Organ Evolution: Emergence of Multicellular Function.

Instances of multicellularity across the tree of life have fostered the evolution of complex organs composed of distinct cell types that cooperate, producing emergent biological functions. How organs originate is a fundamental evolutionary problem that has eluded deep mechanistic and conceptual understanding. Here I propose a cell- to organ-level transitions framework, whereby cooperative division of labor originates and becomes entrenched between cell types through a process of functional niche creation, cell-type subfunctionalization, and irreversible ratcheting of cell interdependencies. Comprehending this transition hinges on explaining how these processes unfold molecularly in evolving populations. Recent single-cell transcriptomic studies and analyses of terminal fate specification indicate that cellular functions are conferred by modular gene expression programs. These discrete components of functional variation may be deployed or combined within cells to introduce new properties into multicellular niches, or partitioned across cells to establish division of labor. Tracing gene expression program evolution at the level of single cells in populations may reveal transitions toward organ complexity.

The Budding Neuroscience of Ant Social Behavior.

Ant physiology has been fashioned by 100 million years of social evolution. Ants perform many sophisticated social and collective behaviors yet possess nervous systems similar in schematic and scale to that of the fruit fly Drosophila melanogaster, a popular solitary model organism. Ants are thus attractive complementary subjects to investigate adaptations pertaining to complex social behaviors that are absent in flies. Despite research interest in ant behavior and the neurobiological foundations of sociality more broadly, our understanding of the ant nervous system is incomplete. Recent technical advances have enabled cutting-edge investigations of the nervous system in a fashion that is less dependent on model choice, opening the door for mechanistic social insect neuroscience. In this review, we revisit important aspects of what is known about the ant nervous system and behavior, and we look forward to how functional circuit neuroscience in ants will help us understand what distinguishes solitary animals from highly social ones.

Circumvention of luteolysis reveals parturition pathways in mice dependent upon innate type 2 immunity.

Although mice normally enter labor when their ovaries stop producing progesterone (luteolysis), parturition can also be triggered in this species through uterus-intrinsic pathways potentially analogous to the ones that trigger parturition in humans. Such pathways, however, remain largely undefined in both species. Here, we report that mice deficient in innate type 2 immunity experienced profound parturition delays when manipulated endocrinologically to circumvent luteolysis, thus obliging them to enter labor through uterus-intrinsic pathways. We found that these pathways were in part driven by the alarmin IL-33 produced by uterine interstitial fibroblasts. We also implicated important roles for uterine group 2 innate lymphoid cells, which demonstrated IL-33-dependent activation prior to labor onset, and eosinophils, which displayed evidence of elevated turnover in the prepartum uterus. These findings reveal a role for innate type 2 immunity in controlling the timing of labor onset through a cascade potentially relevant to human parturition.

The physical soldier caste of an invasive, human-infecting flatworm is morphologically extreme and obligately sterile.

We show that the globally invasive, human-infectious flatworm, Haplorchis pumilio, possesses the most physically specialized soldier caste yet documented in trematodes. Soldiers occur in colonies infecting the first intermediate host, the freshwater snail Melanoides tuberculata, and are readily distinguishable from immature and mature reproductive worms. Soldiers possess a pharynx five times absolutely larger than those of immature and mature reproductives, lack a germinal mass, and have a different developmental trajectory than reproductives, indicating that H. pumilio soldiers constitute a reproductively sterile physical caste. Neither immature nor mature reproductives showed aggression in in vitro trials, but soldiers readily attacked heterospecific trematodes that coinfect their host. Ecologically, we calculate that H. pumilio caused ~94% of the competitive deaths in the guild of trematodes infecting its host snail in its invasive range in southern California. Despite being a dominant competitor, H. pumilio soldiers did not attack conspecifics from other colonies. All prior reports documenting division of labor and a trematode soldier caste have involved soldiers that may be able to metamorphose to the reproductive stage and have been from nonhuman-infectious marine species; this study provides clear evidence for an obligately sterile trematode soldier, while extending the phenomenon of a trematode soldier caste to freshwater and to an invasive species of global public health concern.

The causal effect of mental health on labor market outcomes: The case of stress-related mental disorders following a human-made disaster.

As disasters increase due to climate change, population density, epidemics, and technology, information is needed about postdisaster consequences for people's mental health and how stress-related mental disorders affect multiple spheres of life, including labor-market attachment. We tested the causal hypothesis that individuals who developed stress-related mental disorders as a consequence of their disaster exposure experienced subsequent weak labor-market attachment and poor work-related outcomes. We leveraged a natural experiment in an instrumental variables model, studying a 2004 fireworks factory explosion disaster that precipitated the onset of stress-related disorders (posttraumatic stress disorder, anxiety, and depression) among individuals in the local community (N = 86,726). We measured labor-market outcomes using longitudinal population-level administrative data: sick leave, unemployment benefits, early retirement pension, and income from wages from 2007 to 2010. We found that individuals who developed a stress-related disorder after the disaster were likely to go on sickness benefit, both in the short- and long-term, were likely to use unemployment benefits and to lose wage income in the long term. Stress-related disorders did not increase the likelihood of early retirement. The natural experiment design minimized the possibility that omitted confounders biased these effects of mental health on work outcomes. Addressing the mental health and employment needs of survivors after a traumatic experience may improve their labor-market outcomes and their nations' economic outputs.

Large motherhood penalties in US administrative microdata.

Whereas previous research has described motherhood penalties in US survey data, we leverage administrative data on 811,000 quarterly earnings histories from the US Unemployment Insurance program. We analyze contexts where smaller motherhood penalties might be expected: couples where the woman outearns her male partner prior to childbearing, at firms that are headed by women, and at firms that are predominantly women. Our startling result is that none of these propitious contexts appear to diminish the motherhood penalty, and indeed, the gap often increases in magnitude over time following childbearing. We estimate one of the largest motherhood penalties in "female-breadwinner" families, where higher-earning women experience a 60% drop from their prechildbirth earnings relative to their male partners. Turning to proximate mechanisms, women are less likely to switch to a higher-paying firm postchildbearing than men and are substantially more likely to quit the labor force. On the whole, our findings are discouraging relative even to existing research on motherhood penalties.

US and Chinese preschoolers normalize household labor inequality.

Across many cultural contexts, the majority of women conduct the majority of their household labor. This gendered distribution of labor is often unequal, and thus represents one of the most frequently experienced forms of daily inequality because it occurs within one's own home. Young children are often passive observers of their family's distribution of labor, and yet little is known about the developmental onset of their perceptions of it. By the preschool age, children also show strong normative feelings about both equal resource distribution and gender stereotypes. To investigate the developmental onset of children's recognition of the (in)equality of household labor, we interviewed 3 to 10-y-old children in two distinct cultural contexts (US and China) and surveyed their caregivers about who does more household labor across a variety of tasks. Even at the youngest ages and in both cultural contexts, children's reports largely matched their parents', with both populations reporting that mothers do the majority of household labor. Both children and parents judged this to be generally fair, suggesting that children are observant of the gendered distribution of labor within their households, and show normalization of inequality from a young age. Our results point to preschool age as a critical developmental time period during which it is important to have parent-child discussions about structural constraints surrounding gender norms and household labor.

Trends in racial and ethnic discrimination in hiring in six Western countries.

We examine trends in racial and ethnic discrimination in hiring in six European and North American countries: Canada, France, Germany, Great Britain, the Netherlands, and the United States. Our sample includes all available discrimination estimates from 90 field experimental studies of hiring discrimination, encompassing more than 170,000 applications for jobs. The years covered vary by country, ranging from 1969 to 2017 for Great Britain to 1994 to 2017 for Germany. We examine trends in discrimination against four racial-ethnic origin groups: African/Black, Asian, Latin American/Hispanic, and Middle Eastern or North African. The results indicate that levels of discrimination in callbacks have remained either unchanged or slightly increased overall for most countries and origin categories. There are three notable exceptions. First, hiring discrimination against ethnic groups with origins in the Middle East and North Africa increased during the 2000s relative to the 1990s. Second, we find that discrimination in France declined, although from very high to "merely" high levels. Third, we find evidence that discrimination in the Netherlands has increased over time. Controls for study characteristics do not change these trends. Contrary to the idea that discrimination will tend to decline in Western countries, we find that discrimination has not fallen over the last few decades in five of the six Western countries we examine.

China, the Democratic Republic of the Congo, and artisanal cobalt mining from 2000 through 2020.

From 2000 through 2020, demand for cobalt to manufacture batteries grew 26-fold. Eighty-two percent of this growth occurred in China and China's cobalt refinery production increased 78-fold. Diminished industrial cobalt mine production in the early-to-mid 2000s led many Chinese companies to purchase ores from artisanal cobalt miners in the Democratic Republic of the Congo (DRC), many of whom have been found to be children. Despite extensive research on artisanal cobalt mining, fundamental questions about its production remain unanswered. This gap is addressed here by estimating artisanal cobalt production, processing, and trade. The results show that, while total DRC cobalt mine production grew from 11,000 metric tons (t) in 2000 to 98,000 t in 2020, artisanal production only grew from 1,000 to 2,000 t in 2000 to 9,000 to 11,000 t in 2020 (with a peak of 17,000 to 21,000 t in 2018). Artisanal production's share of world and DRC cobalt mine production peaked around 2008 at 18 to 23% and 40 to 53%, respectively, before trending down to 6 to 8% and 9 to 11% in 2020, respectively. Artisanal production was chiefly exported to China or processed within the DRC by Chinese firms. An average of 72 to 79% of artisanal production was processed at facilities within the DRC from 2016 through 2020. As such, these facilities may be potential monitoring points for artisanal production and its downstream consumers. This finding may help to support responsible sourcing initiatives and better address abuses related to artisanal cobalt mining by focusing local efforts at the artisanal processing facilities through which most artisanal cobalt production flows.

Genetics and Evolution of Social Behavior in Insects.

The study of insect social behavior has offered tremendous insight into the molecular mechanisms mediating behavioral and phenotypic plasticity. Genomic applications to the study of eusocial insect species, in particular, have led to several hypotheses for the processes underlying the molecular evolution of behavior. Advances in understanding the genetic control of social organization have also been made, suggesting an important role for supergenes in the evolution of divergent behavioral phenotypes. Intensive study of social phenotypes across species has revealed that behavior and caste are controlled by an interaction between genetic and environmentally mediated effects and, further, that gene expression and regulation mediate plastic responses to environmental signals. However, several key methodological flaws that are hindering progress in the study of insect social behavior remain. After reviewing the current state of knowledge, we outline ongoing challenges in experimental design that remain to be overcome in order to advance the field.

Serpin family E member 1 enhances myometrium contractility by increasing ATP production during labor.

The uterine contraction during labor, a process with repetitive hypoxia and high energy consumption, is essential for successful delivery. However, the molecular mechanism of myometrial contraction regulation is unknown. Serpin family E member 1 (SERPINE1), one of the most upregulated genes in laboring myometrium in both transcriptome and proteome, was highlighted in our previous study. Here, we confirmed SERPINE1 is upregulated in myometrium during labor. Blockade of SERPINE1 using small interfering RNA (siRNA) or inhibitor (Tiplaxtinin) under hypoxic conditions in myocytes or myometrium in vitro showed a decrease contractility, which was achieved by regulating ATP production. Chromatin immunoprecipitation (ChIP-seq), Co-immunoprecipitation (Co-IP), and glutathione-S-transferase (GST) pull down explored that the promoter of SERPINE1 is directly activated by hypoxia-inducible factor-1α (HIF-1α) and SERPINE1 interacts with ATP Synthase Peripheral Stalk Subunit F6 (ATP5PF). Together they enhance hypoxia driven myometrial contraction by maintaining ATP production in the key oxidative phosphorylation pathway. The results provide new insight for uterine contraction regulation, and potential novel therapeutic targets for labor management.

Behavioral genetics and genomics: Mendel's peas, mice, and bees.

The question of the heritability of behavior has been of long fascination to scientists and the broader public. It is now widely accepted that most behavioral variation has a genetic component, although the degree of genetic influence differs widely across behaviors. Starting with Mendel's remarkable discovery of "inheritance factors," it has become increasingly clear that specific genetic variants that influence behavior can be identified. This goal is not without its challenges: Unlike pea morphology, most natural behavioral variation has a complex genetic architecture. However, we can now apply powerful genome-wide approaches to connect variation in DNA to variation in behavior as well as analyses of behaviorally related variation in brain gene expression, which together have provided insights into both the genetic mechanisms underlying behavior and the dynamic relationship between genes and behavior, respectively, in a wide range of species and for a diversity of behaviors. Here, we focus on two systems to illustrate both of these approaches: the genetic basis of burrowing in deer mice and transcriptomic analyses of division of labor in honey bees. Finally, we discuss the troubled relationship between the field of behavioral genetics and eugenics, which reminds us that we must be cautious about how we discuss and contextualize the connections between genes and behavior, especially in humans.

When being flexible matters: Ecological underpinnings for the evolution of collective flexibility and task allocation.

Task allocation is a central feature of collective organization. Living collective systems, such as multicellular organisms or social insect colonies, have evolved diverse ways to allocate individuals to different tasks, ranging from rigid, inflexible task allocation that is not adjusted to changing circumstances to more fluid, flexible task allocation that is rapidly adjusted to the external environment. While the mechanisms underlying task allocation have been intensely studied, it remains poorly understood whether differences in the flexibility of task allocation can be viewed as adaptive responses to different ecological contexts­for example, different degrees of temporal variability. Motivated by this question, we develop an analytically tractable mathematical framework to explore the evolution of task allocation in dynamic environments. We find that collective flexibility is not necessarily always adaptive, and fails to evolve in environments that change too slowly (relative to how long tasks can be left unattended) or too quickly (relative to how rapidly task allocation can be adjusted). We further employ the framework to investigate how environmental variability impacts the internal organization of task allocation, which allows us to propose adaptive explanations for some puzzling empirical observations, such as seemingly unnecessary task switching under constant environmental conditions, apparent task specialization without efficiency benefits, and high levels of individual inactivity. Altogether, this work provides a general framework for probing the evolved diversity of task allocation strategies in nature and reinforces the idea that considering a system's ecology is crucial to explaining its collective organization.

Uterine Excitability and Ion Channels and Their Changes with Gestation and Hormonal Environment.

We address advances in the understanding of myometrial physiology, focusing on excitation and the effects of gestation on ion channels and their relevance to labor. This review moves through pioneering studies to exciting new findings. We begin with the myometrium and its myocytes and describe how excitation might initiate and spread in this myogenic smooth muscle. We then review each of the ion channels in the myometrium: L- and T-type Ca2+ channels, KATP (Kir6) channels, voltage-dependent K channels (Kv4, Kv7, and Kv11), twin-pore domain K channels (TASK, TREK), inward rectifier Kir7.1, Ca2+-activated K+ channels with large (KCNMA1, Slo1), small (KCNN1-3), and intermediate (KCNN4) conductance, Na-activated K channels (Slo2), voltage-gated (SCN) Na+ and Na+ leak channels, nonselective (NALCN) channels, the Na K-ATPase, and hyperpolarization-activated cation channels. We finish by assessing how three key hormones- oxytocin, estrogen, and progesterone-modulate and integrate excitability throughout gestation.

Bitter taste receptors in the reproductive system: Function and therapeutic implications.

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single-cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders.

Neural mechanisms distinguishing two types of cooperative problem-solving approaches: An fNIRS hyperscanning study.

Collaborative cooperation (CC) and division of labor cooperation (DLC) are two prevalent forms of cooperative problem-solving approaches in daily life. Despite extensive research on the neural mechanisms underlying cooperative problem-solving approaches, a notable gap exists between the neural processes that support CC and DLC. The present study utilized a functional near-infrared spectroscopy (fNIRS) hyperscanning technique along with a classic cooperative tangram puzzle task to investigate the neural mechanisms engaged by both friends and stranger dyads during CC versus DLC. The key findings of this study were as follows: (1) Dyads exhibited superior behavioral performance in the DLC task than in the CC task. The CC task bolstered intra-brain functional connectivity and inter-brain synchrony (IBS) in regions linked to the mirror neuron system (MNS), spatial perception (SP) and cognitive control. (2) Friend dyads showed stronger IBS in brain regions associated with the MNS than stranger dyads. (3) Perspective-taking predicted not only dyads' behavioral performance in the CC task but also their IBS in brain regions associated with SP during the DLC task. Taken together, these findings elucidate the divergent behavioral performance and neural connection patterns between the two cooperative problem-solving approaches. This study provides novel insights into the various neurocognitive processes underlying flexible coordination strategies in real-world cooperative contexts.

Analyzing Substance Levels and Pain Perception in Painless Labor: The Impact of Spinal Epidural Analgesia.

BACKGROUND: Inflammation affects labor by influencing contractions and dilation. Pain, often linked to tissue ischemia, involves mediators like nitric oxide (NO), TNF-α, and substance P (SP). Neuraxial analgesia, including combined spinal epidural analgesia (SEA) with levobupivacaine, is preferred for its effectiveness and minimal side effects in painless labor. Understanding the impact of painless labor techniques on biomolecular processes such as NO, TNF-α, and substance P levels is crucial for improving pain management strategies. This study investigates these effects in parturients undergoing SEA with levobupivacaine, contributing to the development of novel pain medications and enhancing obstetric care. METHODS: This experimental study, conducted at a General Hospital in Indonesia, involved 60 expectant mothers in labor or in the third trimester, expected to give birth vaginally at Permata Hati Metro Hospital. Blood serum was used for analysis, and serum NO, TNF-α, and SP levels were assessed using ELISA kit. RESULTS: There's a significant decrease in NO levels before and post-treatment in the SEA group compared to the control group (p < 0.05). However, no significant difference in TNF-α levels was observed between groups before and after treatment (p > 0.05). Additionally, there was no significant difference in SP levels between groups before treatment, but a significant difference was seen after treatment (p < 0.05). SEA significantly reduced labor pain compared to the control group (P < 0.05), with notable improvements in vital signs and APGAR scores, while also shortening labor duration (P < 0.001). CONCLUSION: In conclusion, SEA with levobupivacaine during painless labor reduces NO levels significantly and shows a trend of decreasing TNF-α and substance P levels, although not statistically significant, with clinical benefits for both patients and babies.

Bringing home the benefits: do pro-family employee benefits mitigate the risk of depression from competing workplace and domestic labor roles?

Despite significant historical progress toward sex/gender parity in employment status in the United States, women remain more likely to provide domestic labor, creating role competition which may increase depression symptoms. Pro-family employee benefits may minimize the stress of competing roles. We tested whether depressive symptoms were higher among women with competing roles versus without competing roles and whether this effect was greater among women without (vs with) pro-family benefits. Data included employed women (n = 9884 person-years) surveyed across 4 waves (2010, 2015, 2017, and 2019) of the National Longitudinal Survey 1997. Depression symptoms were measured with the 5-item short version of the Mental Health Inventory (MHI-5). The effect of interaction between competing roles and pro-family employee benefits on depressive symptoms was also compared with that of non-family-related benefits, using marginal structural models to estimate longitudinal effects in the presence of time-varying confounding. MHI-5 scores were 0.56 points higher (95% CI, 0.15-0.97) among women in competing roles (vs not). Among women without pro-family benefits, competing roles increased MHI-5 scores by 6.10 points (95% CI, 1.14-11.1). In contrast, there was no association between competing roles and MHI-5 scores among women with access to these benefits (MHI-5 difference = 0.44; 95% CI, -0.2 to 1.0). Results were similar for non-family-related benefits. Dual workplace and domestic labor role competition increases women's depression symptoms, though broad availability of workplace benefits may attenuate that risk. This article is part of a Special Collection on Mental Health.

Membrane inflammasome activation by choriodecidual Ureaplasma parvum infection without intra-amniotic infection in a Non-Human Primate model†.

Intrauterine infection is a significant cause of neonatal morbidity and mortality. Ureaplasma parvum is a microorganism commonly isolated from cases of preterm birth and preterm premature rupture of membranes (pPROM). However, the mechanisms of early stage ascending reproductive tract infection remain poorly understood. To examine inflammation in fetal (chorioamnionic) membranes we utilized a non-human primate (NHP) model of choriodecidual U. parvum infection. Eight chronically catheterized pregnant rhesus macaques underwent maternal-fetal catheterization surgery at ~105-112 days gestation and choriodecidual inoculation with U. parvum (105 CFU/mL, n =4) or sterile media (controls; n = 4) starting at 115-119 days, repeated at 5-day intervals until C-section at 136-140 days (term=167 days). The average inoculation to delivery interval was 21 days, and Ureaplasma infection of the amniotic fluid (AF) was undetectable in all animals. Choriodecidual Ureaplasma infection resulted in increased fetal membrane expression of MMP-9 and PTGS2, but did not result in preterm labor or increased concentrations of AF pro-inflammatory cytokines. However, membrane expression of inflammasome sensors, NLRP3, NLRC4, AIM2, and NOD2, and adaptor ASC (PYCARD) gene expression were significantly increased. Gene expression of IL-1ß, IL-18, IL-18R1  , CASPASE-1, and pro-CASPASE-1 protein increased with Ureaplasma infection. Downstream inflammatory genes MYD88 and NFκB (Nuclear factor kappa-light-chain-enhancer of activated B cells) were also significantly upregulated. These results demonstrate that choriodecidual Ureaplasma infection, can cause activation of inflammasome complexes and pathways associated with pPROM and preterm labor prior to microbes being detectable in the AF.

Methyl-CpG-binding protein 2 regulates CYP27A1-induced myometrial contraction during preterm labor.

Persistent and intense uterine contraction is a risk factor for preterm labor. We previously found that methyl-CpG-binding protein 2 (MeCP2), as a target of infection-related microRNA miR-212-3p, may play an inhibitory role in regulating myometrium contraction. However, the molecular mechanisms by which MeCP2 regulates myometrial contraction are still unknown. In this study, we found that MeCP2 protein expression was lower in myometrial specimens obtained from preterm labor cases, compared to those obtained from term labor cases. Herein, using RNA sequence analysis of global gene expression in human uterine smooth muscle cells (HUSMCs) following siMeCP2, we show that MeCP2 silencing caused dysregulation of the cholesterol metabolism pathway. Notably, MeCP2 silencing resulted in the upregulation of CYP27A1, the key enzyme involved in regulating cholesterol homeostasis, in HUSMCs. Methylation-specific PCR, chromatin immunoprecipitation, and dual luciferase reporter gene technology indicated that MeCP2 could bind to the methylated CYP27A1 promoter region and repress its transcription. Administration of siCYP27A1 in a lipopolysaccharide (LPS)-induced preterm labor mouse model delayed the onset of preterm labor. Human preterm myometrium and the LPS-induced preterm labor mouse model both showed lower expression of MeCP2 and increased expression of CYP27A1. These results demonstrated that aberrant upregulation of CYP27A1 induced by MeCP2 silencing is one of the mechanisms facilitating inappropriate myometrial contraction. CYP27A1 could be exploited as a novel therapeutic target for preterm birth.