Archival single-cell genomics reveals persistent subclones during DCIS progression.

Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3-31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2-16 years later show that many primary DCIS had already undergone whole-genome doubling and clonal diversification and that they shared genomic lineages with persistent subclones in the recurrences. Evolutionary analysis suggests that most DCIS cases in our cohort underwent an evolutionary bottleneck, and further identified chromosome aberrations in the persistent subclones that were associated with recurrence.

Single-Cell Profiling of Ebola Virus Disease In Vivo Reveals Viral and Host Dynamics.

Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, finding that immature, proliferative monocyte-lineage cells with reduced antigen-presentation capacity replace conventional monocyte subsets, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying intracellular viral RNA, we identify molecular determinants of tropism among circulating immune cells and examine temporal dynamics in viral and host gene expression. Within infected cells, EBOV downregulates STAT1 mRNA and interferon signaling, and it upregulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating pathways the virus manipulates for its replication. This study sheds light on EBOV tropism, replication dynamics, and elicited immune response and provides a framework for characterizing host-virus interactions under maximum containment.

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands.

RIG-I is an essential innate immune receptor for detecting and responding to infection by RNA viruses. RIG-I specifically recognizes the unique molecular features of viral RNA molecules and selectively distinguishes them from closely related RNAs abundant in host cells. The physical basis for this exquisite selectivity is revealed through a series of high-resolution cryo-EM structures of RIG-I in complex with host and viral RNA ligands. These studies demonstrate that RIG-I actively samples double-stranded RNAs in the cytoplasm and distinguishes them by adopting two different types of protein folds. Upon binding viral RNA, RIG-I adopts a high-affinity conformation that is conducive to signaling, while host RNA induces an autoinhibited conformation that stimulates RNA release. By coupling protein folding with RNA binding selectivity, RIG-I distinguishes RNA molecules that differ by as little as one phosphate group, thereby explaining the molecular basis for selective antiviral sensing and the induction of autoimmunity upon RIG-I dysregulation.

Second-Strand Synthesis-Based Massively Parallel scRNA-Seq Reveals Cellular States and Molecular Features of Human Inflammatory Skin Pathologies.

High-throughput single-cell RNA-sequencing (scRNA-seq) methodologies enable characterization of complex biological samples by increasing the number of cells that can be profiled contemporaneously. Nevertheless, these approaches recover less information per cell than low-throughput strategies. To accurately report the expression of key phenotypic features of cells, scRNA-seq platforms are needed that are both high fidelity and high throughput. To address this need, we created Seq-Well S3 ("Second-Strand Synthesis"), a massively parallel scRNA-seq protocol that uses a randomly primed second-strand synthesis to recover complementary DNA (cDNA) molecules that were successfully reverse transcribed but to which a second oligonucleotide handle, necessary for subsequent whole transcriptome amplification, was not appended due to inefficient template switching. Seq-Well S3 increased the efficiency of transcript capture and gene detection compared with that of previous iterations by up to 10- and 5-fold, respectively. We used Seq-Well S3 to chart the transcriptional landscape of five human inflammatory skin diseases, thus providing a resource for the further study of human skin inflammation.

Plasmacytoid Dendritic Cells: Development, Regulation, and Function.

Plasmacytoid dendritic cells (pDCs) are a unique sentinel cell type that can detect pathogen-derived nucleic acids and respond with rapid and massive production of type I interferon. This review summarizes our current understanding of pDC biology, including transcriptional regulation, heterogeneity, role in antiviral immune responses, and involvement in immune pathology, particularly in autoimmune diseases, immunodeficiency, and cancer. We also highlight the remaining gaps in our knowledge and important questions for the field, such as the molecular basis of unique interferon-producing capacity of pDCs. A better understanding of cell type-specific positive and negative control of pDC function should pave the way for translational applications focused on this immune cell type.

High life satisfaction reported among small-scale societies with low incomes.

Global polls have shown that people in high-income countries generally report being more satisfied with their lives than people in low-income countries. The persistence of this correlation, and its similarity to correlations between income and life satisfaction within countries, could lead to the impression that high levels of life satisfaction can only be achieved in wealthy societies. However, global polls have typically overlooked small-scale, nonindustrialized societies, which can provide an alternative test of the consistency of this relationship. Here, we present results from a survey of 2,966 members of Indigenous Peoples and local communities among 19 globally distributed sites. We find that high average levels of life satisfaction, comparable to those of wealthy countries, are reported for numerous populations that have very low monetary incomes. Our results are consistent with the notion that human societies can support very satisfying lives for their members without necessarily requiring high degrees of monetary wealth.

For living well, behaviors and circumstances matter just as much as psychological traits.

In 2004 through 2016, three studies in the national Midlife in the United States (MIDUS) project asked participants the open-ended question "What do you do to make life go well?". We use verbatim responses to this question to evaluate the relative importance of psychological traits and circumstances for predicting self-reported, subjective well-being. The use of an open-ended question allows us to test the hypothesis that psychological traits are more strongly associated with self-reported well-being than objective circumstances because psychological traits and well-being are similarly self-rated-meaning that they both ask respondents to decide how to place themselves on provided and unfamiliar survey scales. For this, we use automated zero-shot classification to score statements about well-being without training on existing survey measures, and we evaluate this scoring through subsequent hand-labeling. We then assess associations of this measure and closed-ended measures for health behaviors, socioeconomic circumstances, biomarkers for inflammation and glycemic control, and mortality risk over follow-up. Although the closed-ended measures were far more strongly associated with other multiple-choice self-ratings, including Big 5 personality traits, the closed- and open-ended measures were similarly associated with relatively objective indicators of health, wealth, and social connectedness. The findings suggest that psychological traits, when collected through self-ratings, predict subjective reports of well-being so strongly because of a measurement advantage-and that circumstance matters just as much when assessed using a fairer comparison.

Income and emotional well-being: A conflict resolved.

Do larger incomes make people happier? Two authors of the present paper have published contradictory answers. Using dichotomous questions about the preceding day, [Kahneman and Deaton, Proc. Natl. Acad. Sci. U.S.A. 107, 16489-16493 (2010)] reported a flattening pattern: happiness increased steadily with log(income) up to a threshold and then plateaued. Using experience sampling with a continuous scale, [Killingsworth, Proc. Natl. Acad. Sci. U.S.A. 118, e2016976118 (2021)] reported a linear-log pattern in which average happiness rose consistently with log(income). We engaged in an adversarial collaboration to search for a coherent interpretation of both studies. A reanalysis of Killingsworth's experienced sampling data confirmed the flattening pattern only for the least happy people. Happiness increases steadily with log(income) among happier people, and even accelerates in the happiest group. Complementary nonlinearities contribute to the overall linear-log relationship. We then explain why Kahneman and Deaton overstated the flattening pattern and why Killingsworth failed to find it. We suggest that Kahneman and Deaton might have reached the correct conclusion if they had described their results in terms of unhappiness rather than happiness; their measures could not discriminate among degrees of happiness because of a ceiling effect. The authors of both studies failed to anticipate that increased income is associated with systematic changes in the shape of the happiness distribution. The mislabeling of the dependent variable and the incorrect assumption of homogeneity were consequences of practices that are standard in social science but should be questioned more often. We flag the benefits of adversarial collaboration.

Generational differences in mental health trends in the twenty-first century.

Given the observed deterioration in mental health among Australians over the past decade, this study investigates to what extent this differs in people born in different decades-i.e., possible birth cohort differences in the mental health of Australians. Using 20 y of data from a large, nationally representative panel survey (N = 27,572), we find strong evidence that cohort effects are driving the increase in population-level mental ill-health. Deteriorating mental health is particularly pronounced among people born in the 1990s and seen to a lesser extent among the 1980s cohort. There is little evidence that mental health is worsening with age for people born prior to the 1980s. The findings from this study highlight that it is the poorer mental health of Millennials that is driving the apparent deterioration in population-level mental health. Understanding the context and changes in society that have differentially affected younger people may inform efforts to ameliorate this trend and prevent it continuing for emerging cohorts.

Label-free proteome quantification and evaluation.

The label-free quantification (LFQ) has emerged as an exceptional technique in proteomics owing to its broad proteome coverage, great dynamic ranges and enhanced analytical reproducibility. Due to the extreme difficulty lying in an in-depth quantification, the LFQ chains incorporating a variety of transformation, pretreatment and imputation methods are required and constructed. However, it remains challenging to determine the well-performing chain, owing to its strong dependence on the studied data and the diverse possibility of integrated chains. In this study, an R package EVALFQ was therefore constructed to enable a performance evaluation on >3000 LFQ chains. This package is unique in (a) automatically evaluating the performance using multiple criteria, (b) exploring the quantification accuracy based on spiking proteins and (c) discovering the well-performing chains by comprehensive assessment. All in all, because of its superiority in assessing from multiple perspectives and scanning among over 3000 chains, this package is expected to attract broad interests from the fields of proteomic quantification. The package is available at https://github.com/idrblab/EVALFQ.

Cortical microstructural brain network mediates the association between personality trait of agreeableness and life satisfaction.

Personality traits are commonly regarded as relatively stable, whereas life satisfaction can fluctuate with time and circumstances, shaped by external influences and personal encounters. The correlation between personality traits and life satisfaction is well-established, yet the underlying neural mechanisms of the myelin-based microstructural brain network connecting them remain unclear. Here, we constructed individual-level whole-brain myelin microstructural networks from the MRI data of 1,043 healthy adults and performed correlation analysis to detect significant personality trait-related and life satisfaction-related subnetworks. A mediation analysis was used to verify whether the shared structural basis of personality traits and life satisfaction significantly mediated their association. The results showed that agreeableness positively correlated with life satisfaction. We identified a shared structural basis of the personality trait of agreeableness and life satisfaction. The regions comprising this overlapping network include the superior parietal lobule, inferior parietal lobule, and temporoparietal junction. Moreover, the shared microstructural connections mediate the association between the personality trait of agreeableness and life satisfaction. This large-scale neuroimaging investigation substantiates a mediation framework for understanding the microstructural connections between personality and life satisfaction, offering potential targets for assessment and interventions to promote human well-being.

How Can People Become Happier? A Systematic Review of Preregistered Experiments.

Can happiness be reliably increased? Thousands of studies speak to this question. However, many of them were conducted during a period in which researchers commonly "p-hacked," creating uncertainty about how many discoveries might be false positives. To prevent p-hacking, happiness researchers increasingly preregister their studies, committing to analysis plans before analyzing data. We conducted a systematic literature search to identify preregistered experiments testing strategies for increasing happiness. We found surprisingly little support for many widely recommended strategies (e.g., performing random acts of kindness). However, our review suggests that other strategies-such as being more sociable-may reliably promote happiness. We also found strong evidence that governments and organizations can improve happiness by providing underprivileged individuals with financial support. We conclude that happiness research stands on the brink of an exciting new era, in which modern best practices will be applied to develop theoretically grounded strategies that can produce lasting gains in life satisfaction.

Psychological Flexibility, Chronic Pain, and Health.

Psychological flexibility is a model of human performance and well-being. It essentially entails an approach to life circumstances that includes openness, awareness, and engagement. It has roots in behavior analysis, and it is linked to a philosophy of science called functional contextualism and to a specific therapy approach called Acceptance and Commitment Therapy. One of the earliest and most developed research areas in which this model and therapy have been applied is chronic pain. This review describes psychological flexibility and its facets in more detail, sets them in a context of relevant psychological models, and examines related assessment and treatment methods. It also examines evidence, current challenges, and future directions. It is proposed that psychological flexibility, or an expanded model very much like it, could provide a basis for integrating current research and treatment approaches in chronic pain and health generally. This, in turn, could produce improved treatments for people with chronic pain and other conditions.

Relational diversity in social portfolios predicts well-being.

We document a link between the relational diversity of one's social portfolio-the richness and evenness of relationship types across one's social interactions-and well-being. Across four distinct samples, respondents from the United States who completed a preregistered survey (n = 578), respondents to the American Time Use Survey (n = 19,197), respondents to the World Health Organization's Study on Global Aging and Adult Health (n = 10,447), and users of a French mobile application (n = 21,644), specification curve analyses show that the positive relationship between social portfolio diversity and well-being is robust across different metrics of well-being, different categorizations of relationship types, and the inclusion of a wide range of covariates. Over and above people's total amount of social interaction and the diversity of activities they engage in, the relational diversity of their social portfolio is a unique predictor of well-being, both between individuals and within individuals over time.

Genetics, leadership position, and well-being: An investigation with a large-scale GWAS.

SignificanceOur study presents the largest whole-genome investigation of leadership phenotypes to date. We identified genome-wide significant loci for leadership phenotypes, which are overlapped with top hits for bipolar disorder, schizophrenia, and intelligence. Our study demonstrated the polygenetic nature of leadership, the positive genetic correlations between leadership traits and a broad range of well-being indicators, and the unique association of leadership with well-being after accounting for genetic influences related to other socioeconomic status measures. Our findings offer insights into the biological underpinnings of leadership.

Wealth redistribution promotes happiness.

How much happiness could be gained if the world's wealth were distributed more equally? Despite decades of research investigating the relationship between money and happiness, no experimental work has quantified this effect for people across the global economic spectrum. We estimated the total gain in happiness generated when a pair of high-net-worth donors redistributed US$2 million of their wealth in $10,000 cash transfers to 200 people. Our preregistered analyses offer causal evidence that cash transfers substantially increase happiness among economically diverse individuals around the world. Recipients in lower-income countries exhibited happiness gains three times larger than those in higher-income countries. Still, the cash provided detectable benefits for people with household incomes up to $123,000.

The societal responses to COVID-19: Evidence from the G7 countries.

This paper provides a picture of how societies in the G7 countries have responded to the COVID-19 pandemic. Our point of departure is to examine the effects of the pandemic in terms of four fundamental normative sources for well-being: Solidarity (S; willingness for social cooperation), Agency (A; empowerment to shape one's prospects through one's own efforts), GDP (G), and Environmental Performance (E)-SAGE for short. The normative foundations of SAGE are communitarianism, classical liberalism, materialistic utilitarianism, and ecoethics. We find that although G and E responded predictably and uniformly to the pandemic (such as G declining and carbon emissions improving), the societal responses were strikingly different. Societies that are cohesive and empowered (high S and A) may be expected to cope with the pandemic better than those that are fragmented and disempowered (low S and A). Furthermore, the pandemic has had diverse effects on S and A; while some societies became cohering and empowering (rising S and A), others became fragmenting and disempowering (falling S and A), and yet others became fragmenting and empowering. We also show that most G7 countries experienced greater tribalization (measured as the difference between inward S and outward S) during the pandemic. These trends are a matter of concern since they suggest that the willingness and perceived ability to address collective challenges collectively have waned. The analysis also suggests that governments' social policies may have an important role to play alongside economic and health policies in coping with the pandemic.

When peer comparison information harms physician well-being.

Policymakers and business leaders often use peer comparison information-showing people how their behavior compares to that of their peers-to motivate a range of behaviors. Despite their widespread use, the potential impact of peer comparison interventions on recipients' well-being is largely unknown. We conducted a 5-mo field experiment involving 199 primary care physicians and 46,631 patients to examine the impact of a peer comparison intervention on physicians' job performance, job satisfaction, and burnout. We varied whether physicians received information about their preventive care performance compared to that of other physicians in the same health system. Our analyses reveal that our implementation of peer comparison did not significantly improve physicians' preventive care performance, but it did significantly decrease job satisfaction and increase burnout, with the effect on job satisfaction persisting for at least 4 mo after the intervention had been discontinued. Quantitative and qualitative evidence on the mechanisms underlying these unanticipated negative effects suggest that the intervention inadvertently signaled a lack of support from leadership. Consistent with this account, providing leaders with training on how to support physicians mitigated the negative effects on well-being. Our research uncovers a critical potential downside of peer comparison interventions, highlights the importance of evaluating the psychological costs of behavioral interventions, and points to how a complementary intervention-leadership support training-can mitigate these costs.

Self-reported COVID-19 infection and implications for mental health and food insecurity among American college students.

While the COVID-19 pandemic affected mental health and increased food insecurity across the general population, less is known about the virus's impact on college students. A fall 2020 survey of more than 100,000 students at 202 colleges and universities in 42 states reveals sociodemographic variation in self-reported infections, as well as associations between self-reported infection and food insecurity and mental health. We find that 7% of students self-reported a COVID-19 infection, with sizable differences by race/ethnicity, socioeconomic status, parenting status, and student athlete status. Students who self-reported COVID-19 infections were more likely to experience food insecurity, anxiety, and depression. Implications for higher education institutions, policy makers, and students are discussed.

Early life lead exposure from private well water increases juvenile delinquency risk among US teens.

Early life exposure to environmental lead (Pb) has been linked to decreased IQ, behavior problems, lower lifetime earnings, and increased criminal activity. Beginning in the 1970s, limits on Pb in paint, gasoline, food cans, and regulated water utilities sharply curtailed US environmental Pb exposure. Nonetheless, hundreds of thousands of US children remain at risk. This study reports on how unregulated private well water is an underrecognized Pb exposure source that is associated with an increased risk of teenage juvenile delinquency. We build a longitudinal dataset linking blood Pb measurements for 13,580 children under age 6 to their drinking water source, individual- and neighborhood-level demographics, and reported juvenile delinquency records. We estimate how early life Pb exposure from private well water influences reported delinquency. On average, children in homes with unregulated private wells had 11% higher blood Pb than those with community water service. This higher blood Pb was significantly associated with reported delinquency. Compared to children with community water service, those relying on private wells had a 21% (95% CI: 5 to 40%) higher risk of being reported for any delinquency and a 38% (95% CI: 10 to 73%) increased risk of being reported for serious delinquency after age 14. These results suggest that there could be substantial but as-yet-unrecognized social benefits from intervention programs to prevent children's exposure to Pb from private wells, on which 13% of the US population relies.