Cell competition: Winning out by losing notch

Cell competition where ‘loser’ cells are eliminated by neighbors with higher fitness is a widespread phenomenon in development. However, a growing body of evidence argues cells with somatic mutations compete with their wild type counterparts in the earliest stages of cancer development. Recent studies have begun to shed light on the molecular and cellular mechanisms that alter the competitiveness of cells carrying somatic mutations in adult tissues. Cells with a ‘winner’ phenotype create clones which may expand into extensive fields of mutant cells within normal appearing epithelium, favoring the accumulation of further genetic alterations and the evolution of cancer. Here we focus on how mutations which disrupt the Notch signaling pathway confer a ‘super competitor’ status on cells in squamous epithelia and consider the broader implications for cancer evolution.     

SMAD4 contributes to chondrocyte and osteocyte development

Different cellular and molecular mechanisms contribute to chondrocyte and osteocyte development. Although vital roles of the mothers against decapentaplegic homolog 4 (also called ‘SMAD4’) have been discussed in different cancers and stem cell‐related studies, there are a few reviews summarizing the roles of this protein in the skeletal development and bone homeostasis. In order to fill this gap, we discuss the critical roles of SMAD4 in the skeletal development. To this end, we review the different signalling pathways and also how SMAD4 defines stem cell features. We also elaborate how the epigenetic factors—ie DNA methylation, histone modifications and noncoding RNAs—make a contribution to the chondrocyte and osteocyte development. To better grasp the important roles of SMAD4 in the cartilage and bone development, we also review the genotype‐phenotype correlation in animal models. This review helps us to understand the importance of the SMAD4 in the chondrocyte and bone development and the potential applications for therapeutic goals.     

Social structure of primate interaction networks facilitates the emergence of cooperation

Animal cooperation has puzzled biologists for a long time as its existence seems to contravene the basic notion of evolutionary biology that natural selection favours ‘selfish’ genes that promote only their own well-being. Evolutionary game theory has shown that cooperators can prosper in populations of selfish individuals if they occur in clusters, interacting more frequently with each other than with the selfish. Here we show that social networks of primates possess the necessary social structure to promote the emergence of cooperation. By simulating evolutionary dynamics of cooperative behaviour on interaction networks of 70 primate groups, we found that for most groups network reciprocity augmented the fixation probability for cooperation. The variation in the strength of this effect can be partly explained by the groups’ community modularity—a network measure for the groups’ heterogeneity. Thus, given selective update and partner choice mechanisms, network reciprocity has the potential to explain socially learned forms of cooperation in primate societies.     

Power through ‘Us’: Leaders’ Use of We-Referencing Language Predicts Election Victory

Leaders have been observed to use distinct rhetorical strategies, but it is unclear to what extent such strategies are effective. To address this issue we analyzed the official election campaign speeches of successful and unsuccessful Prime Ministerial candidates in all 43 Australian Federal elections since independence from Britain in 1901 and measured candidates'' use of personal (‘I’, ‘me’) and collective pronouns (‘we’, ‘us’). Victors used more collective pronouns than their unsuccessful opponents in 80% of all elections. Across all elections, victors made 61% more references to ‘we’ and ‘us’ and used these once every 79 words (vs. every 136 words for losers). Extending social identity theorizing, this research suggests that electoral endorsement is associated with leaders'' capacity to engage with, and speak on behalf of, a collective identity that is shared with followers whose support and energies they seek to mobilize.     

Genetic composition of social groups influences male aggressive behaviour and fitness in natural genotypes of Drosophila melanogaster

Indirect genetic effects (IGEs) describe how an individual''s behaviour—which is influenced by his or her genotype—can affect the behaviours of interacting individuals. IGE research has focused on dyads. However, insights from social networks research, and other studies of group behaviour, suggest that dyadic interactions are affected by the behaviour of other individuals in the group. To extend IGE inferences to groups of three or more, IGEs must be considered from a group perspective. Here, I introduce the ‘focal interaction’ approach to study IGEs in groups. I illustrate the utility of this approach by studying aggression among natural genotypes of Drosophila melanogaster. I chose two natural genotypes as ‘focal interactants’: the behavioural interaction between them was the ‘focal interaction’. One male from each focal interactant genotype was present in every group, and I varied the genotype of the third male—the ‘treatment male’. Genetic variation in the treatment male''s aggressive behaviour influenced the focal interaction, demonstrating that IGEs in groups are not a straightforward extension of IGEs measured in dyads. Further, the focal interaction influenced male mating success, illustrating the role of IGEs in behavioural evolution. These results represent the first manipulative evidence for IGEs at the group level.     

Src/FAK-mediated regulation of E-cadherin as a mechanism for controlling collective cell movement: Insights from in vivo imaging

Recent advances in confocal and multi-photon microscopy, together with fluorescent probe development, have enabled cancer biology studies to go beyond the culture dish and interrogate cancer-associated processes in the complex in vivo environment. Regulation of the tumor suppressor protein E-cadherin plays an important role in cancer development and progression, and may contribute to the decision between ‘single cell’ and ‘collective invasion’ in vivo. Mounting evidence from in vitro and in vivo experiments places the two nonreceptor protein tyrosine kinases Src and Focal Adhesion Kinase at the heart of E-cadherin regulation and the crosstalk between integrins and cadherins. Here we discuss recent insights, attained using high-resolution fluorescent in vivo imaging, into the regulation of E-cadherin and collective invasion. We focus on the regulatory crosstalk between the Src/FAK signaling axis and E-cadherin in vivo.Key words: Src, FAK, E-cadherin, EMT, fluorescent in vivo imaging     

Ecological fitness, genomic islands and bacterial pathogenicity. A Darwinian view of the evolution of microbes

The compositions of bacterial genomes can be changed rapidly and dramatically through a variety of processes including horizontal gene transfer. This form of change is key to bacterial evolution, as it leads to ‘evolution in quantum leaps’. Horizontal gene transfer entails the incorporation of genetic elements transferred from another organism—perhaps in an earlier generation—directly into the genome, where they form ‘genomic islands’, i.e. blocks of DNA with signatures of mobile genetic elements. Genomic islands whose functions increase bacterial fitness, either directly or indirectly, have most likely been positively selected and can be termed ‘fitness islands’. Fitness islands can be divided into several subtypes: ‘ecological islands’ in environmental bacteria and ‘saprophytic islands’, ‘symbiosis islands’ or ‘pathogenicity islands’ (PAIs) in microorganisms that interact with living hosts. Here we discuss ways in which PAIs contribute to the pathogenic potency of bacteria, and the idea that genetic entities similar to genomic islands may also be present in the genomes of eukaryotes.     

Out of the blue: understanding abrupt and wayward transitions in thought using probability and predictive processing

Thoughts that appear to come to us ‘out of the blue’ or ‘out of nowhere’ are a familiar aspect of mental experience. Such thoughts tend to elicit feelings of surprise and spontaneity. Although we are beginning to understand the neural processes that underlie the arising of such thoughts, little is known about what accounts for their peculiar phenomenology. Here, we focus on one central aspect of this phenomenology—the experience of surprise at their occurrence, as it relates to internal probabilistic predictions regarding mental states. We introduce a distinction between two phenomenologically different types of transitions in thought content: (i) abrupt transitions, which occur at surprising times but lead to unsurprising thought content, and (ii) wayward transitions, which occur at surprising times and also lead to surprising thought content. We examine these two types of transitions using a novel approach that combines probabilistic and predictive processing concepts and principles. We employ two different probability metrics—transition and occurrence probability—to characterize and differentiate between abrupt and wayward transitions. We close by discussing some potentially beneficial ways in which these two kinds of transitions in thought content may contribute to mental function, and how they may be implemented at the neural level.This article is part of the theme issue ‘Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation’.     

Nutritional biology: a neglected basic discipline of nutritional science

On the basis of a scientific-philosophical analysis, this paper tries to show that the approaches in current nutritional science—including its subdisciplines which focus on molecular aspects—are predominantly application-oriented. This becomes particularly evident through a number of conceptual problems characterized by the triad of ‘dearth of theoretical foundation,’ ‘particularist research questions,’ and ‘reductionist understanding of nutrition.’ The thesis presented here is that an interpretive framework based on nutritional biology is able to shed constructive light on the fundamental problems of nutritional science. In this context, the establishment of ‘nutritional biology’ as a basic discipline in research and education would be a first step toward recognizing the phenomenon of ‘nutrition’ as an oecic process as a special case of an organism–environment interaction. Modern nutritional science should be substantively grounded on ecological—and therefore systems biology as well as organismic—principles. The aim of nutritional biology, then, should be to develop near-universal ‘law statements’ in nutritional science—a task which presents a major challenge for the current science system.     

Click and Cut: a click chemistry approach to developing oxidative DNA damaging agents

Metallodrugs provide important first-line treatment against various forms of human cancer. To overcome chemotherapeutic resistance and widen treatment possibilities, new agents with improved or alternative modes of action are highly sought after. Here, we present a click chemistry strategy for developing DNA damaging metallodrugs. The approach involves the development of a series of polyamine ligands where three primary, secondary or tertiary alkyne-amines were selected and ‘clicked’ using the copper-catalysed azide-alkyne cycloaddition reaction to a 1,3,5-azide mesitylene core to produce a family of compounds we call the ‘Tri-Click’ (TC) series. From the isolated library, one dominant ligand (TC1) emerged as a high-affinity copper(II) binding agent with potent DNA recognition and damaging properties. Using a range of in vitro biophysical and molecular techniques—including free radical scavengers, spin trapping antioxidants and base excision repair (BER) enzymes—the oxidative DNA damaging mechanism of copper-bound TC1 was elucidated. This activity was then compared to intracellular results obtained from peripheral blood mononuclear cells exposed to Cu(II)–TC1 where use of BER enzymes and fluorescently modified dNTPs enabled the characterisation and quantification of genomic DNA lesions produced by the complex. The approach can serve as a new avenue for the design of DNA damaging agents with unique activity profiles.     

Human–wildlife conflict in the roof of the world: Understanding multidimensional perspectives through a systematic review

Human–wildlife conflicts have intensified by many folds and at different levels in recent years. The same is true in the case of the Hindu Kush Himalaya (HKH), the roof of the world, and a region known for its wealth in biodiversity. We present a systematic literature review (SLR) using the search, appraisal, synthesis, and analysis (SALSA) framework; and for spatial and network analysis, we employed the VOSviewer software. The review—covering 240 peer—articles within a span of 27 years (from 1982 to 2019)—revealed that in the last decade, there was a 57% increase in publications but with a disproportionate geographical and thematic focus. About 82% of the research concentrated on protected areas and large carnivores and mega herbivores played a big role in such conflicts. About 53% of the studies were based on questionnaires, and the main driver reported was habitat disturbance of animals due to land‐cover change, urbanization, and increase in human population. On the management front, the studies reported the use of traditional protection techniques like guarding and fencing. Our analysis of 681 keywords revealed a prominent focus on ‘human‐wildlife conflict,’ ‘Nepal,’ ‘Bhutan,’ ‘Snow Leopard,’ and ‘Leopard’ indicating the issue linked with these species and countries. The involvement of 640 authors from 36 countries indicates increasing interest, and Nepal and India are playing key roles in the region. As for the spatial analysis that was conducted, while it showed regional variations, there were conspicuous limitations in terms of having a transboundary focus. Thus, particular attention ought to be paid to building transboundary partnerships and improving management interventions; there is also a pressing need to understand the patterns of human–wildlife convergence, especially involving meso‐mammals.     

How do site-specific DNA-binding proteins find their targets?

Essentially all the biological functions of DNA depend on site-specific DNA-binding proteins finding their targets, and therefore ‘searching’ through megabases of non-target DNA. In this article, we review current understanding of how this sequence searching is done. We review how simple diffusion through solution may be unable to account for the rapid rates of association observed in experiments on some model systems, primarily the Lac repressor. We then present a simplified version of the ‘facilitated diffusion’ model of Berg, Winter and von Hippel, showing how non-specific DNA–protein interactions may account for accelerated targeting, by permitting the protein to sample many binding sites per DNA encounter. We discuss the 1-dimensional ‘sliding’ motion of protein along non-specific DNA, often proposed to be the mechanism of this multiple site sampling, and we discuss the role of short-range diffusive ‘hopping’ motions. We then derive the optimal range of sliding for a few physical situations, including simple models of chromosomes in vivo, showing that a sliding range of ~100 bp before dissociation optimizes targeting in vivo. Going beyond first-order binding kinetics, we discuss how processivity, the interaction of a protein with two or more targets on the same DNA, can reveal the extent of sliding and we review recent experiments studying processivity using the restriction enzyme EcoRV. Finally, we discuss how single molecule techniques might be used to study the dynamics of DNA site-specific targeting of proteins.     

Tethering-facilitated DNA ‘opening’ and complementary roles of β-hairpin motifs in the Rad4/XPC DNA damage sensor protein

XPC/Rad4 initiates eukaryotic nucleotide excision repair on structurally diverse helix-destabilizing/distorting DNA lesions by selectively ‘opening’ these sites while rapidly diffusing along undamaged DNA. Previous structural studies showed that Rad4, when tethered to DNA, could also open undamaged DNA, suggesting a ‘kinetic gating’ mechanism whereby lesion discrimination relied on efficient opening versus diffusion. However, solution studies in support of such a mechanism were lacking and how ‘opening’ is brought about remained unclear. Here, we present crystal structures and fluorescence-based conformational analyses on tethered complexes, showing that Rad4 can indeed ‘open’ undamaged DNA in solution and that such ‘opening’ can largely occur without one or the other of the β-hairpin motifs in the BHD2 or BHD3 domains. Notably, the Rad4-bound ‘open’ DNA adopts multiple conformations in solution notwithstanding the DNA’s original structure or the β-hairpins. Molecular dynamics simulations reveal compensatory roles of the β-hairpins, which may render robustness in dealing with and opening diverse lesions. Our study showcases how fluorescence-based studies can be used to obtain information complementary to ensemble structural studies. The tethering-facilitated DNA ‘opening’ of undamaged sites and the dynamic nature of ‘open’ DNA may shed light on how the protein functions within and beyond nucleotide excision repair in cells.     

Further Explorations of the Facing Bias in Biological Motion Perception: Perspective Cues,Observer Sex,and Response Times

The human visual system has evolved to be highly sensitive to visual information about other persons and their movements as is illustrated by the effortless perception of point-light figures or ‘biological motion’. When presented orthographically, a point-light walker is interpreted in two anatomically plausible ways: As ‘facing the viewer’ or as ‘facing away’ from the viewer. However, human observers show a ‘facing bias’: They perceive such a point-light walker as facing towards them in about 70-80% of the cases. In studies exploring the role of social and biological relevance as a possible account for the facing bias, we found a ‘figure gender effect’: Male point-light figures elicit a stronger facing bias than female point-light figures. Moreover, we also found an ‘observer gender effect’: The ‘figure gender effect’ was stronger for male than for female observers. In the present study we presented to 11 males and 11 females point-light walkers of which, very subtly, the perspective information was manipulated by modifying the earlier reported ‘perspective technique’. Proportions of ‘facing the viewer’ responses and reaction times were recorded. Results show that human observers, even in the absence of local shape or size cues, easily pick up on perspective cues, confirming recent demonstrations of high visual sensitivity to cues on whether another person is potentially approaching. We also found a consistent difference in how male and female observers respond to stimulus variations (figure gender or perspective cues) that cause variations in the perceived in-depth orientation of a point-light walker. Thus, the ‘figure gender effect’ is possibly caused by changes in the relative locations and motions of the dots that the perceptual system tends to interpret as perspective cues. Third, reaction time measures confirmed the existence of the facing bias and recent research showing faster detection of approaching than receding biological motion.     

Followers Are Not Enough: A Multifaceted Approach to Community Detection in Online Social Networks

In online social media networks, individuals often have hundreds or even thousands of connections, which link these users not only to friends, associates, and colleagues, but also to news outlets, celebrities, and organizations. In these complex social networks, a ‘community’ as studied in the social network literature, can have very different meaning depending on the property of the network under study. Taking into account the multifaceted nature of these networks, we claim that community detection in online social networks should also be multifaceted in order to capture all of the different and valuable viewpoints of ‘community.’ In this paper we focus on three types of communities beyond follower-based structural communities: activity-based, topic-based, and interaction-based. We analyze a Twitter dataset using three different weightings of the structural network meant to highlight these three community types, and then infer the communities associated with these weightings. We show that interesting insights can be obtained about the complex community structure present in social networks by studying when and how these four community types give rise to similar as well as completely distinct community structure.