players and the pairwise
interactions between them. Both for large networks (in which statistical
analysis is often framed in terms of the abundance of repeated small subgraphs)
and for small networks which can be analyzed in greater detail (or even
synthesized in vivo and subjected to experiment), revealing the relationship
between the topology of small subgraphs and their biological function has been
a central goal. We here seek to pose this revelation as a statistical task,
illustrated using a particular setup which has been constructed experimentally
and for which parameterized models of transcriptional regulation have been
studied extensively. The question "how does function follow form" is here
mathematized by identifying which topological attributes correlate with the
diverse possible information-processing tasks which a transcriptional
regulatory network can realize. The resulting method reveals one form-function
relationship which had earlier been predicted based on analytic results, and
reveals a second for which we can provide an analytic interpretation. Resulting
source code is distributed via http://formfunction.sourceforge.net.Comment: To appear in Proc. Natl. Acad. Sci. USA. 17 pages, 9 figures, 2
table
Telling time with an intrinsically noisy clock
Intracellular transmission of information via chemical and transcriptional
networks is thwarted by a physical limitation: the finite copy number of the
constituent chemical species introduces unavoidable intrinsic noise. Here we
provide a method for solving for the complete probabilistic description of
intrinsically noisy oscillatory driving. We derive and numerically verify a
number of simple scaling laws. Unlike in the case of measuring a static
quantity, response to an oscillatory driving can exhibit a resonant frequency
which maximizes information transmission. Further, we show that the optimal
regulatory design is dependent on the biophysical constraints (i.e., the
allowed copy number and response time). The resulting phase diagram illustrates
under what conditions threshold regulation outperforms linear regulation.Comment: 10 pages, 5 figure
Temporal precision of molecular events with regulation and feedback
Cellular behaviors such as migration, division, and differentiation rely on
precise timing, and yet the molecular events that govern these behaviors are
highly stochastic. We investigate regulatory strategies that decrease the
timing noise of molecular events. Autoregulatory feedback increases noise. Yet,
we find that in the presence of regulation by a second species, autoregulatory
feedback decreases noise. To explain this finding, we develop a method to
calculate the optimal regulation function that minimizes the timing noise. The
method reveals that the combination of feedback and regulation minimizes noise
by maximizing the number of molecular events that must happen in sequence
before a threshold is crossed. We compute the optimal timing precision for all
two-node networks with regulation and feedback, derive a generic lower bound on
timing noise, and discuss our results in the context of neuroblast migration
during Caenorhabditis elegans development.Comment: 8 pages, 4 figure
A stochastic spectral analysis of transcriptional regulatory cascades
The past decade has seen great advances in our understanding of the role of
noise in gene regulation and the physical limits to signaling in biological
networks. Here we introduce the spectral method for computation of the joint
probability distribution over all species in a biological network. The spectral
method exploits the natural eigenfunctions of the master equation of
birth-death processes to solve for the joint distribution of modules within the
network, which then inform each other and facilitate calculation of the entire
joint distribution. We illustrate the method on a ubiquitous case in nature:
linear regulatory cascades. The efficiency of the method makes possible
numerical optimization of the input and regulatory parameters, revealing design
properties of, e.g., the most informative cascades. We find, for threshold
regulation, that a cascade of strong regulations converts a unimodal input to a
bimodal output, that multimodal inputs are no more informative than bimodal
inputs, and that a chain of up-regulations outperforms a chain of
down-regulations. We anticipate that this numerical approach may be useful for
modeling noise in a variety of small network topologies in biology
Efeito do pré-condicionamento ácido nas forças de adesão em esmalte in vitro de dois sistemas adesivos: universal vs. self-etch
Tese de Mestrado, Medicina Dentária, Universidade de Lisboa, Faculdade de Medicina Dentária, 2014Objectives: The purpose of this study was to evaluate the effect of pre-etching on in vitro enamel bond strength of two adhesive systems: one universal adhesive and one two-step self-etch. Methods: In this study were used 8 caries-free human molars. The specimens were partially split in two halves and were assigned to two groups (n=8). On the enamel surfaces were applied two different adhesive systems: Scotchbond Universal (3M ESPE Seefeld, Germany) following manufacturer's instructions as a total-etch; Clearfil SE Bond (Kuraray, Okayama, Japan) applied as a total-etch. Build-ups were constructed with ENAMEL plus HRi (Micerium S.p.A. Avegno (GE) Italy) and cured in three increments of 2mm each. Specimens were kept in 37ÂşC destilated water for 24 hours and then sectioned with a slow-speed Diamond saw under water in X and Y directions to obtain bonded beams that were tested to failure in tension at a crosshead speed of 1 mm/minute. Statistical analyses were computed using T-student. The failures interfaces were observed under an optical microscope and registered. Results: There were not statistically significant differences among the two groups. Conclusions: A new universal adhesive system has similar bond strength than a two-step self-etch adhesive when pre-etching is performed.Objetivos: O presente trabalho tem como objetivo avaliar o efeito do prĂ©-condicionamento ácido nas forças de adesĂŁo em esmalte in vitro de dois sistemas adesivos: um adesivo universal e um self-etch de dois passos. Materiais e MĂ©todos: Neste estudo utilizaram-se 8 dentes molares humanos livres de cárie. Foram realizados cortes de maneira a hemissecionar as coroas dos dentes mesiodistalmente e estas foram aleatoriamente divididas em 2 grupos (n=8). Ă€s superfĂcies em esmalte foram aplicados 2 sistemas adesivos distintos: Scotchbond Universal (3M ESPE Seefeld, Germany) segundo instruções do fabricante pela tĂ©cnica total-etch; Clearfil SE Bond (Kuraray, Okayama, Japan) pela tĂ©nica total-etch, tendo sido restauradas com o compĂłsito ENAMEL plus HRi (Micerium S.p.A. Avegno (GE) Italy) fotopolimerizados em trĂŞs incrementos, cada um com 2mm. Os espĂ©cimenes foram armazenados em água destilada a 37ÂşC durante 24h e depois seccionados em palitos de aproximadamente 1mm2 com um disco de diamante sob refrigeração com água, nas direções X e Y de maneira a obter palitos. Todas as amostras foram testadas atĂ© Ă fratura em testes de microtração, a uma velocidade de 1mm/minuto. A análise estatĂstica foi feita utilizando o T-student. As fraturas foram observadas num estereomicroscĂłpio e registadas. Resultados: Os dois grupos estudados nĂŁo apresentam diferenças estatisticamente significativas (p<0,05). ConclusĂŁo: Um adesivo universal parece proporcionar forças de adesĂŁo em esmalte similares a adesivos self-etch de dois passos quando efectuado prĂ©-condicionamento ácido
Pulse Sequence Resilient Fast Brain Segmentation
Accurate automatic segmentation of brain anatomy from
-weighted~(-w) magnetic resonance images~(MRI) has been a
computationally intensive bottleneck in neuroimaging pipelines, with
state-of-the-art results obtained by unsupervised intensity modeling-based
methods and multi-atlas registration and label fusion. With the advent of
powerful supervised convolutional neural networks~(CNN)-based learning
algorithms, it is now possible to produce a high quality brain segmentation
within seconds. However, the very supervised nature of these methods makes it
difficult to generalize them on data different from what they have been trained
on. Modern neuroimaging studies are necessarily multi-center initiatives with a
wide variety of acquisition protocols. Despite stringent protocol harmonization
practices, it is not possible to standardize the whole gamut of MRI imaging
parameters across scanners, field strengths, receive coils etc., that affect
image contrast. In this paper we propose a CNN-based segmentation algorithm
that, in addition to being highly accurate and fast, is also resilient to
variation in the input -w acquisition. Our approach relies on building
approximate forward models of -w pulse sequences that produce a typical
test image. We use the forward models to augment the training data with test
data specific training examples. These augmented data can be used to update
and/or build a more robust segmentation model that is more attuned to the test
data imaging properties. Our method generates highly accurate, state-of-the-art
segmentation results~(overall Dice overlap=0.94), within seconds and is
consistent across a wide-range of protocols.Comment: Accepted at MICCAI 201
Stochastic pump effect and geometric phases in dissipative and stochastic systems
The success of Berry phases in quantum mechanics stimulated the study of
similar phenomena in other areas of physics, including the theory of living
cell locomotion and motion of patterns in nonlinear media. More recently,
geometric phases have been applied to systems operating in a strongly
stochastic environment, such as molecular motors. We discuss such geometric
effects in purely classical dissipative stochastic systems and their role in
the theory of the stochastic pump effect (SPE).Comment: Review. 35 pages. J. Phys. A: Math, Theor. (in press
Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor
Many developmental processes depend on precise temporal control of gene expres-sion. We have previously established a theoretical framework for regulatory strategies that can govern such high temporal precision, but experimental validation of these predictions was still lacking. Here, we use the time-dependent expression of a Wnt receptor that controls neuroblast migration in Caenorhabditis elegans as a tractable system to study a robust, cell-intrinsic timing mechanism in vivo. Single-molecule mRNA quantification showed that the expression of the receptor increases non-linearly, a dynamic that is predicted to enhance timing precision over an unregulated, linear increase in timekeeper abundance. We show that this upregulation depends on transcriptional activation, providing in vivo evidence for a model in which the timing of receptor expression is regulated through an accumulating activator that triggers expression when a specific threshold is reached. This timing mechanism acts across a cell division that occurs in the neuroblast lineage and is influenced by the asymmetry of the division. Finally, we show that positive feedback oreceptor expression through the canonical Wnt pathway enhances temporal precision. We conclude that robust cell-intrinsic timing can be achieved by combining regulation and feedback of the timekeeper gene
Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor
Many developmental processes depend on precise temporal control of gene expres-sion. We have previously established a theoretical framework for regulatory strategies that can govern such high temporal precision, but experimental validation of these predictions was still lacking. Here, we use the time-dependent expression of a Wnt receptor that controls neuroblast migration in Caenorhabditis elegans as a tractable system to study a robust, cell-intrinsic timing mechanism in vivo. Single-molecule mRNA quantification showed that the expression of the receptor increases non-linearly, a dynamic that is predicted to enhance timing precision over an unregulated, linear increase in timekeeper abundance. We show that this upregulation depends on transcriptional activation, providing in vivo evidence for a model in which the timing of receptor expression is regulated through an accumulating activator that triggers expression when a specific threshold is reached. This timing mechanism acts across a cell division that occurs in the neuroblast lineage and is influenced by the asymmetry of the division. Finally, we show that positive feedback oreceptor expression through the canonical Wnt pathway enhances temporal precision. We conclude that robust cell-intrinsic timing can be achieved by combining regulation and feedback of the timekeeper gene
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