SARS-CoV-2 RNA: Exclusive friends and common foes.

Infection with SARS-CoV-2 sets off a molecular arms race between virus replication and host cell defense. In this issue of Cell, Flynn, Belk, et al. integrate an advanced large-scale RNA-centered approach with custom CRISPR screens to functionally characterize the interactome of the SARS-CoV-2 RNA genome during infection.

The B7:CD28 family and friends: Unraveling coinhibitory interactions.

Immune responses must be tightly regulated to ensure both optimal protective immunity and tolerance. Costimulatory pathways within the B7:CD28 family provide essential signals for optimal T cell activation and clonal expansion. They provide crucial inhibitory signals that maintain immune homeostasis, control resolution of inflammation, regulate host defense, and promote tolerance to prevent autoimmunity. Tumors and chronic pathogens can exploit these pathways to evade eradication by the immune system. Advances in understanding B7:CD28 pathways have ushered in a new era of immunotherapy with effective drugs to treat cancer, autoimmune diseases, infectious diseases, and transplant rejection. Here, we discuss current understanding of the mechanisms underlying the coinhibitory functions of CTLA-4, PD-1, PD-L1:B7-1 and PD-L2:RGMb interactions and less studied B7 family members, including HHLA2, VISTA, BTNL2, and BTN3A1, as well as their overlapping and unique roles in regulating immune responses, and the therapeutic potential of these insights.

Friends in Low Places: Intestinal Commensals Limit Colitis through Molecular Mimicry.

Inflammatory bowel disease is thought to arise from inappropriate inflammation to gut bacteria, yet mechanisms preventing these responses remain elusive. In this issue of Cell, Nanjundappa et al. report that Bacteroides share an epitope with a pancreas-specific peptide that induces protective CD8+ T cells, identifying molecular mimicry as a mechanism to enforce tolerance in the gut.

Microbial Skin Inhabitants: Friends Forever.

To gain insight into the stability of the microbial communities that inhabit our skin, Oh et al., in a tour-de-force effort, map the human skin metagenomes over time. Remarkably, their data indicate that the individual, not the environment, primarily drives the composition of skin microbial communities.

A Friend in Need (of Nutrients) Is a .

Endophytic fungi are found within the roots of healthy plants, but their function is poorly understood. In this issue, Hiruma et al. demonstrate that, under phosphate-limiting conditions, the endophytic fungus, Colletotrichum tofieldiae, provides growth-promoting and fitness benefits to Arabidopsis, but the plant must restrict fungal growth or risk pathogenesis.

Microglia Get a Little Help from "Th"-eir Friends.

The presence of CD4+ T cells in the healthy brain parenchyma remains controversial due to the barrier function of the glia limitans. Pasciuto, Burton, Roca et al. in Cell describe the dynamic recruitment of CD4+ T cells within the brain parenchyma, their unexpected contribution to microglial maturation, and, ultimately, their influence on behavior.

Social capital I: measurement and associations with economic mobility.

Social capital-the strength of an individual's social network and community-has been identified as a potential determinant of outcomes ranging from education to health1-8. However, efforts to understand what types of social capital matter for these outcomes have been hindered by a lack of social network data. Here, in the first of a pair of papers9, we use data on 21 billion friendships from Facebook to study social capital. We measure and analyse three types of social capital by ZIP (postal) code in the United States: (1) connectedness between different types of people, such as those with low versus high socioeconomic status (SES); (2) social cohesion, such as the extent of cliques in friendship networks; and (3) civic engagement, such as rates of volunteering. These measures vary substantially across areas, but are not highly correlated with each other. We demonstrate the importance of distinguishing these forms of social capital by analysing their associations with economic mobility across areas. The share of high-SES friends among individuals with low SES-which we term economic connectedness-is among the strongest predictors of upward income mobility identified to date10,11. Other social capital measures are not strongly associated with economic mobility. If children with low-SES parents were to grow up in counties with economic connectedness comparable to that of the average child with high-SES parents, their incomes in adulthood would increase by 20% on average. Differences in economic connectedness can explain well-known relationships between upward income mobility and racial segregation, poverty rates, and inequality12-14. To support further research and policy interventions, we publicly release privacy-protected statistics on social capital by ZIP code at https://www.socialcapital.org .

Social capital II: determinants of economic connectedness.

Low levels of social interaction across class lines have generated widespread concern1-4 and are associated with worse outcomes, such as lower rates of upward income mobility4-7. Here we analyse the determinants of cross-class interaction using data from Facebook, building on the analysis in our companion paper7. We show that about half of the social disconnection across socioeconomic lines-measured as the difference in the share of high-socioeconomic status (SES) friends between people with low and high SES-is explained by differences in exposure to people with high SES in groups such as schools and religious organizations. The other half is explained by friending bias-the tendency for people with low SES to befriend people with high SES at lower rates even conditional on exposure. Friending bias is shaped by the structure of the groups in which people interact. For example, friending bias is higher in larger and more diverse groups and lower in religious organizations than in schools and workplaces. Distinguishing exposure from friending bias is helpful for identifying interventions to increase cross-SES friendships (economic connectedness). Using fluctuations in the share of students with high SES across high school cohorts, we show that increases in high-SES exposure lead low-SES people to form more friendships with high-SES people in schools that exhibit low levels of friending bias. Thus, socioeconomic integration can increase economic connectedness in communities in which friending bias is low. By contrast, when friending bias is high, increasing cross-SES interactions among existing members may be necessary to increase economic connectedness. To support such efforts, we release privacy-protected statistics on economic connectedness, exposure and friending bias for each ZIP (postal) code, high school and college in the United States at https://www.socialcapital.org .

Intestinal Tolerance, with a Little Help from Our Microbial Friends.

The intestinal immune system performs a tightrope walk between anti-pathogen immunity and tolerance to innocuous luminal antigens. In this issue of Immunity, Kim et al. (2018) demonstrate that the microbiota is driving tolerance to food antigens and dampening inflammatory responses through CX3CR1+ mononuclear phagocytes.

Help from my friends-cooperation of BMAL1 with noncircadian transcription factors.

The circadian clock in the suprachiasmatic nucleus (SCN) of mammals drives 24-h rhythms of sleep/wake cycles. Peripheral clocks present in other organs coordinate local and global physiology according to rhythmic signals from the SCN and via metabolic cues. The core circadian clockwork is identical in all cells. However, there is only a small amount of overlap of the circadian transcriptomes in different organs and tissues. A novel study by Beytebiere and colleagues (pp. 294-309) indicates that the regulation of tissue-specific rhythmic gene expression involves the cooperation of the circadian transcription factor (TF) BMAL1:CLOCK with tissue-specific TFs (ts-TFs) and correlates with the potential of BMAL1:CLOCK to facilitate rhythmic enhancer-enhancer interactions.

Hello darkness, my old friend: 3-KETOACYL-COENZYME A SYNTHASE4 is a branch point in the regulation of triacylglycerol synthesis in Arabidopsis thaliana.

Plant lipids are important as alternative sources of carbon and energy when sugars or starch are limited. Here, we applied combined heat and darkness or extended darkness to a panel of ∼300 Arabidopsis (Arabidopsis thaliana) accessions to study lipid remodeling under carbon starvation. Natural allelic variation at 3-KETOACYL-COENZYME A SYNTHASE4 (KCS4), a gene encoding an enzyme involved in very long chain fatty acid (VLCFA) synthesis, underlies the differential accumulation of polyunsaturated triacylglycerols (puTAGs) under stress. Ectopic expression of KCS4 in yeast and plants proved that KCS4 is a functional enzyme localized in the endoplasmic reticulum with specificity for C22 and C24 saturated acyl-CoA. Allelic mutants and transient overexpression in planta revealed the differential role of KCS4 alleles in VLCFA synthesis and leaf wax coverage, puTAG accumulation, and biomass. Moreover, the region harboring KCS4 is under high selective pressure and allelic variation at KCS4 correlates with environmental parameters from the locales of Arabidopsis accessions. Our results provide evidence that KCS4 plays a decisive role in the subsequent fate of fatty acids released from chloroplast membrane lipids under carbon starvation. This work sheds light on both plant response mechanisms and the evolutionary events shaping the lipidome under carbon starvation.

CD14-New Tricks of an Old Acquaintance.

Zanoni et al. (2017) show that the LPS receptor CD14 promotes internalization of oxidized phospholipids, a hallmark of dying cells, triggering hyperactivation of dendritic cells and macrophages. Their findings reveal CD14 as a regulator of responses to infection and damage, relaying context-dependent signals that determine inflammatory cell fate decisions.

We Can Still Be Friends: IFN-γ Breaks Up Macrophage Enhancers.

Interferon (IFN)-γ can prime macrophages for inflammatory responses by several mechanisms, including enhancer establishment and gene activation. In this issue of Immunity, Kang et al. (2017) provide insight into the mechanisms of IFN-γ-mediated gene repression as they show that IFN-γ promotes the disassembly of select active enhancers by interfering with enhancer-binding transcription factor MAF.

Preexisting social ties among Auschwitz prisoners support Holocaust survival.

Survivor testimonies link survival in deadly POW camps, Gulags, and Nazi concentration camps to the formation of close friendships with other prisoners. To provide evidence free of survival bias on the importance of social ties for surviving the Holocaust, we study individual histories of 30 thousand Jewish prisoners who entered the Auschwitz-Birkenau concentration camp on transports from the Theresienstadt ghetto. We ask whether the availability of potential friends among fellow prisoners on a transport influenced the chances of surviving the Holocaust. Relying on multiple proxies of preexisting social networks and varying social-linkage composition of transports, we uncover a significant survival advantage to entering Auschwitz with a larger group of potential friends.

Abstract cognitive maps of social network structure aid adaptive inference.

Social navigation-such as anticipating where gossip may spread, or identifying which acquaintances can help land a job-relies on knowing how people are connected within their larger social communities. Problematically, for most social networks, the space of possible relationships is too vast to observe and memorize. Indeed, people's knowledge of these social relations is well known to be biased and error-prone. Here, we reveal that these biased representations reflect a fundamental computation that abstracts over individual relationships to enable principled inferences about unseen relationships. We propose a theory of network representation that explains how people learn inferential cognitive maps of social relations from direct observation, what kinds of knowledge structures emerge as a consequence, and why it can be beneficial to encode systematic biases into social cognitive maps. Leveraging simulations, laboratory experiments, and "field data" from a real-world network, we find that people abstract observations of direct relations (e.g., friends) into inferences of multistep relations (e.g., friends-of-friends). This multistep abstraction mechanism enables people to discover and represent complex social network structure, affording adaptive inferences across a variety of contexts, including friendship, trust, and advice-giving. Moreover, this multistep abstraction mechanism unifies a variety of otherwise puzzling empirical observations about social behavior. Our proposal generalizes the theory of cognitive maps to the fundamental computational problem of social inference, presenting a powerful framework for understanding the workings of a predictive mind operating within a complex social world.

Triadic influence as a proxy for compatibility in social relationships.

Networks of social interactions are the substrate upon which civilizations are built. Often, we create new bonds with people that we like or feel that our relationships are damaged through the intervention of third parties. Despite their importance and the huge impact that these processes have in our lives, quantitative scientific understanding of them is still in its infancy, mainly due to the difficulty of collecting large datasets of social networks including individual attributes. In this work, we present a thorough study of real social networks of 13 schools, with more than 3,000 students and 60,000 declared positive and negative relationships, including tests for personal traits of all the students. We introduce a metric-the "triadic influence"-that measures the influence of nearest neighbors in the relationships of their contacts. We use neural networks to predict the sign of the relationships in these social networks, extracting the probability that two students are friends or enemies depending on their personal attributes or the triadic influence. We alternatively use a high-dimensional embedding of the network structure to also predict the relationships. Remarkably, using the triadic influence (a simple one-dimensional metric) achieves the best accuracy, and adding the personal traits of the students does not improve the results, suggesting that the triadic influence acts as a proxy for the social compatibility of students. We postulate that the probabilities extracted from the neural networks-functions of the triadic influence and the personalities of the students-control the evolution of real social networks, opening an avenue for the quantitative study of these systems.

Structuralism and Adaptationism: Friends? Or foes?

Historically, the empirical study of phenotypic diversification has fallen into two rough camps; (1) "structuralist approaches" focusing on developmental constraint, bias, and innovation (with evo-devo at the core); and (2) "adaptationist approaches" focusing on adaptation, and natural selection. Whilst debates, such as that surrounding the proposed "Extended" Evolutionary Synthesis, often juxtapose these two positions, this review focuses on the grey space in between. Specifically, here I present a novel analysis of structuralism which enables us to take a more nuanced look at the motivations behind the structuralist and adaptationist positions. This makes clear how the two approaches can conflict, and points of potential commensurability. The review clarifies (a) the value of the evo-devo approach to phenotypic diversity, but also (b) how it properly relates to other predominant approaches to the same issues in evolutionary biology more broadly.

Romantic relationships attenuated competition between lovers: evidence from brain synchronization.

Competition is an essential component of social interaction and is influenced by interpersonal relationships. This study is based on social exchange theory and explores the relationship between brain synchronization and competition in the binary system of romantic relationships through electroencephalogram hyperscanning technology. The results found that females had a greater win rate in the romantic and friend groups. During the early stage (0-200 ms), when the competitive target appeared, the stranger group exhibited greater interbrain synchronicity in the Alpha frequency band. However, during the later stage (600-800 ms), the romantic group showed higher Alpha band interbrain synchrony when the competitive target appeared. Significant interbrain synchronizations were observed in the Theta frequency band of the stranger and friend groups at 400-600 ms and 800-1000 ms. Moreover, these interbrain synchronizations were significantly positively correlated with the winning rates of females in the competition. These findings suggest a close relationship between interpersonal coordination and interbrain synchronization. Furthermore, romantic relationships reduce participants' willingness to compete, affecting their attention regulation, emotional processing, and goal orientation, thus influencing competition. This study investigated the impact of romantic relationships on competition, providing a theoretical foundation for promoting the positive and healthy development of romantic relationships.

Algorithms for seeding social networks can enhance the adoption of a public health intervention in urban India.

Targeting structurally influential individuals within social networks can enhance adoption of health interventions within populations. We tested the effectiveness of two algorithms to improve social contagion that do not require knowledge of the whole network structure. We mapped the social interactions of 2,491 women in 50 residential buildings (chawls) in Mumbai, India. The buildings, which are social units, were randomized to (1) targeting 20% of the women at random, (2) targeting friends of such randomly chosen women, (3) targeting pairs of people composed of randomly chosen women and a friend, or (4) no targeting. Both targeting algorithms, friendship nomination and pair targeting, enhanced adoption of a public health intervention related to the use of iron-fortified salt for anemia. In particular, the targeting of pairs of friends, which is relatively easily implementable in field settings, enhanced adoption of novel practices through both social influence and social reinforcement.

Fast response times signal social connection in conversation.

Clicking is one of the most robust metaphors for social connection. But how do we know when two people "click"? We asked pairs of friends and strangers to talk with each other and rate their felt connection. For both friends and strangers, speed in response was a robust predictor of feeling connected. Conversations with faster response times felt more connected than conversations with slower response times, and within conversations, connected moments had faster response times than less-connected moments. This effect was determined primarily by partner responsivity: People felt more connected to the degree that their partner responded quickly to them rather than by how quickly they responded to their partner. The temporal scale of these effects (<250 ms) precludes conscious control, thus providing an honest signal of connection. Using a round-robin design in each of six closed networks, we show that faster responders evoked greater feelings of connection across partners. Finally, we demonstrate that this signal is used by third-party listeners as a heuristic of how well people are connected: Conversations with faster response times were perceived as more connected than the same conversations with slower response times. Together, these findings suggest that response times comprise a robust and sufficient signal of whether two minds "click."