Reductionist Approach Research Articles

A reductionist approach to determine the effect of cell-cell contact on human epidermal stem cell differentiation

The balance between stem cell renewal and differentiation is determined by the interplay between intrinsic cellular controls and extrinsic factors presented by the microenvironment, or ‘niche’. Previous studies on cultured human epidermis have utilised suspension culture and restricted cell spreading to investigate regulation of differentiation in single keratinocytes. However, keratinocytes are typically adherent to neighbouring cells in vivo. We therefore developed experimental models to investigate the combined effects of cell-ECM adhesion and cell-cell contact. We utilized lipid-modified oligonucleotides to form clusters of keratinocytes which were subsequently placed in suspension to induce terminal differentiation. In this experimental model cell-cell contact had no effect on suspension-induced differentiation of keratinocytes. We next developed a high-throughput platform for robust geometrical confinement of keratinocytes to hexagonal ECM-coated islands permitting direct cell-cell contact between single cells. As in the case of circular islands, differentiation was stimulated on the smallest single hexagonal islands. However, the percentage of involucrin-positive cells on small bowtie islands was significantly lower than on single islands, demonstrating that cell-cell contact reduced differentiation in response to decreased substrate adhesion. None of the small bowtie islands contained two involucrin-positive cells. Rather, if one cell was involucrin-positive the other was involucrin-negative. This suggests that there is intrinsic asymmetry in the effect of cell-cell contact in decreasing differentiation. Thus, our reductionist approaches provide new insights into the effect of the niche on keratinocyte differentiation. Statement of significanceStem cell behaviour is regulated by a combination of external signals, including the nature of the adhesive substrate and cell-cell interactions. An understanding of how different signals are integrated creates the possibility of developing new biomaterials to promote tissue regeneration and broaden our understanding of skin diseases such as eczema and psoriasis, in which stem cell proliferation and differentiation are perturbed. In this study we have applied two methods to engineer intercellular adhesion of human epidermal stem cells, one involving lipid-modified DNA and the other involving hexagonal micropatterns. We show that the effect of cell-cell adhesion depends on cell-substrate adhesion and uncover evidence that two cells in equivalent environments can nevertheless behave differently.

What Do We Mean by Corporate Social Irresponsibility? Examining the Concept in the Literature

In this paper, we examine the ontological and epistemological properties of Corporate Social Irresponsibility (CSiR), in order to provide an evaluation of its current status as a concept. More specifically, we analyze CSiR definitions, operationalization, related concepts, and empirical evidence in the business and management literature. We find that scholars adopt three different approaches to define CSiR: the stakeholder-based approach, the typification approach, and the reductionist approach. Moreover, our analysis shows that the field of CSiR is being developed with a strong quantitative orientation, and that the phenomenon is explored mostly on the context of large and multinational companies. Based on our findings, we provide a definition of CSiR and recommendations for future research in three main areas: (1) CSiR conceptualization and theory development; (2) methodology and measurement enhancements and (3) exploration of new contexts.

Essential Biodiversity for Understanding Change

The biodiversity crisis we are experiencing requires more than ever the establishment of an observation and monitoring system to help us understand where we have the greatest problems, to inform actions to help halt and reverse biodiversity loss in those places, and to anticipate the impact of our future actions. The Essential Biodiversity Variable framework concept (EBV; Pereira et al. 2013), was conceptually conceived to provide an analytical framework for biodiversity monitoring, which includes functional, structural, and compositional aspects at different levels of organization, from genes to ecosystems, which, as opposed to reductionist approaches, tries to think of biodiversity from a holistic and systemic viewpoint. After some years of working on refining this concept (e.g., Proença et al. 2017, Kissling et al. 2017, Jetz et al. 2019), in collaboration with the Group on Earth Observations Biodiversity Observation Networks (GEO BON) user community, we have taken the next step, which is precisely to work on grounding this concept through a proposed structure, standard, and tools, which facilitates interoperability and the process of sharing and accessing this information. Our vision for boosting the adoption and use of the EBV framework, named for the different dimensions of the planetary life system that it is intended to capture, is to facilitate access to multiple EBV data products organized under a consistent data structure and with standardized annotation across EBV classes. We propose to leverage the Network Common Data Form (NetCDF) data structure in combination with the Attribute Convention for Data Discovery (ACDD) terms and the Ecological Metadata Language (EML) syntax and adapt them to describe hierarchically organized, spatially explicit, gridded data on biodiversity observations, model predictions, and scenarios using a combination of a web portal and an R package for publication and exploration. We believe that this data structure metadata and supporting tools, initially tested using diverse biodiversity datasets that cover the full scope of the Essential Biodiversity Variables framework, will allow us to better serve the community of users interested in different aspects of global change, to be able to ask questions framed in specific times and spaces in order to obtain, analyze, and visualize the time series registered somewhere on the planet and gain knowledge and insights that will inform decision-making and help us drive and direct development trajectories towards a more sustainable future.

Management of abiotic stresses by microbiome-based engineering of the rhizosphere.

Abiotic stresses detrimentally affect both plant and soil health, threatening food security in an ever-increasing world population. Sustainable agriculture is necessary to augment crop yield with simultaneous management of stresses. Limitations of conventional bioinoculants have shifted the focus to more effective alternatives. With the realization of the potential of rhizospheric microbiome engineering in enhancing plant's fitness under stress, efforts have accelerated in this direction. Though still in its infancy, microbiome-based engineering has gained popularity because of its advantages over the microbe-based approach. This review briefly presents major abiotic stresses afflicting arable land, followed by an introduction to the conventional approach of microbe-based enhancement of plant attributes and stress mitigation with its inherent limitations. It then focuses on the significance of the rhizospheric microbiome and possibilities of harnessing its potential by its strategic engineering for stress management. Further, success stories related to two major approaches of microbiome engineering (generation of synthetic microbial community/consortium, and host-mediated artificial selection) pertaining to stress management have been critically presented. Together with bringing forth the challenges associated with the wide application of rhizospheric microbiome engineering in agriculture, the review proposes the adoption of a combinational scheme for the same, bringing together ecological and reductionist approaches for improvised sustainable agricultural practices.

More is different with a vengeance.

In his 1972 landmark paper "More is Different," Philip W. Anderson established "complexity" as a fundamentally important subject of inquiry. He highlighted the profound limitations of reductionist approaches in understanding nature's complexity, and he set in motion new lines of investigation that have, among other things, led to systems biology.

Exploring shear alignment of concentrated wormlike micelles using rheology coupled with small-angle neutron scattering

Wormlike micelles (WLMs) are vital components of many consumer products and industrial fluids, adding a shear-dependent viscous texture through their entanglement in solutions. It is now well accepted from experiments such as coupling rheology and scattering that, similar to many polymer solutions and dispersions of highly anisotropic particles, WLM behavior during shear arises from the alignment of the “worms” with the shear field, resulting in ordering that is rapidly lost in the cessation of shear. Most studies of such systems have been limited to dilute systems that are far below concentrations used industrially and commercially, due to the complexity of analyzing shear-induced many-body effects in high volume fraction dispersions. Here, we explore the shear alignment of concentrated WLM solutions comprising sodium laureth sulfate and cocamidopropyl betaine in 0.38 M aqueous sodium chloride. By analyzing only scattering data at high values of the scattering vector (i.e., correlations at short length scales that are dominant in such concentrated systems), we explore whether useful information can be obtained by naïvely approximating the WLMs as an ensemble of unconnected short rods representing sections of the worms. By taking this reductionist approach to analyzing the obtained two-dimensional scattering patterns from these systems under shear, we find that in this regime, such concentrated worms can be approximated as cylinders that become more aligned with the direction of shear as volume fraction and shear rate increase.

The Paradox of Classical Reasoning

Intuitively, the more powerful a theory is, the greater the variety and quantity of ideas can be expressed through its formal language. Therefore, when comparing two theories concerning the same subject, it seems only reasonable to compare the expressive powers of their formal languages. On condition that the quantum mechanical description is universal and so can be applied to macroscopic systems, quantum theory is required to be more powerful than classical mechanics. This implies that the formal language of Hilbert space theory must be more expressive than that of Zermelo-Fraenkel set theory (the language of classical formalism). However, as shown in the paper, such a requirement cannot be met. As a result, classical and quantum formalisms cannot be in a hierarchical relation, that is, include one another. This fact puts in doubt the quantum-classical correspondence and undermines the reductionist approach to the physical world.

Multimodal or multilingual? Native English teachers’ engagement with translanguaging in Hong Kong TESOL classrooms

Abstract Although the potential of translanguaging within ESL/EFL classroom contexts to promote students’ linguistic learning has been well-documented, most studies have focused on ESL/EFL teachers (whose L1 is not English) and their students’ ideologies and experiences, with little attention paid to the experiences and perspectives of native English teachers (NETs) working in the Global South and postcolonial areas. This study examined 11 native English teachers’ engagement with translanguaging in Hong Kong TESOL classrooms. Data were gathered through in-depth semi-structured individual interviews and video recordings of classroom interactions. A recursive qualitative analysis elicited a taxonomy of NET teachers’ engagement with translanguaging, comprising resistant, ambivalent, and reductionistic approaches. The findings also demonstrate that ambivalent engagement with translanguaging turned out to be adopted the most among the NET participants. The findings call for examining two new translanguaging forms through NET teachers who have worked under a linguistically policed discourse, i.e., the underground and disguised translanguaging, and multimodal translanguaging without involving students’ L1. The findings indicate that multimodality can be used as a bridge to create a translanguaging space, and that creating a translanguaging space through multimodality appears to be more politically neutral for NET teachers.

Lost in translation: IT business value research and resource complementarity—an integrative framework, shortcomings and future research directions

Despite longstanding research efforts, there is still ambiguity surrounding the business value created by IT. To approach this conundrum, research focus has progressed from an isolated investigation of IT to the assessment of complementarity between IT and different non-IT resources such as work practices or decision structures. However, incoherence around the characteristics and scope of these complementary non-IT resources has created a fragmented body of research, preventing a sustainable knowledge creation. Thus, in this paper we synthesize the dispersed research efforts, identify shortcomings in the extant literature, and derive opportunities for future research. Specifically, we present a converging definition of complementary non-IT resources and specify their role in the value creation process from IT by viewing it through three distinct lenses: microeconomic theory, resource-based view, and contingency theory. We structure current research efforts by organizing complementary non-IT resources into distinct categories, namely strategy, structure, practices, processes, and culture (organizational resources), top management support, internal relations, and external relations (relational resources), worker skill (non-IT human resources), non-IT physical resources, as well as internal funds and external funds (financial resources). Finally, we highlight five important shortcomings in the current literature, such as the predominant use of reductionist approaches or monolithic IT measures, and make actionable recommendations to resolve them.

P53 TAD2 Domain (38-61) Forms Amyloid-like Aggregates in Isolation.

A strong association between protein aggregation and human diseases (such as Alzheimer's, Parkinson's, and Huntington's disease) is well demonstrated. Misfolding and aggregation of p53, a central transcriptional mediator, has been revealed by various experimental evidence in different types of cancers. Aggregation studies focusing on different p53 domains, mostly, the central core domain and its mutants under the influence of various environmental conditions, and the p53 transactivation domain (TAD) (1-63) have been reported. However, the specific subdomains responsible for p53 aggregation are not known. p53 TADs interact with diverse cellular factors to modulate the function of p53 and elicit appropriate cellular responses under different stress conditions. In this study, the aggregation of the p53 TAD2 domain (38-61) has been studied in isolation. The aggregates were generated in vitro under acidic pH conditions after in silico scoring for amyloidogenic tendency and characterized using dye-based assays (ThT and bis-ANS fluorescence), CD spectroscopy, and microscopy (scanning electron microscoy, transmission electron microscopy, and atomic force microscopy). It was observed that p53 TAD2 forms characteristic β-sheet-rich amyloid-like fibrils. Via a reductionist approach, this study highlights the nature of p53 TAD2 domain (38-61) aggregation.

In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity.

Obesity is a growing medical and social problem worldwide. The control of energy homeostasis in the brain is achieved by various regions including the arcuate hypothalamic nucleus (ARH). The latter comprises a number of neuronal populations including the first order metabolic neurons, appetite-stimulating agouti-related peptide (AgRP) neurons and appetite-suppressing proopiomelanocortin (POMC) neurons. Using an in vivo reductionist approach and POMCCre-dependent CRISPR-Cas9, we demonstrate that miR-15a-5p protects from obesity. Moreover, we have identified Bace1, a gene previously linked to energy metabolism imbalance, as a direct target of miR-15a-5p. This work warrants further investigations of non-coding RNA-mediated regulation of energy homeostasis and might contribute to the development of novel therapeutic approaches to treat metabolic diseases.

When the end modifies its means: the origins of novelty and the evolution of innovation

Abstract The origin of novel complex traits constitutes a central yet largely unresolved challenge in evolutionary biology. Intriguingly, many of the most promising breakthroughs in understanding the genesis of evolutionary novelty in recent years have occurred not in evolutionary biology itself, but through the comparative study of development and, more recently, the interface of developmental biology and ecology. Here, I discuss how these insights are changing our understanding of what matters in the origin of novel, complex traits in ontogeny and evolution. Specifically, my essay has two major objectives. First, I discuss how the nature of developmental systems biases the production of phenotypic variation in the face of novel or stressful environments toward functional, integrated and, possibly, adaptive variants. This, in turn, allows the production of novel phenotypes to precede (rather than follow) changes in genotype and allows developmental processes that are the product of past evolution to shape evolutionary change that has yet to occur. Second, I explore how this nature of developmental systems has itself evolved over time, increasing the repertoire of ontogenies to pursue a wider range of objectives across an expanding range of conditions, thereby creating an increasingly extensive affordance landscape in development and developmental evolution. Developmental systems and their evolution can thus be viewed as dynamic processes that modify their own means across ontogeny and phylogeny. The study of these dynamics necessitates more than the strict reductionist approach that currently dominates the fields of developmental and evolutionary developmental biology.

Bioengineering approaches for modelling retinal pathologies of the outer blood-retinal barrier.

Alterations of the junctional complex of the outer blood-retinal barrier (oBRB), which is integrated by the close interaction of the retinal pigment epithelium, the Bruch's membrane, and the choriocapillaris, contribute to the loss of neuronal signalling and subsequent vision impairment in several retinal inflammatory disorders such as age-related macular degeneration and diabetic retinopathy. Reductionist approaches into the mechanisms that underlie such diseases have been hindered by the absence of adequate in vitro models using human cells to provide the 3D dynamic architecture that enables expression of the in vivo phenotype of the oBRB. Conventional in vitro cell models are based on 2D monolayer cellular cultures, unable to properly recapitulate the complexity of living systems. The main drawbacks of conventional oBRB models also emerge from the cell sourcing, the lack of an appropriate Bruch's membrane analogue, and the lack of choroidal microvasculature with flow. In the last years, the advent of organ-on-a-chip, bioengineering, and stem cell technologies is providing more advanced 3D models with flow, multicellularity, and external control over microenvironmental properties. By incorporating additional biological complexity, organ-on-a-chip devices can mirror physiologically relevant properties of the native tissue while offering additional set ups to model and study disease. In this review we first examine the current understanding of oBRB biology as a functional unit, highlighting the coordinated contribution of the different components to barrier function in health and disease. Then we describe recent advances in the use of pluripotent stem cells-derived retinal cells, Bruch's membrane analogues, and co-culture techniques to recapitulate the oBRB. We finally discuss current advances and challenges of oBRB-on-a-chip technologies for disease modelling.

Introducing Systems Thinking Techniques into an Undergraduate Engineering Education

AbstractThe world is faced with producing more complex, interdependent systems, and systems of systems. Due to the complexity and interdependencies, these systems do not lend themselves to the traditional reductionist approach, which is feasible only for complicated systems. To architect and develop complex systems requires the use of systems thinking tools and competencies which are an enabler for developing complex engineered systems, humanitarian systems, organizational structures, business strategies, production optimization, solving socio‐technical problems, etc. Because of the power of systems thinking and its global applicability, the question becomes; how can we better produce system thinkers? There are currently many effective systems thinking methods and tools which have been successfully adopted by practicing engineers. This paper will describe how we can introduce similar systems thinking elements into an existing undergraduate education through lectures/mentoring, labs/projects/experiments, case studies/background research, and multi‐discipline capstone projects/internships. Some universities have recently added systems thinking elements to their curricula, and through INCOSE's influence, the Accreditation Board for Engineering and Technology (ABET) now mandates systems thinking for all undergraduate engineering programs. This paper acts to describe a variety of implementation methods to serve as exemplars for those implementing systems thinking into existing curricula. The motivation of this work is to ultimately produce engineers who are better suited to engineering complex systems when they enter the workforce.

Maslow’un İhtiyaçlar Hiyerarşisi Modeli’nin Bütünleşik Bir Süreç Olarak Yeniden Yorumlanması

ÖZ Maslow’un ihtiyaçlar teorisi, çağdaş motivasyon teorilerinin gelişiminin temellerini oluşturmakta ve hâlen hem akademide hem de pratik iş hayatında yönetici ve çalışan motivasyonunun açıklanmasına rehberlik ve kaynaklık etmektedir. Maslow’un ihtiyaçlar teorisine yönelik yapılan eleştiriler ise özünde, ihtiyaçlar teorisinin hiyerarşik yapısı ve kendini gerçekleştirme safhasına yönelik olarak yaygın ve yüzeysel bir şekilde gerçekleştirilen, yani modelin kendisiyle ilgili bir yanlışlama içermeyen birtakım indirgemeci yaklaşım ve tenkitlerden ibarettir. Bu çalışmayı diğerlerinden ayırt eden en önemli hususiyet ise, kritikle birlikte modelin yeniden açıklanmasına yönelik yeni bir yorumun getirilmiş olmasıdır. Bu kapsamda bu çalışmada evvela model Maslow’un ortaya koyduğu şekliyle birincil kaynaklardan istifade ile izah edilecek, sonrasında modelin hiyerarşik yapısına yönelik eleştiriler toparlanacak ve modelin kendini gerçekleştirme safhası sofistike bir bakış açısıyla yeniden irdelenecek ve son bölümde ise modelin yeniden bütünleşik bir biçimde yeniden yorumlanmasına yönelik bir öneri ortaya koyulacaktır.

Abstract 4190: Combining dual CAR iPSC-derived immune cells with antibody for multi-antigen targeting to overcome clonal resistance in multiple myeloma

Abstract Resistance to CAR-T cell therapy through antigen loss and clonal heterogeneity is a major limiting factor in achieving durable responses, even in highly persistent cell therapies. Simultaneous targeting of multiple tumor antigens with a single therapeutic modality offers the potential to treat heterogeneous tumor populations, prevent antigen escape, and induce durable clinical remission. Here, we demonstrate the application of a unique dual-CAR approach simultaneously targeting two tumor associated antigens (TAA) for the treatment of multiple myeloma (MM) using an off-the-shelf induced pluripotent stem cell (iPSC) derived NK cell platform. The iPSC background has been functionally enhanced and can be combined with therapeutic antibodies. A CAR targeting B cell maturation antigen (BCMA), a well-defined TAA in MM, was designed utilizing a previously published high-affinity binding sequence shown to exhibit high selectivity to BCMA with enhanced recognition of low-BCMA expressing myeloma cells (Bluhm et al., Molec Ther 2018). This CAR was combined with a companion CAR targeting the pan-TAAs, MICA and MICB. The CAR binding sequence targets the conserved α3 domain of MICA/MICB, which we have previously shown to inhibit MICA/B shedding by blocking the putative cleavage site (Andrade et al., Science 2018). The designed anti-MICA/B-α3 CAR exhibits selective targeting potential against a broad range of tumor types. To determine the suitability of co-targeting BCMA and MICA/B in MM, we surveyed surface expression of BCMA and MICA/B on a variety of MM cancer cell lines and observed a complimentary pattern of co-expression compatible with a dual-CAR to broaden the targeting approach of malignant plasma cells. In a reductionist approach, dual CAR-iNK cells exhibited antigen-specific activation, degranulation and cytotoxicity against a Nalm6 target line constitutively expressing the BCMA and MICA/B. Similar trends were observed in a series of long-term cytotoxicity assays against several MM lines, consistent with antibody staining on target cells, illustrating that co-targeting of MICA/B and BCMA expands the breadth of coverage against MM. Known modulators of antigen expression were tested for their ability to provide further depth of response, and therapeutic antibodies such as anti-CD38 were tested in combination to exploit the non-cleavable CD16 and CD38KO edits in the iPSC backbone. These combinations were further tested in vivo against a disseminated model of multiple myeloma where BCMA/MICA dual CAR-iNK cells demonstrated superior tumor control relative to single-CAR controls, and TGI was augmented with the addition of Daratumamab. These data highlight the applicability of a multi-targeted approach in MM patients, whereby MM dual-CAR NK and/or T cells maintain responsiveness to malignant cells that shed or downregulate tumor antigens to evade treatment. Citation Format: Ketan Mathavan, John Reiser, Sajid Mahmood, Yijia Pan, Bryan Hancock, Robert Blum, Wen-I Yeh, Andrew Houk, Chia-Wei Chang, Tom Lee, Bobby Goulding, Jode Goodridge, Ryan Bjordahl, Bahram Valamehr, Uta Hoepken, Armin Rehm, Kai Wucherpfennig. Combining dual CAR iPSC-derived immune cells with antibody for multi-antigen targeting to overcome clonal resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4190.

Shattering Dietary Taboos in Post-Pandemic Era: Human-Animal Interaction in J. M. Coetzee’s Elizabeth Costello

Many conspiracy theories and worst-case scenarios have been produced about the COVID-19 pandemic. With a reductionist approach, this new coronavirus disease outbreak has been regrettably confined to the simple matter that humans are exposed to viral pathogens of certain wild animals. However, the global reasons and outcomes of the present outbreak should not simply be correlated with the physiologies of a group of animals but with human activities subject to wanton consumption, interference with living spaces, intense commercialization and, particularly, dietary habits. Thus, reconceptualizing pandemics as a multidimensional “ecological crisis” posing a threat to the future of human and nonhuman beings rather than a “disease” endangering human welfare seems to become the sole prerequisite for a significant policy shift in the relationship between humans and animals. With this in mind, the eponymous protagonist of the novel, Elizabeth Costello, a vegetarian like her creator, gives the traces of an ecological philosophy which reinforces the notion that it is not the sheer scientific productivity driven by the rationalization but the reconsideration of animal-human interactions that can prevent post-pandemic era from recurring outbreaks. In the novel, through her understanding of environmental ethics, J. M. Coetzee’s vegetarian and writer protagonist provides discussions that help rethinking literature as one of the guiding disciplines that can offer new insights into the natural habitat of animals. This study intends to handle how Coetzee’s thoughts on vegetarianism and human-animal interactions can become an ethical model for the future world in dire need of a post-pandemic paradigm shift.

Structural dynamics of Zika virus NS1 via a reductionist approach reveal the disordered nature of its β-roll domain in isolation

Flavivirus Non-structural 1 (NS1) protein performs multiple functions and it is highly plausible that significant structural and folding dynamics of NS1 might play a role in its multifunctionality. It is important to understand the structural conformations of NS1 and its domains in isolation, possibly highlighting the implications on the overall NS1 protein dynamics. Therefore, we have employed extensively long molecular dynamic (MD) simulations in understanding the dynamics of the three structural domains (i.e., β-roll, wing, and β-ladder) in isolation, as a reductionist approach. We also found that the β-ladder domain is highly flexible, while the β-roll domain is disordered during long simulations. Further, we experimentally validated our findings using CD spectroscopy and confirmed the intrinsically disordered behavior of NS1 β-roll in isolation and lipid mimetic environments. Therefore, we believe this study may have implications for significant dynamics played by NS1 protein, specifically during oligomerization of NS1.

Cellular and Engineered Organoids for Cardiovascular Models.

An ensemble of in vitro cardiac tissue models has been developed over the past several decades to aid our understanding of complex cardiovascular disorders using a reductionist approach. These approaches often rely on recapitulating single or multiple clinically relevant end points in a dish indicative of the cardiac pathophysiology. The possibility to generate disease-relevant and patient-specific human induced pluripotent stem cells has further leveraged the utility of the cardiac models as screening tools at a large scale. To elucidate biological mechanisms in the cardiac models, it is critical to integrate physiological cues in form of biochemical, biophysical, and electromechanical stimuli to achieve desired tissue-like maturity for a robust phenotyping. Here, we review the latest advances in the directed stem cell differentiation approaches to derive a wide gamut of cardiovascular cell types, to allow customization in cardiac model systems, and to study diseased states in multiple cell types. We also highlight the recent progress in the development of several cardiovascular models, such as cardiac organoids, microtissues, engineered heart tissues, and microphysiological systems. We further expand our discussion on defining the context of use for the selection of currently available cardiac tissue models. Last, we discuss the limitations and challenges with the current state-of-the-art cardiac models and highlight future directions.

Dissecting cell fate dynamics in pediatric glioblastoma through the lens of complex systems and cellular cybernetics.

Cancers are complex dynamic ecosystems. Reductionist approaches to science are inadequate in characterizing their self-organized patterns and collective emergent behaviors. Since current approaches to single-cell analysis in cancer systems rely primarily on single time-point multiomics, many of the temporal features and causal adaptive behaviors in cancer dynamics are vastly ignored. As such, tools and concepts from the interdisciplinary paradigm of complex systems theory are introduced herein to decode the cellular cybernetics of cancer differentiation dynamics and behavioral patterns. An intuition for the attractors and complex networks underlying cancer processes such as cell fate decision-making, multiscale pattern formation systems, and epigenetic state-transitions is developed. The applications of complex systems physics in paving targeted therapies and causal pattern discovery in precision oncology are discussed. Pediatric high-grade gliomas are discussed as a model-system to demonstrate that cancers are complex adaptive systems, in which the emergence and selection of heterogeneous cellular states and phenotypic plasticity are driven by complex multiscale network dynamics. In specific, pediatric glioblastoma (GBM) is used as a proof-of-concept model to illustrate the applications of the complex systems framework in understanding GBM cell fate decisions and decoding their adaptive cellular dynamics. The scope of these tools in forecasting cancer cell fate dynamics in the emerging field of computational oncology and patient-centered systems medicine is highlighted.