Towards real-world complexity: an introduction to multiplex networks

Many real-world complex systems are best modeled by multiplex networks of interacting network layers. The multiplex network study is one of the newest and hottest themes in the statistical physics of complex networks. Pioneering studies have proven that the multiplexity has broad impact on the system's structure and function. In this Colloquium paper, we present an organized review of the growing body of current literature on multiplex networks by categorizing existing studies broadly according to the type of layer coupling in the problem. Major recent advances in the field are surveyed and some outstanding open challenges and future perspectives will be proposed.Comment: 20 pages, 10 figure

Infected or informed? Social structure and the simultaneous transmission of information and infectious disease

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record Social interactions present opportunities for both information and infection to spread through populations. Social learning is often proposed as a key benefit of sociality, while infectious disease spread are proposed as a major cost. Multiple empirical and theoretical studies have demonstrated the importance of social structure for the transmission of either information or harmful pathogens and parasites, but rarely in combination. We provide an overview of relevant empirical studies, discuss differences in the transmission processes of infection and information, and review how these processes have been modelled. Finally, we highlight ways in which animal social network structure and dynamics might mediate the tradeoff between the sharing of information and infection. We reveal how modular social network structures can promote the spread of information and mitigate against the spread of infection relative to other network structures. We discuss how the maintenance of long-term social bonds, clustering of social contacts in time, and adaptive plasticity in behavioural interactions, all play important roles in influencing the transmission of information and infection. We provide novel hypotheses and suggest new directions for research that quantifies the transmission of information and infection simultaneously across different network structures to help tease apart their influence on the evolution of social behaviour.University of Exete

The fundamental benefits of multiplexity in ecological networks

Acknowledgements and Funding Statement YM was supported Max Planck Society, and was partially supported by the University of Aberdeen Elphinstone Fellowship at earlier stages of this work. The work at Arizona State University was supported by Office of Naval Research under Grant No. N00014-21-1-2323.Peer reviewedPostprin

Xeno-free 3D Culture of Mesenchymal Stromal Cells For Bone Tissue Engineering

Clinical translation of innovative regenerative approaches using mesenchymal stromal cells (MSCs) is urgently needed for the treatment of challenging bone defects. The overall aim of this thesis, comprising of one systematic review and four original studies, was to optimize a xeno-free three-dimensional (3D) culture system of MSCs, as a clinically relevant strategy for bone tissue engineering (BTE). Secondary aims were to identify a minimally invasive source for MSCs, and to promote angiogenesis within the xeno-free 3D cultures. Human platelet lysate (HPL) represents a favourable supplement for xeno-free expansion of MSCs (Study I). To standardize HPL production, the storage time of platelet concentrates was optimized in terms of HPL cytokine content and biological efficacy on MSCs. Advantages of HPL culture (vs. bovine serum) were observed in relation to all relevant in vitro aspects of MSCs, i.e., growth, immunophenotype and osteogenic differentiation (Studies II and III). Progenitor cells showing a characteristic MSC-like phenotype and multipotency were isolated from human gingiva (GPCs) and periodontal ligament (PDLCs). Both GPCs and PDLCs demonstrated superior growth and osteogenic differentiation in HPL vs. FBS; a subset of GPCs also showed potent neurogenic differentiation (Study III). Given their relative ease of isolation and minimally invasive tissue harvesting, GPCs were prioritized in subsequent experiments. To overcome the limitations of traditional monolayer (2D) culture, 3D spheroid cultures were established in HPL. Both GPCs and BMSCs demonstrated significantly increased expression of stemness- and osteogenesis-related genes in spheroids vs. monolayers, confirmed at the protein level by immunocytochemistry. Moreover, the cytokine release profile of GPC and BMSC spheroids was considerably enhanced compared to monolayers. Under osteogenic conditions, GPC spheroids showed in vitro mineralization comparable to that of BMSCs (Study III). When implanted in vivo, xeno-free GPCs and BMSCs showed ectopic mineralization after 4 and 8 weeks based on micro-CT and histology; implanted human cells were identified at the mineralization sites via in situ hybridization. In the case of BMSCs, significantly greater mineralization was observed in constructs containing spheroids vs. single cells (Study V). To enhance angiogenesis, a coculture strategy was tested using a xeno-free spheroid coculture model of GPCs and human umbilical vein ECs (HUVECs) embedded in an HPL-hydrogel (HPLG). When cultured as spheroids, HUVECs showed characteristic in vitro sprouting angiogenesis in HPLG. A trend for increased in vitro HUVEC-sprouting was observed in co-culture with GPCs. Constructs of coculture and HUVEC spheroids in HPLG comparably supported in vivo neoangiogenesis in a chorioallantoic membrane (CAM) assay (Study IV). Clinically relevant BTE constructs were designed combining BMSCs (as spheroids or single cells) encapsulated in HPLG and 3D printed copolymer scaffolds. Viability and osteogenic differentiation of cells within the constructs was confirmed up to 21 days in vitro; greater mineralization was observed in constructs containing spheroids vs. single cells. When implanted in rats’ calvarial defects, constructs of both spheroids and single cells revealed abundant in vivo bone regeneration for up to 12 weeks (Study V). The results herein suggest clear advantages of xeno-free 3D cultures of MSCs for BTE. GPCs represent a promising alternative to BMSCs with osteogenic and proangiogenic potential, and further work is needed to facilitate clinical translation. In particular, the constructs of xeno-free MSCs, HPLG and 3D printed scaffolds developed herein, represent a clinically relevant strategy for BTE

Synthetic epigenetics in yeast

Epigenetics is the study of heritable biological variation not related to changes in DNA sequence. Epigenetic processes are responsible for establishing and maintaining transcriptional programs that define cell identity. Defects to epigenetic processes have been linked to a host of disorders, including mental retardation, aging, cancer and neurodegenerative diseases. The ability to control and engineer epigenetic systems would be valuable both for the basic study of these critical cellular processes as well as for synthetic biology. Indeed, while synthetic biology has made progress using bottom-up approaches to engineer transcriptional and signaling circuitry, epigenetic systems have remained largely underutilized. The predictive engineering of epigenetic systems could enable new functions to be implemented in synthetic organisms, including programmed phenotypic diversity, memory, reversibility, inheritance, and hysteresis. This thesis broadly focuses on the development of foundational tools and intellectual frameworks for applying synthetic biology to epigenetic regulation in the model eukaryote, Saccharomyces cerevisiae. Epigenetic regulation is mediated by diverse molecular mechanisms: e.g. self-sustaining feedback loops, protein structural templating, modifications to chromatin, and RNA silencing. Here we develop synthetic tools and circuits for controlling epigenetic states through (1) modifications to chromatin and (2) self-templating protein conformations. On the former, the synthetic tools we develop make it possible to study and direct how chromatin regulators operate to produce distinct gene expression programs. On the latter, we focus our studies on yeast prions, which are self-templating protein conformations that act as elements of inheritance, developing synthetic tools for detecting and controlling prion states in yeast cells. This thesis explores the application of synthetic biology to these epigenetic systems through four aims: Aim 1. Development of inducible expression systems for precise temporal expression of epigenetic regulators Aim 2. Construction of a library of chromatin regulators to study and program chromatin-based epigenetic regulation. Aim 3. Development of a genetic tool for quantifying protein aggregation and prion states in high-throughput Aim 4. Dynamics and control of prion switching Our tools and studies enable a deeper functional understanding of epigenetic regulation in cells, and the repurposing of these systems for synthetic biology toward addressing industrial and medical applications.2019-10-08T00:00:00

Guest-Host Interactions To Engineer Injectable Hydrogels With Controlled Degradation And Release For Cardiac Repair

Guest-host chemistry is an emerging tool in the preparation of biomaterials. Towards the design of hydrogels, guest-host chemistry has been used to impart unique shear-thinning and self-healing properties that allow these materials to be injected through syringes and catheters as a single component, avoiding complications associated with traditional covalent systems. As a treatment for myocardial infarction, injectable guest-host hydrogels may be injected directly into the myocardial wall and have shown therapeutic benefit in a number of strategies, including drug delivery, cell delivery, and tissue bulking. As delivery systems, injectable hydrogels provide controlled release of payloads that attenuate maladaptive remodeling of the left ventricle, by inhibiting expression of proteases, recruiting cells to the region, or otherwise stimulating therapeutic biological processes such as angiogenesis. Guest-host biomaterials must be refined and advanced to overcome challenges associated with delivering therapeutics in these areas, as well as to provide novel materials platforms for investigating therapeutic delivery in the future. This dissertation describes the engineering of two injectable hydrogel platforms that address challenges in the delivery of therapeutics after myocardial infarction. Each of these systems is investigated both in vitro for an understanding of material properties and the parameters that tune them, as well as in vivo, in a number of clinically relevant animal models and therapeutic targets. In the first aim of this thesis, isotropic guest-host hydrogels are designed for the sustained release of a variety of small molecules. Through the control of small molecule binding with cyclodextrin host moieties engineered in the hydrogel, we show that both cyclodextrin content and molecule affinity for cyclodextrin are critical factors that provide tunable release of small molecules from these systems. Furthermore, we demonstrate that this system is broadly applicable to the release of a number of pharmaceutical small molecule payloads. In the second aim of this thesis, isotropic guest-host hydrogels are specifically formulated for the delivery of the small molecule protease inhibitor SD-7300, a therapeutic requiring local delivery after myocardial infarction. Here we demonstrate that the engineered guest-host hydrogels provide sustained release and retain activity of this molecule, which in turn provides improved functional and biological outcomes in a large-animal model of myocardial infarction. In the third aim of this thesis, guest-host chemistry is utilized to assemble microstructured granular hydrogels for the design of multifunctional material platforms. Granular hydrogels are demonstrated to have disease responsivity in myocardial infarction, and functional benefit through the delivery of the chemokine SDF-1α