ASU Scholarship Showcase

Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi003-A] and a non-demented control (NDC) patient [ASUi004-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and retained the ability to differentiate into cells representative of the three germ layers.

Nonsense-mediated RNA decay (NMD) is a highly conserved pathway that selectively degrades specific subsets of RNA transcripts. Here, we provide evidence that NMD regulates early human developmental cell fate. We found that NMD factors tend to be expressed at higher levels in human pluripotent cells than in differentiated cells, raising the possibility that NMD must be downregulated to permit differentiation. Loss- and gain-of-function experiments in human embryonic stem cells (hESCs) demonstrated that, indeed, NMD downregulation is essential for efficient generation of definitive endoderm. RNA-seq analysis identified NMD target transcripts induced when NMD is suppressed in hESCs, including many encoding signaling components. This led us to test the role of TGF-β and BMP signaling, which we found NMD acts through to influence definitive endoderm versus mesoderm fate. Our results suggest that selective RNA decay is critical for specifying the developmental fate of specific human embryonic cell lineages.

Most previous works on complete synchronization of chaotic oscillators focused on the one-channel interaction scheme where the oscillators are coupled through only one variable or a symmetric set of variables. Using the standard framework of master-stability function (MSF), we investigate the emergence of complex synchronization behaviors under all possible configurations of two-channel coupling, which include, for example, all possible cross coupling schemes among the dynamical variables. Utilizing the classic Rössler and Lorenz oscillators, we find a rich variety of synchronization phenomena not present in any previously extensively studied, single-channel coupling configurations. For example, in many cases two coupling channels can enhance or even generate synchronization where there is only weak or no synchronization under only one coupling channel, which has been verified in a coupled neuron system. There are also cases where the oscillators are originally synchronized under one coupling channel, but an additional synchronizable coupling channel can, however, destroy synchronization. Direct numerical simulations of actual synchronization dynamics verify the MSF-based predictions. Our extensive computation and heuristic analysis provide an atlas for synchronization of chaotic oscillators coupled through two channels, which can be used as a systematic reference to facilitate further research in this area.

In the decade since Yamanaka and colleagues described methods to reprogram somatic cells into a pluripotent state, human induced pluripotent stem cells (hiPSCs) have demonstrated tremendous promise in numerous disease modeling, drug discovery, and regenerative medicine applications. More recently, the development and refinement of advanced gene transduction and editing technologies have further accelerated the potential of hiPSCs. In this review, we discuss the various gene editing technologies that are being implemented with hiPSCs. Specifically, we describe the emergence of technologies including zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 that can be used to edit the genome at precise locations, and discuss the strengths and weaknesses of each of these technologies. In addition, we present the current applications of these technologies in elucidating the mechanisms of human development and disease, developing novel and effective therapeutic molecules, and engineering cell-based therapies. Finally, we discuss the emerging technological advances in targeted gene editing methods.

Adult and pluripotent stem cells represent a ready supply of cellular raw materials that can be used to generate the functionally mature cells needed to replace damaged or diseased heart tissue. However, the use of stem cells for cardiac regenerative therapies is limited by the low efficiency by which stem cells are differentiated in vitro to cardiac lineages as well as the inability to effectively deliver stem cells and their derivatives to regions of damaged myocardium. In this review, we discuss the various biomaterial-based approaches that are being implemented to direct stem cell fate both in vitro and in vivo. First, we discuss the stem cell types available for cardiac repair and the engineering of naturally and synthetically derived biomaterials to direct their in vitro differentiation to the cell types that comprise heart tissue. Next, we describe biomaterial-based approaches that are being implemented to enhance the in vivo integration and differentiation of stem cells delivered to areas of cardiac damage. Finally, we present emerging trends of using stem cell-based biomaterial approaches to deliver pro-survival factors and fully vascularized tissue to the damaged and diseased cardiac tissue.

The field of tissue engineering entered a new era with the development of human pluripotent stem cells (hPSCs), which are capable of unlimited expansion whilst retaining the potential to differentiate into all mature cell populations. However, these cells harbor significant risks, including tumor formation upon transplantation. One way to mitigate this risk is to develop expandable progenitor cell populations with restricted differentiation potential. Here, we used a cellular microarray technology to identify a defined and optimized culture condition that supports the derivation and propagation of a cell population with mesodermal properties. This cell population, referred to as intermediate mesodermal progenitor (IMP) cells, is capable of unlimited expansion, lacks tumor formation potential, and, upon appropriate stimulation, readily acquires properties of a sub-population of kidney cells. Interestingly, IMP cells fail to differentiate into other mesodermally-derived tissues, including blood and heart, suggesting that these cells are restricted to an intermediate mesodermal fate.

Resource allocation takes place in various types of real-world complex systems such as urban traffic, social services institutions, economical and ecosystems. Mathematically, the dynamical process of resource allocation can be modeled as minority games. Spontaneous evolution of the resource allocation dynamics, however, often leads to a harmful herding behavior accompanied by strong fluctuations in which a large majority of agents crowd temporarily for a few resources, leaving many others unused. Developing effective control methods to suppress and eliminate herding is an important but open problem. Here we develop a pinning control method, that the fluctuations of the system consist of intrinsic and systematic components allows us to design a control scheme with separated control variables. A striking finding is the universal existence of an optimal pinning fraction to minimize the variance of the system, regardless of the pinning patterns and the network topology. We carry out a generally applicable theory to explain the emergence of optimal pinning and to predict the dependence of the optimal pinning fraction on the network topology. Our work represents a general framework to deal with the broader problem of controlling collective dynamics in complex systems with potential applications in social, economical and political systems.

Successful identification of directed dynamical influence in complex systems is relevant to significant problems of current interest. Traditional methods based on Granger causality and transfer entropy have issues such as difficulty with nonlinearity and large data requirement. Recently a framework based on nonlinear dynamical analysis was proposed to overcome these difficulties. We find, surprisingly, that noise can counterintuitively enhance the detectability of directed dynamical influence. In fact, intentionally injecting a proper amount of asymmetric noise into the available time series has the unexpected benefit of dramatically increasing confidence in ascertaining the directed dynamical influence in the underlying system. This result is established based on both real data and model time series from nonlinear ecosystems. We develop a physical understanding of the beneficial role of noise in enhancing detection of directed dynamical influence.

A remarkable phenomenon in spatiotemporal dynamical systems is chimera state, where the structurally and dynamically identical oscillators in a coupled networked system spontaneously break into two groups, one exhibiting coherent motion and another incoherent. This phenomenon was typically studied in the setting of non-local coupling configurations. We ask what can happen to chimera states under systematic changes to the network structure when links are removed from the network in an orderly fashion but the local coupling topology remains invariant with respect to an index shift. We find the emergence of multicluster chimera states. Remarkably, as a parameter characterizing the amount of link removal is increased, chimera states of distinct numbers of clusters emerge and persist in different parameter regions. We develop a phenomenological theory, based on enhanced or reduced interactions among oscillators in different spatial groups, to explain why chimera states of certain numbers of clusters occur in certain parameter regions. The theoretical prediction agrees well with numerics.

We investigate the emergence of extreme events in interdependent networks. We introduce an inter-layer traffic resource competing mechanism to account for the limited capacity associated with distinct network layers. A striking finding is that, when the number of network layers and/or the overlap among the layers are increased, extreme events can emerge in a cascading manner on a global scale. Asymptotically, there are two stable absorption states: a state free of extreme events and a state of full of extreme events, and the transition between them is abrupt. Our results indicate that internal interactions in the multiplex system can yield qualitatively distinct phenomena associated with extreme events that do not occur for independent network layers. An implication is that, e.g., public resource competitions among different service providers can lead to a higher resource requirement than naively expected. We derive an analytical theory to understand the emergence of global-scale extreme events based on the concept of effective betweenness. We also articulate a cost-effective control scheme through increasing the capacity of very few hubs to suppress the cascading process of extreme events so as to protect the entire multi-layer infrastructure against global-scale breakdown.