How to make models more useful Barton, C. Michael; Lee, Allen; Janssen, Marco A. ...
Proceedings of the National Academy of Sciences - PNAS,
08/2022, Letnik:
119, Številka:
35
Journal Article
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, due in part to the propensity of lung cancer to metastasize. Aberrant epithelial-to-mesenchymal transition ...(EMT) is a proposed model for the initiation of metastasis. During EMT cell-cell adhesion is reduced allowing cells to dissociate and invade. Of the EMT-associated transcription factors, ZEB1 uniquely promotes NSCLC disease progression. Here we apply two independent screens, BioID and an Epigenome shRNA dropout screen, to define ZEB1 interactors that are critical to metastatic NSCLC. We identify the NuRD complex as a ZEB1 co-repressor and the Rab22 GTPase-activating protein TBC1D2b as a ZEB1/NuRD complex target. We find that TBC1D2b suppresses E-cadherin internalization, thus hindering cancer cell invasion and metastasis.
Social complexity has long been a subject of considerable interest and study among archaeologists; it is generally taken to refer to human societies consisting of large numbers of people, many social ...and economic roles, large permanent settlements, along with a variety of other marker criteria. When viewed from a more general complex systems perspective, however, all human societies are complex systems regardless of size or organizational structure. Complex adaptive systems (CAS) represent systems which are dynamic in space, time, organization, and membership and which are characterized by information transmission and processing that allow them to adjust to changing external and internal conditions. Complex systems approaches offer the potential for new insights into processes of social change, linkages between the actions of individual human agents and societal-level characteristics, interactions between societies and their environment, and allometric relationships between size and organizational complexity. While complex systems approaches have not yet coalesced into a comprehensive theoretical framework, they have identified important isomorphic properties of organization and behavior across diverse phenomena. However, it is difficult to operationalize complex systems concepts in archaeology using the descriptive/confirmatory statistics that dominate quantitative aspects of modern archaeological practice. These are not designed to deal with complex interactions and multilevel feedbacks that vary across space and time. Nor do narratives that simply state that societies are characterized by interacting agent/actors who share cultural knowledge, and whose interacting practices create emergent social-level phenomena add much to our understanding. New analytical tools are needed to make effective use of the conceptual tools of complex systems approaches to human social dynamics. Computational and systems dynamics modeling offer the first generation of such analytical protocols especially oriented towards the systematic study of CAS. A computational model of small-scale society with subsistence agriculture is used to illustrate the complexity of even "simple" societies and the potential for new modeling methods to assist archaeologists in their study.
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic
mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the
...tumor suppressor in nearly 70% of patients. Most
alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between
effectors and mutant p53 remains largely undefined. We show that oncogenic
effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor
, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced
and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic
and mutant p53 to mitigate metastasis. SIGNIFICANCE: Oncogenic
and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic
effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis.
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This article introduces an agent-based modeling laboratory for investigating how evolving hazard information, propagated through forecaster, media, public official, and peer information networks, ...affects patterns of public protective-action decisions during hurricane threats. The model, called CHIME ABM, provides a platform for integrating atmospheric science, social science, and computer and information science knowledge and data to explore the complex socio-ecological dynamics of modern hazard information and decision systems from a new perspective. First, the model's interdisciplinary conceptualization and implementation is described. Results are then presented from experiments demonstrating the model's behaviors and comparing patterns of evacuation decisions when key agent parameters and the geographical population distribution, forecast skill, and storm are varied. The article illustrates how this type of theoretically and empirically informed digital laboratory can be used to develop new insights into the interactions among environmental hazards, information flow, protective decisions, and societal outcomes.
•Agent-based modeling helps elucidate how evolving hazards, information, and decisions interact.•Information propagates across space, time, and people to influence evacuation patterns.•As threat uncertainty decreases, feedback loops rapidly increase risk assessments.
Numerous studies have shown that the relative frequency of retouched pieces can help to distinguish forager mobility strategies amongst individual layers at a single site and, potentially, at ...multiple sites across regions (Riel-Salvatore & Barton, 2004; Riel-Salvatore et al., 2008; Barton & Riel-Salvatore, 2014). We use this proxy measure and other lines of evidence to evaluate Late Pleistocene human land-use practices from 47 Upper Paleolithic and Mesolithic sites in northern coastal Spain.
To monitor mobility strategies we examine the proportion of retouched pieces to total lithics, focusing on backed pieces which probably served mostly as replaceable inserts in organic armatures for hunting weapons. Kuhn (1995) argued that foragers at some distance from a residential base would have had to rely on replaceable elements for the tools and weapons they carried with them. Assemblages with low total lithic densities but a high proportion of backed pieces would most likely represent the remains of short-term camps where hunting weapons were repaired in the field, whereas those with high lithic densities and relatively few backed pieces would likely represent residential bases where hunting weapons were manufactured.
The analysis also links variation in lithic assemblages to paleoclimate and topography and uses 951 radiocarbon dates to identify demographic ‘pulses’ under the assumption that – ceteris paribus – the density of dates and the density of population are at least roughly linearly correlated with one another (French & Collins, 2015). Increases and decreases in regional population density can be detected and compared to episodes of climate change measured by the GISP2 and NGRIP2 ice cores over the Pleniglacial, Tardiglacial (MIS 2) and the early Holocene. Data insufficiencies, incomparable typologies, and adequacy of reporting are also discussed.
The unprecedented use of Earth's resources by humans, in combination with
increasing natural variability in natural processes over the past century, is
affecting the evolution of the Earth system. To ...better understand natural
processes and their potential future trajectories requires improved
integration with and quantification of human processes. Similarly, to
mitigate risk and facilitate socio-economic development requires a better
understanding of how the natural system (e.g. climate variability and
change, extreme weather events, and processes affecting soil fertility)
affects human processes. Our understanding of these interactions and feedback
between human and natural systems has been formalized through a variety of
modelling approaches. However, a common conceptual framework or set of
guidelines to model human–natural-system feedbacks is lacking. The presented
research lays out a conceptual framework that includes representing
model coupling configuration in combination with the frequency of interaction
and coordination of communication between coupled models. Four different
approaches used to couple representations of the human and natural system are
presented in relation to this framework, which vary in the processes
represented and in the scale of their application. From the development and
experience associated with the four models of coupled human–natural systems,
the following eight lessons were identified that if taken into account by
future coupled human–natural-systems model developments may increase their
success: (1) leverage the power of sensitivity analysis with models,
(2) remember modelling is an iterative process, (3) create a common language,
(4) make code open-access, (5) ensure consistency, (6) reconcile
spatio-temporal mismatch, (7) construct homogeneous units, and
(8) incorporating feedback increases non-linearity and variability. Following a discussion of
feedbacks, a way forward to expedite model coupling and increase the
longevity and interoperability of models is given, which suggests the use of
a wrapper container software, a standardized applications programming
interface (API), the incorporation of standard names, the mitigation of sunk costs by
creating interfaces to multiple coupling frameworks, and the adoption of
reproducible workflow environments to wire the pieces together.
Humans have made profound changes to the Earth. The resulting societal challenges of the Anthropocene (e.g., climate change and impacts, renewable energy, adaptive infrastructure, disasters, ...pandemics, food insecurity, and biodiversity loss) are complex and systemic, with causes, interactions, and consequences that cascade across a globally connected system of systems. In this Critical Review, we turn to our “origin story” for insight, briefly tracing the formation of the Universe and the Earth, the emergence of life, the evolution of multicellular organisms, mammals, primates, and humans, as well as the more recent societal transitions involving agriculture, urbanization, industrialization, and computerization. Focusing on the evolution of the Earth, genetic evolution, the evolution of the brain, and cultural evolution, which includes technological evolution, we identify a nested evolutionary sequence of geophysical, biophysical, sociocultural, and sociotechnical systems, emphasizing the causal mechanisms that first formed, and then transformed, Earth systems into Anthropocene systems. Describing how the Anthropocene systems coevolved, and briefly illustrating how the ensuing societal challenges became tightly integrated across multiple spatial, temporal, and organizational scales, we conclude by proposing an evolutionary, system-of-systems, convergence paradigm for the entire family of interdependent societal challenges of the Anthropocene.
System-of-systems approaches for integrated assessments have become prevalent in recent years. Such approaches integrate a variety of models from different disciplines and modeling paradigms to ...represent a socio-environmental (or social-ecological) system aiming to holistically inform policy and decision-making processes. Central to the system-of-systems approaches is the representation of systems in a multi-tier framework with nested scales. Current modeling paradigms, however, have disciplinary-specific lineage, leading to inconsistencies in the conceptualization and integration of socio-environmental systems. In this paper, a multidisciplinary team of researchers, from engineering, natural and social sciences, have come together to detail socio-technical practices and challenges that arise in the consideration of scale throughout the socio-environmental modeling process. We identify key paths forward, focused on explicit consideration of scale and uncertainty, strengthening interdisciplinary communication, and improvement of the documentation process. We call for a grand vision (and commensurate funding) for holistic system-of-systems research that engages researchers, stakeholders, and policy makers in a multi-tiered process for the co-creation of knowledge and solutions to major socio-environmental problems.
•Scale incompatibilities among system representations are a key challenge in socio-environmental systems modeling.•Issues of scale arise from the complexity, size and heterogeneity of the constituent systems and their interactions.•A more holistic systems-of-systems modeling framework is needed within which to integrate current approaches and tools.•Socio-technical considerations for system-of-systems modeling is presented from a range of disciplinary perspectives.
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