Punctuational evolution is pervasive in distal site metastatic colonization.

The evolution of metastasis represents a lethal stage of cancer progression. Yet, the evolutionary kinetics of metastatic disease remain unresolved. Here, using single cell CRISPR-Cas9 lineage tracing data, we show that in metastatic disease, gradual molecular evolution is punctuated by episodes of rapid evolutionary change associated with lineage divergence. By measuring punctuational effects across the metastatic cascade, we show that punctuational effects contribute more to the molecular diversity at distal site metastases compared to the paired primary tumor, suggesting qualitatively different modes of evolution may drive primary and metastatic tumor progression. This is the first empirical evidence for distinct patterns of molecular evolution at early and late stages of metastasis and demonstrates the complex interplay of cell intrinsic and extrinsic factors that shape lethal cancer.

Impact of the electric field intensity and treatment time on whey protein aggregate formation.

Whey proteins are being integrated as high-value food product ingredients due to their versatile and tunable techno-functionality. To meet high food quality and clean label expectations by consumers, electric field (EF) technologies have been proposed to open new frontiers in this field. Despite a variety of studies, it remains ambiguous which EF parameters are crucial to achieving targeted whey protein modifications. Reconstituted liquid whey protein concentrate (WPCL) and filtered, non-heat-treated liquid whey (WPL_filt) at low protein dry weight concentrations (0.4% wt/wt) were exposed to microsecond pulsed electric field (µsPEF) treatments at EF intensities between 1.25 and 12.5 kV/cm, pulse repetition frequencies between 0.38 and 85 Hz, and pulse lengths set to 10 or 100 µs. Protein aggregations were quantified spectroscopically. We report here that aggregates formed at lower temperatures for µsPEF compared with purely thermal treatments in identical treatment geometries at similar time-temperature profiles. We suggest that the observed increase in absorbance is linked to protein migration, the isoelectric point, local deprotonation phenomena of thiol groups, and cation precipitation. The µsPEF treatment time, which is dependent on the pulse repetition frequency, pulse length, and time of process, is the main driver of the increase in absorbance. High EF intensities balanced with shorter pulse repetition frequencies to ensure similar energy inputs resulted in no aggregate formation. For WPL_filt, 12.5 kV/cm, 10 µs, 0.38 Hz (620 ± 96 kJ/kg; ± standard deviation) did not result in an increase in absorbance, whereas 1.25 kV/cm, 10 µs, 50 Hz (634 ± 57 kJ/kg) with similar time-temperature profiles increased the absorbance at a wavelength of 380 nm by a factor of 8.2 ± 1.7 compared with untreated WPL_filt. In conclusion, the treatment time seems to dominate over high EF intensities at similar energy inputs for aggregate formation and increase in absorbance.

Preventing extreme polarization of political attitudes.

Extreme polarization can undermine democracy by making compromise impossible and transforming politics into a zero-sum game. "Ideological polarization"-the extent to which political views are widely dispersed-is already strong among elites, but less so among the general public [N. McCarty, Polarization: What Everyone Needs to Know, 2019, pp. 50-68]. Strong mutual distrust and hostility between Democrats and Republicans in the United States, combined with the elites' already strong ideological polarization, could lead to increasing ideological polarization among the public. The paper addresses two questions: 1) Is there a level of ideological polarization above which polarization feeds upon itself to become a runaway process? 2) If so, what policy interventions could prevent such dangerous positive feedback loops? To explore these questions, we present an agent-based model of ideological polarization that differentiates between the tendency for two actors to interact ("exposure") and how they respond when interactions occur, positing that interaction between similar actors reduces their difference, while interaction between dissimilar actors increases their difference. Our analysis explores the effects on polarization of different levels of tolerance to other views, responsiveness to other views, exposure to dissimilar actors, multiple ideological dimensions, economic self-interest, and external shocks. The results suggest strategies for preventing, or at least slowing, the development of extreme polarization.

Poly-aneuploid cancer cells promote evolvability, generating lethal cancer.

Cancer cells utilize the forces of natural selection to evolve evolvability allowing a constant supply of heritable variation that permits a cancer species to evolutionary track changing hazards and opportunities. Over time, the dynamic tumor ecosystem is exposed to extreme, catastrophic changes in the conditions of the tumor-natural (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. Poly-aneuploid cancer cells (PACCs) may serve as efficient sources of heritable variation that allows cancer cells to evolve rapidly, speciate, evolutionarily track their environment, and most critically for patient outcome and survival, permit evolutionary rescue, therapy resistance, and metastasis. As a conditional evolutionary strategy, they permit the cancer cells to accelerate evolution under stress and slow down the generation of heritable variation when conditions are more favorable or when the cancer cells are closer to an evolutionary optimum. We hypothesize that they play a critical and outsized role in lethality by their increased capacity for invasion and motility, for enduring novel and stressful environments, and for generating heritable variation that can be dispensed to their 2N+ aneuploid progeny that make up the bulk of cancer cells within a tumor, providing population rescue in response to therapeutic stress. Targeting PACCs is essential to cancer therapy and patient cure-without the eradication of the resilient PACCs, cancer will recur in treated patients.

Structure-property relationships of cellulose nanofibril hydro- and aerogels and their building blocks.

As abundant and renewable materials with excellent mechanical and functional properties, cellulose nanomaterials are utilized in advanced structural, optical and electronic applications. However, in order to further improve and develop new cellulose nanomaterials, a better understanding of the interplay between the self-assembled materials and their building blocks is crucial. This paper describes the structure-property relationships between cellulose nanofibrils (CNFs) and their resulting self-assembled structures in the form of hydrogels and aerogels. Rheological experiments revealed that the transition from viscous to elastic state with the corresponding evolution of the properties of the CNF dispersion depends on the aspect ratio and can be described in terms of the dynamic overlap concentration. The elastic shear modulus was dependent on the aspect ratio at very low CNF concentrations, reaching a plateau, where only the concentration of CNFs was relevant. This transition point in shear modulus was exploited to determine the mesh size of the fibril network, which was found to be in excellent agreement with predictions from scaling arguments. These findings highlight the possibility to tune the self-assembled materials response directly from the bottom-up by the CNF particle structure and thus, suggest new assembly routes starting directly from the CNF design.

Convergent Evolution, Evolving Evolvability, and the Origins of Lethal Cancer.

Advances in curative treatment to remove the primary tumor have increased survival of localized cancers for most solid tumor types, yet cancers that have spread are typically incurable and account for >90% of cancer-related deaths. Metastatic disease remains incurable because, somehow, tumors evolve resistance to all known compounds, including therapies. In all of these incurable patients, de novo lethal cancer evolves capacities for both metastasis and resistance. Therefore, cancers in different patients appear to follow the same eco-evolutionary path that independently manifests in affected patients. This convergent outcome, that always includes the ability to metastasize and exhibit resistance, demands an explanation beyond the slow and steady accrual of stochastic mutations. The common denominator may be that cancer starts as a speciation event when a unicellular protist breaks away from its multicellular host and initiates a cancer clade within the patient. As the cancer cells speciate and diversify further, some evolve the capacity to evolve: evolvability. Evolvability becomes a heritable trait that influences the available variation of other phenotypes that can then be acted upon by natural selection. Evolving evolvability may be an adaptation for cancer cells. By generating and maintaining considerable heritable variation, the cancer clade can, with high certainty, serendipitously produce cells resistant to therapy and cells capable of metastasizing. Understanding that cancer cells can swiftly evolve responses to novel and varied stressors create opportunities for adaptive therapy, double-bind therapies, and extinction therapies; all involving strategic decision making that steers and anticipates the convergent coevolutionary responses of the cancers.

The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells.

The ability of a population of PC3 prostate epithelial cancer cells to become resistant to docetaxel therapy and progress to a mesenchymal state remains a fundamental problem. The progression towards resistance is difficult to directly study in heterogeneous ecological environments such as tumors. In this work, we use a micro-fabricated "evolution accelerator" environment to create a complex heterogeneous yet controllable in-vitro environment with a spatially-varying drug concentration. With such a structure we observe the rapid emergence of a surprisingly large number of polyploid giant cancer cells (PGCCs) in regions of very high drug concentration, which does not occur in conventional cell culture of uniform concentration. This emergence of PGCCs in a high drug environment is due to migration of diploid epithelial cells from regions of low drug concentration, where they proliferate, to regions of high drug concentration, where they rapidly convert to PGCCs. Such a mechanism can only occur in spatially-varying rather than homogeneous environments. Further, PGCCs exhibit increased expression of the mesenchymal marker ZEB1 in the same high-drug regions where they are formed, suggesting the possible induction of an epithelial to mesenchymal transition (EMT) in these cells. This is consistent with prior work suggesting the PGCC cells are mediators of resistance in response to chemotherapeutic stress. Taken together, this work shows the key role of spatial heterogeneity and the migration of proliferative diploid cells to form PGCCs as a survival strategy for the cancer population, with implications for new therapies.

Nanostructural Properties and Twist Periodicity of Cellulose Nanofibrils with Variable Charge Density.

Cellulose nanofibrils (CNFs) are a renewable and facile to produce nanomaterial that recently gained a lot of attention in soft material research. The nanostructural properties of the fibrils largely determine their self-organizing functionalities, and the ability to tune the CNF nanostructure through control of the processing parameters is therefore crucial for developing new applications. In this study, we systematically altered the CNF production parameters (i.e., variation in cellulose source, chemical, and mechanical treatment) to observe their impact on the nanostructural properties of the resulting fibrils. Atomic force microscopy (AFM) allowed detailed topological examination of individual CNFs to elucidate fibril properties such as contour length, kink distribution and the right-handed twist periodicity of individual fibrils. Statistical analysis revealed a large dependency of the fibril properties on the industrial treatment of the cellulose source material. Our results furthermore confirm that the average charge density of the fibrils regulates both contour length and twist periodicity and, thus, has a very strong impact on the final morphology of CNFs. These results provide a route to tune the detailed nanostructure of CNFs with potential impact on the self-organization of these biological colloids and their optimal use in new nanomaterials.

Cancer as a Social Dysfunction-Why Cancer Research Needs New Thinking.

The incidence and mortality for many cancers continue to rise. As such, critical action is needed on many fronts to reshape how a society thinks, discusses, and fights cancer especially as the population grows and ages. Cancer can be described as a broken social contract that requires different conceptual frameworks such as game theory. To this end, it is our hope that this perspective will catalyze a discussion to rethink the way we approach, communicate, and fund cancer research; thinking of cancer as a broken social contract is only one example. Importantly, this endeavor will require infusion of ideas from other fields such as physics, computational medicine, complexity science, agent-based modeling, sociology, and ecology, all of which have the capacity to drive new insights into cancer biology and clinical medicine. Mol Cancer Res; 16(9); 1346-7. ©2018 AACR.

Strategic aspects of cyberattack, attribution, and blame.

Cyber conflict is now a common and potentially dangerous occurrence. The target typically faces a strategic choice based on its ability to attribute the attack to a specific perpetrator and whether it has a viable punishment at its disposal. We present a game-theoretic model, in which the best strategic choice for the victim depends on the vulnerability of the attacker, the knowledge level of the victim, payoffs for different outcomes, and the beliefs of each player about their opponent. The resulting blame game allows analysis of four policy-relevant questions: the conditions under which peace (i.e., no attacks) is stable, when attacks should be tolerated, the consequences of asymmetric technical attribution capabilities, and when a mischievous third party or an accident can undermine peace. Numerous historical examples illustrate how the theory applies to cases of cyber or kinetic conflict involving the United States, Russia, China, Japan, North Korea, Estonia, Israel, Iran, and Syria.

The Paradox of Abstraction: Precision Versus Concreteness.

We introduce a novel measure of abstractness based on the amount of information of a concept computed from its position in a semantic taxonomy. We refer to this measure as precision. We propose two alternative ways to measure precision, one based on the path length from a concept to the root of the taxonomic tree, and another one based on the number of direct and indirect descendants. Since more information implies greater processing load, we hypothesize that nouns higher in precision will have a processing disadvantage in a lexical decision task. We contrast precision to concreteness, a common measure of abstractness based on the proportion of sensory-based information associated with a concept. Since concreteness facilitates cognitive processing, we predict that while both concreteness and precision are measures of abstractness, they will have opposite effects on performance. In two studies we found empirical support for our hypothesis. Precision and concreteness had opposite effects on latency and accuracy in a lexical decision task, and these opposite effects were observable while controlling for word length, word frequency, affective content and semantic diversity. Our results support the view that concepts organization includes amodal semantic structures which are independent of sensory information. They also suggest that we should distinguish between sensory-based and amount-of-information-based abstractness.

Linguistic positivity in historical texts reflects dynamic environmental and psychological factors.

People use more positive words than negative words. Referred to as "linguistic positivity bias" (LPB), this effect has been found across cultures and languages, prompting the conclusion that it is a panhuman tendency. However, although multiple competing explanations of LPB have been proposed, there is still no consensus on what mechanism(s) generate LPB or even on whether it is driven primarily by universal cognitive features or by environmental factors. In this work we propose that LPB has remained unresolved because previous research has neglected an essential dimension of language: time. In four studies conducted with two independent, time-stamped text corpora (Google books Ngrams and the New York Times), we found that LPB in American English has decreased during the last two centuries. We also observed dynamic fluctuations in LPB that were predicted by changes in objective environment, i.e., war and economic hardships, and by changes in national subjective happiness. In addition to providing evidence that LPB is a dynamic phenomenon, these results suggest that cognitive mechanisms alone cannot account for the observed dynamic fluctuations in LPB. At the least, LPB likely arises from multiple interacting mechanisms involving subjective, objective, and societal factors. In addition to having theoretical significance, our results demonstrate the value of newly available data sources in addressing long-standing scientific questions.

Does Causality Matter More Now? Increase in the Proportion of Causal Language in English Texts.

The vast majority of the work on culture and cognition has focused on cross-cultural comparisons, largely ignoring the dynamic aspects of culture. In this article, we provide a diachronic analysis of causal cognition over time. We hypothesized that the increased role of education, science, and technology in Western societies should be accompanied by greater attention to causal connections. To test this hypothesis, we compared word frequencies in English texts from different time periods and found an increase in the use of causal language of about 40% over the past two centuries. The observed increase was not attributable to general language effects or to changing semantics of causal words. We also found that there was a consistent difference between the 19th and the 20th centuries, and that the increase happened mainly in the 20th century.

Timing of cyber conflict.

Nations are accumulating cyber resources in the form of stockpiles of zero-day exploits as well as other novel methods of engaging in future cyber conflict against selected targets. This paper analyzes the optimal timing for the use of such cyber resources. A simple mathematical model is offered to clarify how the timing of such a choice can depend on the stakes involved in the present situation, as well as the characteristics of the resource for exploitation. The model deals with the question of when the resource should be used given that its use today may well prevent it from being available for use later. The analysis provides concepts, theory, applications, and distinctions to promote the understanding strategy aspects of cyber conflict. Case studies include the Stuxnet attack on Iran's nuclear program, the Iranian cyber attack on the energy firm Saudi Aramco, the persistent cyber espionage carried out by the Chinese military, and an analogous case of economic coercion by China in a dispute with Japan. The effects of the rapidly expanding market for zero-day exploits are also analyzed. The goal of the paper is to promote the understanding of this domain of cyber conflict to mitigate the harm it can do, and harness the capabilities it can provide.

Launching "the evolution of cooperation".

This article describes three aspects of the author's early work on the evolution of the cooperation. First, it explains how the idea for a computer tournament for the iterated Prisoner's Dilemma was inspired by the artificial intelligence research on computer checkers and computer chess. Second, it shows how the vulnerability of simple reciprocity of misunderstanding or misimplementation can be eliminated with the addition of some degree of generosity or contrition. Third, it recounts the unusual collaboration between the author, a political scientist, and William D. Hamilton, an evolutionary biologist.

Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments.

We propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example. We refer to this as "ecological therapy" for cancer.

Evolution of cooperation among tumor cells.

The evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the tissue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell-stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as by-product mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.