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Nie Q.,Center for Complex Biological Systems | Nie Q.,University of California at Irvine | Enciso G.,Center for Complex Biological Systems
Biophysical Journal | Year: 2010

Multisite phosphorylation is a common form of posttranslational protein regulation which has been used to increase the switchlike behavior of the protein response to increasing kinase concentrations. In this letter, we show that the switchlike response of multisite phosphoproteins is strongly enhanced by nonessential phosphorylation sites, a mechanism that is robust to parameter changes and easily implemented in nature. We obtained analytic estimates for the Hill exponent (or coefficient) of the switchlike response, and we observed that a tradeoff exists between the switch and the kinase threshold for activation. This also suggests a possible evolutionary mechanism for the relatively large numbers of phosphorylation sites found in various proteins. © 2010 by the Biophysical Society.


Olivas N.D.,University of California at Los Angeles | Peng T.,Center for Complex Biological Systems | Holmes T.C.,University of California at Irvine | Nie Q.,Center for Complex Biological Systems
Journal of Physiology | Year: 2016

In the mammalian neocortex, excitatory neurons provide excitation in both columnar and laminar dimensions, which is modulated further by inhibitory neurons. However, our understanding of intracortical excitatory and inhibitory synaptic inputs in relation to principal excitatory neurons remains incomplete, and it is unclear how local excitatory and inhibitory synaptic connections to excitatory neurons are spatially organized on a layer-by-layer basis. In the present study, we combined whole cell recordings with laser scanning photostimulation via glutamate uncaging to map excitatory and inhibitory synaptic inputs to single excitatory neurons throughout cortical layers 2/3-6 in the mouse primary visual cortex (V1). We find that synaptic input sources of excitatory neurons span the radial columns of laminar microcircuits, and excitatory neurons in different V1 laminae exhibit distinct patterns of layer-specific organization of excitatory inputs. Remarkably, the spatial extent of inhibitory inputs of excitatory neurons for a given layer closely mirrors that of their excitatory input sources, indicating that excitatory and inhibitory synaptic connectivity is spatially balanced across excitatory neuronal networks. Strong interlaminar inhibitory inputs are found, particularly for excitatory neurons in layers 2/3 and 5. This differs from earlier studies reporting that inhibitory cortical connections to excitatory neurons are generally localized within the same cortical layer. On the basis of the functional mapping assays, we conducted a quantitative assessment of both excitatory and inhibitory synaptic laminar connections to excitatory cells at single cell resolution, establishing precise layer-by-layer synaptic wiring diagrams of excitatory neurons in the visual cortex. © 2016 The Physiological Society.


Moore T.I.,Center for Complex Biological Systems | Tanaka H.,Center for Complex Biological Systems | Kim H.J.,University of California at Irvine | Jeon N.L.,Seoul National University | And 2 more authors.
Molecular Biology of the Cell | Year: 2013

Yeast cells polarize by projecting up mating pheromone gradients, a classic cell polarity behavior. However, these chemical gradients may shift direction. We examine how yeast cells sense and respond to a 180° switch in the direction of microfluidically generated pheromone gradients. We identify two behaviors: at low concentrations of a-factor, the initial projection grows by bending, whereas at high concentrations, cells form a second projection toward the new source. Mutations that increase heterotrimeric G-protein activity expand the bending-growth morphology to high concentrations;mutations that increase Cdc42 activity result in second projections at low concentrations. Gradient-sensing projection bending requires interaction between Gβγand Cdc24, whereas gradient-nonsensing projection extension is stimulated by Bem1 and hyperactivated Cdc42. Of interest, a mutation in Ga affects both bending and extension. Finally, we find a genetic perturbation that exhibits both behaviors. Overexpression of the formin Bni1, a component of the polarisome, makes both bending- growth projections and second projections at low and high a-factor concentrations, suggesting a role for Bni1 downstream of the heterotrimeric G-protein and Cdc42 during gradient sensing and response. Thus we demonstrate that G-proteins modulate in a ligand-dependent manner two fundamental cell-polarity behaviors in response to gradient directional change. © 2013 Moore et al.


Chou C.-S.,Ohio State University | Lo W.-C.,Center for Complex Biological Systems | Gokoffski K.K.,Center for Complex Biological Systems | Gokoffski K.K.,University of California at Irvine | And 6 more authors.
Biophysical Journal | Year: 2010

In developing and self-renewing tissues, terminally differentiated (TD) cell types are typically specified through the actions of multistage cell lineages. Such lineages commonly include a stem cell and multiple progenitor (transit-amplifying) cell stages, which ultimately give rise to TD cells. As the tissue reaches a tightly controlled steady-state size, cells at different lineage stages assume distinct spatial locations within the tissue. Although tissue stratification appears to be genetically specified, the underlying mechanisms that direct tissue lamination are not yet completely understood. Herein, we use modeling and simulations to explore several potential mechanisms that can be utilized to create stratification during developmental or regenerative growth in general systems and in the model system, the olfactory epithelium of mouse. Our results show that tissue stratification can be generated and maintained through controlling spatial distribution of diffusive signaling molecules that regulate the proliferation of each cell type within the lineage. The ability of feedback molecules to stratify a tissue is dependent on a low TD death rate: high death rates decrease tissue lamination. Regulation of the cell cycle lengths of stem cells by feedback signals can lead to transient accumulation of stem cells near the base and apex of tissue. © 2010 by the Biophysical Society.


Wang P.T.,UCI | Puttock E.J.,Center for Complex Biological Systems | King C.E.,UCI | Schombs A.,UCI | And 12 more authors.
International IEEE/EMBS Conference on Neural Engineering, NER | Year: 2013

Electrocorticography has been widely explored as a long-term signal acquisition platform for brain-computer interface (BCI) control of upper extremity prostheses. However, a comprehensive study of elementary upper extremity movements and their relationship to electrocorticogram (ECoG) signals has yet to be performed. This study examines whether kinematic parameters of 6 elementary upper extremity movements can be decoded from ECoG signals in 3 subjects undergoing subdural electrode placement for epilepsy surgery evaluation. To this end, we propose a 2-stage decoding approach that consists of a state decoder to determine idle/move states, followed by a Kalman filter-based trajectory decoder. This proposed decoder successfully classified idle/move states with an average accuracy of 91%, and the correlation between decoded and measured trajectory averaged 0.70 for position and 0.68 for velocity. These performances represent an improvement over a simple regression-based approach. © 2013 IEEE.


"Much of what's most exciting in science right now is in biology," says Chang Liu, UCI assistant professor of biomedical engineering. "It's an unconquered frontier." For Liu, the fascination comes from two angles: exploring unknown boundaries in life science, and discovering how to use biological materials to build new structures on the molecular and genetic scales. It's this goal of learning how cells, DNA and RNA, enzymes, amino acids and proteins can be taken apart and reassembled like a gooey erector set that has earned him a place in UCI's Henry Samueli School of Engineering. "I came here initially through a search by UCI's multidisciplinary Center for Complex Biological Systems," Liu says. "I was matched with the Samueli School because of my work in genetics, which many consider to be a frontier in engineering." He now runs a lab in UCI's Natural Sciences II building with six Ph.D. students, three postdoctoral scholars, two lab technicians and two undergraduates. The Tucson, Ariz., native earned a bachelor's degree in chemistry at Harvard University, but science wasn't the main reason he moved from the Southwest to Cambridge, Mass. "I was serious about music and concert piano performance at the time, and I had an audition with a very famous pianist, musicologist and music theorist at Harvard," says Liu, who was raised in a family of scientists and amateur musicians. "He only mentors two or three students at a time, and he offered to take me on if I did my undergrad degree there." In addition to music, Liu delved deeply into chemistry and physics. He went on to receive a doctorate in the former from the Scripps Research Institute in La Jolla, Calif. "This period of time was pivotal for me," he says, "because it showed me the importance of understanding how chemistry is done in the service of answering biological questions." Now Liu and his lab mates are attempting to engineer cells that have new capabilities using a novel approach to biological research known as directed evolution, a method used in protein engineering that mimics the process of natural selection to evolve proteins or nucleic acids toward a user-defined goal. "The larger theme of our lab is trying to engineer genetic systems that can process and transfer information," he says. While the role of DNA is to store and propagate information, it doesn't actually "go around performing functions at the cellular level," he notes. Instead, instructions are transcribed from DNA to RNA and translated to proteins, which are the more functional molecules. Liu and his colleagues are working to get to the bottom of this process to see if they can evolve the genome at will to perform such desired actions as attacking diseased cells and boosting healthy ones. Genetics researchers tend to develop a certain level of respect and admiration for this system that has taken eons to evolve to what it is today. Liu says the genome is based on a set of inert chemicals that sorted themselves out billions of years ago, so it's not possible to just go in and rearrange molecules. If a reactive chemical were introduced into the genetic code, "cross talk" would cause the cell to die. Liu's lab has improvised a way around this problem by developing a technique called orthogonal DNA replication, in which the host's genetic code is augmented by an engineered one inserted within the same cell. "We're basically installing reactive and chemically privileged groups into the genetic code that are not normally there so that we can make proteins that are better therapeutics," Liu says. In other words, his team has learned how to create cells with an auxiliary replication system, an enzyme that works with a piece of DNA that's living in the same cell but acting independently of that cell's genome. This allows Liu and his colleagues to experiment on genes at very rapid rates in the lab – the goal being to make cells that accomplish beneficial tasks. "A lot of our projects are figuring out how to experiment on cells at rates necessary to see evolution occur in the time scales of a laboratory rather than in the natural biological world," he says. These efforts have drawn the attention of leaders in this area of research beyond UCI. "Chang Liu's work will play a major role as the field moves from gene editing to actually composing new genes. Directed evolution is the composer's muse and editor combined," says Frances Arnold, the Dickinson Professor of Chemical Engineering, Bioengineering & Biochemistry at the California Institute of Technology. "Chang has an audacious and creative vision tempered by reality and an engineer's ability to get things done." Explore further: Evolutionary oomph: Researchers describe way to create synthetic polymers using genetic coding in DNA


Kline A.D.,Harvey Institute for Human Genetics | Calof A.L.,Center for Complex Biological Systems | Schaaf C.A.,Saint Louis University | Krantz I.D.,Children's Hospital of Philadelphia | And 17 more authors.
American Journal of Medical Genetics, Part A | Year: 2014

Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers, professionals, and schools. The following abstracts are presentations from the 5th Cornelia de Lange Syndrome Scientific and Educational Symposium on June 20-21, 2012, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting, Lincolnshire, IL. The research committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts and subsequently disseminates the information to the families. In addition to the basic science and clinical discussions, there were educationally-focused talks related to practical aspects of management at home and in school. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. Report © 2014 Wiley Periodicals, Inc.


Szymanska A.F.,UCICA | Doty M.,UCICA | Scannell K.V.,Center for Complex Biological Systems | Nenadic Z.,UCICA
2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2014 | Year: 2014

Multi-sensor extracellular recording takes advantage of several electrode channels to record from multiple neurons at the same time. However, the resulting low signal-to-noise ratio (SNR) combined with biological noise makes signal detection, the first step of any neurophysiological data analysis, difficult. A matched filter was therefore designed to better detect extracellular action potentials (EAPs) from multi-sensor extracellular recordings. The detector was tested on tetrode data from a locust antennal lobe and assessed against three trained analysts. 25 EAPs and noise samples were selected manually from the data and used for training. To reduce complexity, the filter assumed that the underlying noise in the data was spatially white. The detector performed with an average TP and FP rate of 84.62% and 16.63% respectively. This high level of performance indicates the algorithm is suitable for widespread use. © 2014 IEEE.


Gord A.,Center for Mathematical and Computational Biology | Gord A.,Center for Complex Biological Systems | Holmes W.R.,Center for Mathematical and Computational Biology | Holmes W.R.,Center for Complex Biological Systems | And 4 more authors.
Journal of the Royal Society Interface | Year: 2014

Skin is a complex organ tasked with, among other functions, protecting the body from the outside world. Its outermost protective layer, the epidermis, is comprised of multiple cell layers that are derived from a single-layered ectoderm during development. Using a new stochastic, multi-scale computational modelling framework, the anisotropic subcellular element method, we investigate the role of cellmorphology and biophysical cell-cell interactions in the formation of this layered structure. This three-dimensional framework describes interactions between collections of hundreds to thousands of cells and (i) accounts for intracellular structure and morphology, (ii) easily incorporates complex cell-cell interactions and (iii) can be efficiently implemented on parallel architectures. We use this approach to construct a model of the developing epidermis that accounts for the internal polarity of ectodermal cells and their columnar morphology. Using this model, we show that cell detachment, which has been previously suggested to have a role in this process, leads to unpredictable, randomized stratification and that this cannot be abrogated by adjustment of cell-cell adhesion interaction strength. Polarized distribution of cell adhesion proteins, motivated by epithelial polarization, can however eliminate this detachment, and in conjunction with asymmetric cell division lead to robust and predictable development. © 2014 The Author(s) Published by the Royal Society. All rights reserved.


Lowengrub J.,University of California at Irvine | Lowengrub J.,Center for Complex Biological Systems | Allard J.,University of California at Irvine | Allard J.,Center for Complex Biological Systems | And 3 more authors.
Journal of Computational Physics | Year: 2016

The formation of membrane vesicles from a larger membrane that occurs during endocytosis and other cell processes is typically orchestrated by curvature-inducing molecules attached to the membrane. Recent reports demonstrate that vesicles can form de novo in a few milliseconds. Membrane dynamics at these scales are strongly influenced by hydrodynamic interactions. To study this problem, we develop new diffuse interface models for the dynamics of inextensible vesicles in a viscous fluid with stiff, curvature-inducing molecules. The model couples the Navier-Stokes equations with membrane-induced bending forces that incorporate concentration-dependent bending stiffness coefficients and spontaneous curvatures, with equations for molecule transport and for a Lagrange multiplier to enforce local inextensibility. Two forms of surface transport equations are considered: Fickian surface diffusion and Cahn-Hilliard surface dynamics, with the former being more appropriate for small molecules and the latter being better for large molecules. The system is solved using adaptive finite element methods in 3D axisymmetric geometries. The results demonstrate that hydrodynamics can indeed enable the rapid formation of a small vesicle attached to the membrane by a narrow neck. When the Fickian model is used, this is a transient state with the steady state being a flat membrane with a uniformly distributed molecule concentration due to diffusion. When the Cahn-Hilliard model is used, molecule concentration gradients are sustained, the neck stabilizes and the system evolves to a steady-state with a small, compact vesicle attached to the membrane. By varying the membrane coverage of molecules in the Cahn-Hilliard model, we find that there is a critical (smallest) neck radius and a critical (fastest) budding time. These critical points are associated with changes in the vesicle morphology from spherical to mushroom-like as the molecule coverage on the membrane is increased. © 2015 Elsevier Inc.

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