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The intracellular signaling pathways that regulate myometrial contractions can be targeted by drugs for tocolysis. The agents, 2-APB, glycyl-H-1152, and HC-067047, have been identified as inhibitors of uterine contractility and may have tocolytic potential. However, the contraction-blocking potency of these novel tocolytics was yet to be comprehensively assessed and compared to agents that have seen greater scrutiny, such as the phosphodiesterase inhibitors, aminophylline and rolipram, or the clinically used tocolytics, nifedipine and indomethacin. We determined the IC50 concentrations (inhibit 50% of baseline contractility) for 2-APB, glycyl-H-1152, HC-067047, aminophylline, rolipram, nifedipine, and indomethacin against spontaneous ex vivo contractions in pregnant human myometrium, and then compared their tocolytic potency. Myometrial strips obtained from term, not-in-labor women, were treated with cumulative concentrations of the contraction-blocking agents. Comprehensive dose–response curves were generated. The IC50 concentrations were 53 µM for 2-APB, 18.2 µM for glycyl-H-1152, 48 µM for HC-067047, 318.5 µM for aminophylline, 4.3 µM for rolipram, 10 nM for nifedipine, and 59.5 µM for indomethacin. A single treatment with each drug at the determined IC50 concentration was confirmed to reduce contraction performance (AUC) by approximately 50%. Of the three novel tocolytics examined, glycyl-H-1152 was the most potent inhibitor. However, of all the drugs examined, the overall order of contraction-blocking potency in decreasing order was nifedipine > rolipram > glycyl-H-1152 > HC-067047 > 2-APB > indomethacin > aminophylline. These data provide greater insight into the contraction-blocking properties of some novel tocolytics, with glycyl-H-1152, in particular, emerging as a potential novel tocolytic for preventing preterm birth.

The mechanism by which human labor is initiated in the presence of elevated circulating progesterone levels remains unknown. Recent evidence indicates that the progesterone-metabolizing enzyme, 20α-hydroxysteroid dehydrogenase (20α-HSD), encoded by the gene AKR1C1, may contribute to functional progesterone withdrawal. We found that AKR1C1 expression significantly increased with labor onset in term myometrium, but not in preterm myometrium. Among preterm laboring deliveries, clinically diagnosed chorioamnionitis was associated with significantly elevated AKR1C1 expression. AKR1C1 expression positively correlated with BMI before labor and negatively correlated with BMI during labor. Analysis by fetal sex showed that AKR1C1 expression was significantly higher in women who delivered male babies compared to women who delivered female babies at term, but not preterm. Further, in pregnancies where the fetus was female, AKR1C1 expression positively correlated with the mother’s age and BMI at the time of delivery. In conclusion, the increase in myometrial AKR1C1 expression with term labor is consistent with 20α-HSD playing a role in local progesterone metabolism to promote birth. Interestingly, this role appears to be specific to term pregnancies where the fetus is male. Upregulated AKR1C1 expression in the myometrium at preterm in-labor with clinical chorioamnionitis suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. The link between AKR1C1 expression and maternal BMI may provide insight into why maternal obesity is often associated with dysfunctional labor. Higher myometrial AKR1C1 expression in male pregnancies may indicate fetal sex-related differences in the mechanisms that precipitate labor onset at term.

The pregnant uterus remains relaxed throughout fetal gestation before transforming to a contractile phenotype at term to facilitate birth. Despite ongoing progress, the precise mechanisms that regulate this phenotypic transformation are not yet understood. This knowledge gap limits our understanding of how dysregulation of uterine smooth muscle biology contributes to life-threatening obstetric complications, including preterm birth, and hampers our ability to develop effective therapeutic intervention strategies. Protein acetylation plays a vital role in regulating protein structure, function, and subcellular localization, as well as gene transcription availability through regulating chromatin condensation. Histone deacetylase inhibitors (HDACis) are a class of compounds that block the removal of acetyl functional groups from proteins and, as such, have profound effects on important cellular events, including phenotypic transformation. A large body of data now demonstrates that HDACis have profound effects on pregnant human myometrium. Studies to date show that HDACis operate through both genomic and non-genomic mechanisms to affect myometrial function and phenotype. Interestingly, the effects of HDACis on pregnant myometrium are largely "pro-relaxation," including the direct inhibition of contractile machinery as well as repression of pro-labor genes. The "dual action" effects of HDACis make them a powerful tool for unlocking the regulatory processes that underpin myometrial phenotypic transformation and raises prospects of their therapeutic applications. Here, we review the new insights into human myometrial biology that have garnered through the application of HDACis and explore their potential therapeutic application toward the development of novel preterm birth prevention strategies.

A perennial challenge of evolutionary psychology is explaining prosocial traits such as a preference for fairness rather than inequality, compassion towards suffering, and an instinctive ability to coordinate within small teams. Considering recent fossil evidence and a novel logical test, we deem present explanations insufficiently explanatory of the divergence of hominins. In answering this question, we focus on the divergence of hominins from the last common ancestor (LCA) shared with Pan. We consider recent fossil discoveries that indicate the LCA was bipedal, which reduces the cogency of this explanation for hominin development. We also review evolutionary theory that claims to explain how hominins developed into modern humans, however it is found that no mechanism differentiates hominins from other primates. Either the mechanism was available to the last common ancestor (LCA) (with P. troglodytes as its proxy), or because early hominins had insufficient cognition to utilise the mechanism. A novel mechanism, sub-group level selection (sGLS) is hypothesised by triangulating two pieces of data rarely considered by evolutionary biologists. These are behavioural dimorphism of Pan (chimpanzees and bonobos) that remain identifiable in modern humans, and the social behaviour of primate troops in a savannah ecology. We then contend that sGLS supplied an exponential effect which was available to LCA who left the forest, but was not sufficiently available to any other primates. In conclusion, while only indirectly supported by various evidence, sGLS is found to be singularly and persuasively explanatory of human's unique evolutionary story.

The mechanisms that bring about the onset of labor in humans remain poorly understood. Previous research has extensively explored signalling pathways that maintain myometrial relaxation and identified roles for key molecules, including cyclic nucleotides, nitric oxide, carbon monoxide, hydrogen sulfide and progesterone. However, these conventional pro-relaxation signalling pathways have fallen out of favor to inflammatory signalling, which is now widely regarded as an instigator of myometrial transformation toward a contractile phenotype and initiator of labor. This article revisits the complex inter-play of conventional pro-relaxation signalling, and explores the concept that progesterone, cAMP, glucocorticoids, and possibly gasotransmitters, work in synergy to constitute a uterine brake that suspends the intrinsic contractility of the myometrium, thus enabling retention of the conceptus and the progression of pregnancy. As term approaches, this uterine brake of relaxatory signalling is ultimately withdrawn, thus permitting restoration of myometrial contractility and culminating in the initiation of labor.

The onset of preterm labor is associated with inflammation. Previous studies suggested that this is distinct from the inflammation observed during term labor. Our previous work on 44 genes differentially expressed in myometria in term labor demonstrated a different pattern of gene expression from that observed in preterm laboring and nonlaboring myometria. We found increased expression of inflammatory genes in preterm labor associated with chorioamnionitis, but in the absence of chorioamnionitis observed no difference in gene expression in preterm myometria regardless of laboring status, suggesting that preterm labor is associated with different myometrial genes or signals originating from outside the myometrium. Given that a small subset of genes were assessed, this study aimed to use RNA sequencing and bioinformatics to assess the myometrial transcriptome during preterm labor in the presence and absence of chorioamnionitis.This study aimed to comprehensively determine protein-coding transcriptomic differences between preterm nonlaboring and preterm laboring myometria with and without chorioamnionitis.Myometria were collected at cesarean delivery from preterm patients not in labor (n=16) and preterm patients in labor with chorioamnionitis (n=8) or without chorioamnionitis (n=6). Extracted RNA from myometrial tissue was prepared and sequenced using Illumina NovaSeq. Gene expression was quantified by mapping the sequence reads to the human reference genome (hg38). Differential gene expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were used to comprehensively interrogate transcriptomic differences and their associated biology.Differential gene expression analysis comparing preterm patients in labor with chorioamnionitis with preterm patients not in labor identified 931 differentially expressed genes, whereas comparing preterm patients in labor without chorioamnionitis with preterm patients not in labor identified no statistically significant gene expression changes. In contrast, gene set enrichment analysis and weighted gene coexpression network analysis demonstrated that preterm labor with and without chorioamnionitis was associated with enrichment of pathways involved in activation of the innate immune system and inflammation, and activation of G protein-coupled receptors. Key genes identified included chemotactic CYP4F3, CXCL8, DOCK2, and IRF1 in preterm labor with chorioamnionitis and CYP4F3, FCAR, CHUK, and IL13RA2 in preterm labor without chorioamnionitis. There was marked overlap in the pathways enriched in both preterm labor subtypes.Differential gene expression analysis demonstrated that myometria from preterm patients in labor without chorioamnionitis and preterm patients not in labor were transcriptionally similar, whereas the presence of chorioamnionitis was associated with marked gene changes. In contrast, comprehensive bioinformatic analysis indicated that preterm labor with or without chorioamnionitis was associated with innate immune activation. All causes of preterm labor were associated with activation of the innate immune system, but this was more marked in the presence of chorioamnionitis. These data suggest that anti-inflammatory therapy may be relevant in managing preterm labor of all etiologies.

The intracellular signaling pathways that regulate myometrial contractions can be targeted by drugs for tocolysis. The agents, 2-APB, glycyl-H-1152, and HC-067047, have been identified as inhibitors of uterine contractility and may have tocolytic potential. However, the contraction-blocking potency of these novel tocolytics was yet to be comprehensively assessed and compared to agents that have seen greater scrutiny, such as the phosphodiesterase inhibitors, aminophylline and rolipram, or the clinically used tocolytics, nifedipine and indomethacin. We determined the IC

Nonapeptides and their receptors regulate a diverse range of physiological processes. We assessed the contractile responsiveness of uteri from the squamate viviparous-oviparous species pair, Pseudemoia entrecasteauxii and Lampropholis guichenoti, as well as the bimodally reproductive species, Saiphos equalis, to arginine vasopressin (AVP). We assessed the resulting uterine contractility as a function of pregnancy status, species and parity mode. We also measured mRNA abundance for the nonapeptide receptor, oxytocin receptor (oxtr), in uteri from P. entrecasteauxii and L. guichenoti and compared expression across pregnancy status and parity mode. We found that pregnant uteri exhibited a significantly greater contractile response to AVP than non-pregnant uteri in all three lizard species studied. Cross-species comparisons revealed that uteri from viviparous P. entrecasteauxii were significantly more responsive to AVP than uteri from oviparous L. guichenoti during both pregnant and non-pregnant states. Conversely, for non-pregnant S. equalis, uteri from viviparous individuals were significantly less responsive to AVP than uteri from oviparous individuals, while during pregnancy, there was no difference in AVP contractile responsiveness. There was no difference in expression of oxtr between L. guichenoti and P. entrecasteauxii, or between pregnant and non-pregnant individuals within each species. We found no significant correlation between oxtr expression and AVP contractile responsiveness. These findings indicate that there are differences in nonapeptide signalling across parity mode and suggest that in these lizards, labour may be triggered either by an increase in plasma nonapeptide concentration, or by an increase in expression of a different nonapeptide receptor from the vasopressin-like receptor family.

Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.

The onset of the term human parturition involves myometrial gene expression changes to transform the uterus from a quiescent to a contractile phenotype. It is uncertain whether the same changes occur in the uterus during preterm labor.This study aimed to compare the myometrial gene expression between term and preterm labor and to determine whether the presence of acute clinical chorioamnionitis or twin gestation affects these signatures.Myometrial specimens were collected during cesarean delivery from the following 7 different groups of patients: term not in labor (n=31), term labor (n=13), preterm not in labor (n=21), preterm labor with acute clinical chorioamnionitis (n=6), preterm labor with no acute clinical chorioamnionitis (n=9), twin preterm not in labor (n=8), and twin preterm labor with no acute clinical chorioamnionitis (n=5). RNA was extracted, reverse transcribed and quantitative polymerase chain reactions were performed on 44 candidate genes (with evidence for differential expression in human term labor) using the Fluidigm platform. Computational analysis was performed using 2-class unpaired Wilcoxon tests and principal component analysis.Computational analysis revealed that gene expression in the preterm myometrium, irrespective of whether in labor or not in labor, clustered tightly and is clearly different from the term labor and term not-in-labor groups. This was true for both singleton and twin pregnancies. Principal component analysis showed that 57% of the variation was explained by 3 principal components. These 44 genes interact in themes of prostaglandin activity and inflammatory signaling known to be important during term labor, but are not a full representation of the myometrium transcriptional activity.The myometrial contractions associated with preterm labor are associated with a pattern of gene expression that is distinct from term labor. Therefore, preterm labor may be initiated by a different myometrial process or processes outside the myometrium.

This article presents an iterative examination of a grounded theory of collaboration in conjunction with social psychology literature. The resulting PILAR (Prospects, Involved, Liked, Agency, Respect) model of collaboration encapsulates over 30 social and group psychology (SGP) theories, including social identity theory, social network analysis, and psychological safety. Selected works of the early 20th-century scholars Lewin, Moreno, Simmel, and Foucault resonate with the PILAR model. We considered that, in constructing a generalized model of collaboration made possible by the availability of modern SGP theory, PILAR may represent advancement toward accomplishing these early scholars’ original intent. To validate PILAR, we proposed an empirical investigation for its consistency with organizational psychology, positive psychology, and appreciative inquiry, and for testing whether learning PILAR may improve collaboration skills for individuals lacking empathy.

Undergraduate group projects are intended to improve the ability of students to collaborate, a skill considered critical by many employers. If such groups become unviable, for instance due to interpersonal conflict or imbalanced effort, intervention by the lecturer may be required to alleviate this problem. The article proposes Collaboration Viability (CoVi) as a construct to indicate the degree to which a team is failing. Peer assessment instruments are designed to establish the relative contributions of team members, but are rarely used to measure emergent group-level properties, such as CoVi. Averaged per-group peer assessment ratings from 458 undergraduate engineers (forming 72 teams) demonstrated an overall weak, but statistically significant, correlation between CoVi and their group mark (r = 0.25, p = 0.04), adjusting for academic ability. A Self and Peer Assessment Resource Kit (SPARKPLUS) online instrument was used that comprised 13 questions, categorised according to whether they related...

The establishment and maintenance of pregnancy rely on a number of hormones, including progesterone and human chorionic gonadotrophin. Throughout gestation, pregnancy is under a progesterone block, which maintains uterine quiescence to permit fetal growth and maturation. As a woman approaches term, there is a functional progesterone withdrawal and functional estrogen activation that upregulate contraction-associated proteins. These hormonal changes appear to coincide with inflammatory changes that further encourage the transformation of the uterus from a resting to a contractile phenotype. During parturition, the release of oxytocin and prostaglandins enhances contractions, and increasing gap junctions allows the synchronization of myocyte activity and rhythmic contractions of the whole uterus. A number of factors can initiate preterm labor, including infection, sterile inflammation, and blood and cellular senescence.

Metastases in thyroid cancer are associated with aggressive disease and increased patient morbidity, but the factors driving metastatic progression are unclear. The precursor for nerve growth factor (proNGF) is increased in primary thyroid cancers, but its expression or significance in metastases is not known. In this study, we analysed the expression of proNGF in a retrospective cohort of thyroid cancer lymph node metastases (n = 56), linked with corresponding primary tumours, by automated immunohistochemistry and digital quantification. Potential associations of proNGF immunostaining with clinical and pathological parameters were investigated. ProNGF staining intensity (defined by the median h-score) was significantly higher in lymph node metastases (h-score 94, interquartile range (IQR) 50&ndash, 147) than in corresponding primary tumours (57, IQR 42&ndash, 84) (p = 0.002). There was a correlation between proNGF expression in primary tumours and corresponding metastases, where there was a 0.68 (95% CI 0 to 1.2) increase in metastatic tumour h-score for each unit increase in the primary tumour h-score. However, larger tumours (both primary and metastatic) had lower proNGF expression. In a multivariate model, proNGF expression in nodal metastases was negatively correlated with lateral neck disease and being male. In conclusion, ProNGF is expressed in locoregional metastases of thyroid cancer and is higher in lymph node metastases than in primary tumours, but is not associated with high-risk clinical features.

Background Nerves and neurotrophic growth factors are emerging promoters of cancer growth. The precursor for Nerve Growth Factor (proNGF) is overexpressed in thyroid cancer, but its potential role as a clinical biomarker has not been reported. Here we have examined the value of proNGF as a serum and biopsy-rinse biomarker for thyroid cancer diagnosis. Methods Patients presenting for thyroid surgery or biopsy were enrolled in separate cohorts examining serum (n = 204, including 46 cases of thyroid cancer) and biopsy-rinse specimens (n = 188, including 26 cases of thyroid cancer). ProNGF levels in clinical samples were analysed by ELISA. Univariate and multivariate statistical analyses were used to compare proNGF levels with malignancy status and clinicopathological parameters. Results ProNGF was not detected in the majority of serum samples (176/204, 86%) and the detection of proNGF was not associated with thyroid cancer diagnosis. In the few cases where proNGF was detected in the serum, thyroidectomy did not affect proNGF concentration, demonstrating that the thyroid was not the source of serum proNGF. Intriguingly, an association between hyperthyroidism and serum proNGF was observed (OR 3.3, 95% CI 1.6–8.7 p = 0.02). In biopsy-rinse, proNGF was detected in 73/188 (39%) cases, with no association between proNGF and thyroid cancer. However, a significant positive association between follicular lesions and biopsy-rinse proNGF was found (OR 3.3, 95% CI 1.2–8.7, p = 0.02). Conclusions ProNGF levels in serum and biopsy-rinse are not increased in thyroid cancer and therefore proNGF is not a clinical biomarker for this condition.

New findings What is the topic of this review? The timing of birth is an important determinant of future health and well-being. This review examines the role of endogenous retroviruses as upstream regulators of key biological functions of the placenta, including cell-cell fusion, modulation of the maternal immune system, and the production of key pregnancy hormones. What advances does it highlight? Endogenous retroviruses are an obligate requirement for successful human reproduction. The products of retroviral elements, incorporated into the germline millions of years ago, have been co-opted to serve vital biological roles within the placenta that ultimately dictate the length of human pregnancy and therefore well-being trajectories. Abstract Gestational length at the time of birth is an important determinant of future health and well-being, yet the physiological regulation of the onset of labour in humans remains obscure. The evolution of egg formation and internal fertilisation in amniotes required a mechanism to suppress the contractile activity of the oviduct that is provided by progesterone. Delivery of the egg is then associated with the withdrawal of progesterone and a return of contractile activity to the reproductive tract. In mammals, the process of pregnancy is complicated further by the need to protect the fetus from potential attack by the maternal immune system. There is increasing evidence that retroviruses incorporated into the mammalian germline in the evolutionary past play a key role in suppressing the maternal immune reaction to the developing conceptus, organising the development of the placenta and perhaps, in humans, modulating the action of progesterone, determining gestational length and the onset of labour. It seems that the presence of an endogenous retrovirus is an obligate requirement for human reproduction.

Background Ex situ analyses of human myometrial tissue has been used to investigate the regulation of uterine quiescence and transition to a contractile phenotype. Following concerns about the validity of cultured primary cells, we examined whether myometrial tissue undergoes culture-induced changes ex situ that may affect the validity of in vitro models. Objectives To determine whether human myometrial tissue undergoes culture-induced changes ex situ in Estrogen receptor 1 (ESR1), Prostaglandin-endoperoxide synthase 2 (PTGS2) and Oxytocin receptor (OXTR) expression. Additionally, to determine whether culture conditions approaching the in vivo environment influence the expression of these key genes. Methods Term non-laboring human myometrial tissues were cultured in the presence of specific treatments, including; serum supplementation, progesterone and estrogen, cAMP, PMA, stretch or NF-κB inhibitors. ESR1, PTGS2 and OXTR mRNA abundance after 48 h culture was determined using quantitative RT-PCR. Results Myometrial tissue in culture exhibited culture-induced up-regulation of ESR1 and PTGS2 and down-regulation of OXTR mRNA expression. Progesterone prevented culture-induced increase in ESR1 expression. Estrogen further up-regulated PTGS2 expression. Stretch had no direct effect, but blocked the effects of progesterone and estrogen on ESR1 and PTGS2 expression. cAMP had no effect whereas PMA further up-regulated PTGS2 expression and prevented decline of OXTR expression. Conclusion Human myometrial tissue in culture undergoes culture-induced gene expression changes consistent with transition toward a laboring phenotype. Changes in ESR1, PTGS2 and OXTR expression could not be controlled simultaneously. Until optimal culture conditions are determined, results of in vitro experiments with myometrial tissues should be interpreted with caution.

Densitometry data generated for Western blots are commonly used to compare protein abundance between samples. In the last decade, it has become apparent that assumptions underpinning these comparisons are often violated in studies reporting Western blot data in the literature. These violations can lead to erroneous interpretations of data and may contribute to poor reproducibility of research. We assessed the reliability of Western blot data obtained to study human myometrial tissue proteins. We ran dilution series of protein lysates to explore the linearity of densitometry data. Proteins analysed included αSMA, HSP27, ERK1/2, and GAPDH. While ideal densitometry data are directly proportional to protein abundance, our data confirm that densitometry data often deviate from this ideal, in which case they can fit nonproportional linear or hyperbolic mathematical models and can reach saturation. Nonlinear densitometry data were observed when Western blots were detected using infrared fluorescence or chemiluminescence, and under different SDS-PAGE conditions. We confirm that ghosting artefacts associated with overabundance of proteins of interest in Western blots can skew findings. We also confirm that when data to be normalised are not directly proportional to protein abundance, it is a mistake to use the normalisation technique of dividing densitometry data from the protein-of-interest with densitometry data from loading control protein(s), as this can cause the normalised data to be unusable for making comparisons. Using spiked proteins in a way that allowed us to control the total protein amount per lane, while only changing the amount of spiked proteins, we confirm that nonlinearity and saturation of densitometry data, and errors introduced from normalisation processes, can occur in routine assays that compare equal amounts of lysate. These findings apply to all Western blot studies, and we highlight quality control checks that should be performed to make Western blot data more quantitative.

The PILAR (prospects, involved, liked, agency, respect) model provides a dynamical systems perspective on collaboration. Two studies are performed using peer assessment data, both testing empirical support for the five Pillars that constitute members’ perceptions of collaboration viability (CoVi). The first study analyses peer assessment data collected online from 458 first-year engineering students (404 males; 54 females). A nine-item instrument was inherited from past year’s usage in the course, expanded with four additional items to elaborate upon the agency and liked Pillars. Exploratory factor analysis was conducted on student responses to test whether they thematically aligned to constructs consistent with the five Pillars. As anticipated, twelve of the thirteen items grouped into five components, each aligned with a Pillar, providing empirical evidence that the five Pillars represent perceptions of collaboration. The second study replicated the first study using a retrospective analysis of 87 items included in the Comprehensive Assessment of Team Member Effectiveness (CATME) peer assessment tool. The associated factor analyses resulted in five components and conceptual alignment of these components with Pillars was evident for three of five CATME components. We recommend a peer assessment instrument based upon PILAR as potentially more parsimonious and reliable than an extensive list of behaviours, such as employed by CATME. We also recommend including items that target inter-rater bias, which is aligned with the liked Pillar, that instruments such as CATME exclude.

The PILAR model provides a dynamical systems perspective on collaboration. Two studies are performed using peer assessment data, both testing empirical support for the five Pillars (prospects, involved, liked, agency, respect) that constitute member’s perceptions of collaboration viability. The first study analyses peer-assessment data collected online from 458 first-year engineering students (404 males; 54 females). A nine-item instrument was inherited from past year’s usage in the course, expanded with four additional items to elaborate upon the agency and liked Pillars. Exploratory factor analysis was conducted on student responses to test whether they thematically aligned to constructs consistent with the five Pillars. As anticipated, twelve of the thirteen items grouped into five components, each aligned with a Pillar, providing empirical evidence that the five Pillars represent perceptions of collaboration. The second study replicated the first study using a retrospective analysis of 87 items included in the Comprehensive Assessment of Team Member Effectiveness (CATME) peer-assessment tool. The associated factor analyses resulted in five components and conceptual alignment of these components with Pillars was evident for three of five CATME components. We recommend a peer-assessment instrument based upon PILAR as potentially more parsimonious and reliable than an extensive list of behaviours, such as employed by CATME. We also recommend including items that target inter-rater bias, which is aligned with the liked Pillar, that instruments such as CATME exclude.

We present a hypothesis for a mechanism involving self-organization of small functional units that leads to organ-level synchronization of uterine contractions in human labor. This view is in contrast to the long-held presumption that the synchronized behavior of the uterus is subject to well-defined internal organization (as is found in the heart) that exists prior to the onset of labor. The contractile units of the uterus are myocytes, which contract in response to both mechanical stretch and electrical stimulation. Throughout pregnancy progesterone maintains quiescence by suppression of “contraction-associated proteins” (CAPs). At the end of pregnancy a functional withdrawal of progesterone and an increasingly estrogenic environment leads to an increase in the production of CAPs. One CAP of particular importance is connexin 43, which creates gap junctions between the myocytes that cause them to become electrically coupled. The electrical connectivity between myocytes, combined with an increase in intrauterine pressure at the end of pregnancy shifts the uterus towards an increasingly unstable critical point, characterized by irregular, uncoordinated contractions. We propose that synchronous, coordinated contractions emerge from this critical point through a process of self-organization, and that the search for a uterine pacemaker has been unfruitful for the sole reason that it is non-existent.

The human uterus has no pacemaker or motor innervation, yet develops rhythmic, powerful contractions that increase intrauterine pressure to dilate the cervix and force the fetus through the pelvis. To achieve the synchronous contractions required for labor, the muscle cells of the uterus act as independent oscillators that become increasingly coupled by gap junctions toward the end of pregnancy. The oscillations are facilitated by changes in resting membrane potential that occur as pregnancy progresses. Reductions of potassium channels in the myocyte membranes in late pregnancy prolong myocyte action potentials, further facilitating transmission of signals and recruitment of neighboring myocytes. Late in pregnancy prostaglandin production increases leading to increased myocyte excitability. Also late in pregnancy myocyte actin polymerizes allowing actin-myosin interactions that generate force, following myocyte depolarization, calcium entry, and activation of myosin kinase. Labor occurs as a consequence of the combination of increased myocyte to myocyte connectivity, increased depolarizations that last longer, and activated intracellular contractile machinery. During labor the synchronous contractions of muscle cells raise intrauterine pressure to dilate the cervix in a process distinct from peristalsis. The synchronous contractions occur in a progressively larger region of the uterine wall. As the size of the region increases with increasing connectivity, the contraction of that larger area leads to an increase in intrauterine pressure. The resulting increased wall tension causes myocyte depolarization in other parts of the uterus, generating widespread synchronous activity and increased force as more linked regions are recruited into the contraction. The emergent behavior of the uterus has parallels in the behavior of crowds at soccer matches that sing together without a conductor. This contrasts with the behavior of the heart where sequential contractions are regulated by a pacemaker in a similar way to the actions of a conductor and an orchestra.

This article assumes that collaborators who adopt a positive-sum, prosocial perspective can build trust-based relationships, which is equivalent to collaborative ability (CA). To improve a collaborator’s CA, we anticipated that content based upon a model of positive-sum collaboration, founded upon ancestral behaviours presented as social norms, might alter a zero-sum, proself, collaborator’s perspective. However, we also postulated that learner’s willingness to engage in positive-sum content may rely on pre-existing prosociality. Intervention participant’s prosociality was assessed via self-assessment of their emotional intelligence (EQ), quality of life (QoL), and goal orientation (GO). Learner’s engagement in online content was assessed by the three stage reached: examine website front matter; examine website content; learn website content. Tukey’s multiple comparison showed a statistically significant difference between stages one and three, in the mean of respondent’s self-assessed QoL. This suggests that participants who wished to learn content had, on average, higher quality of life, and potentially therefore greater prosociality. In general, these findings support a claim that any intervention designed to increase individual prosociality may need to consider the target population’s reticence to engage.

Background: Ex situ analyses of human myometrial tissue has been used to investigate the regulation of uterine quiescence and transition to a contractile phenotype. Following concerns about the validity of cultured primary cells, we examined whether myometrial tissue undergoes culture-induced changes ex situ that may affect the validity of in vitro models. Objectives: To determine whether human myometrial tissue undergoes culture-induced changes ex situ in Estrogen receptor 1 (ESR1), Prostaglandin-endoperoxide synthase 2 (PTGS2) and Oxytocin receptor (OXTR) expression. Additionally, to determine whether culture conditions approaching the in vivo environment influence the expression of these key genes. Methods: Term non-laboring human myometrial tissues were cultured in the presence of specific treatments, including; serum supplementation, progesterone and estrogen, cAMP, PMA, stretch or NF-κB inhibitors. ESR1, PTGS2 and OXTR mRNA abundance after 48 h culture was determined using quantitative RT-PCR. Results: Myometrial tissue in culture exhibited culture-induced up-regulation of ESR1 and PTGS2 and down-regulation of OXTR mRNA expression. Progesterone prevented culture-induced increase in ESR1 expression. Estrogen further up-regulated PTGS2 expression. Stretch had no direct effect, but blocked the effects of progesterone and estrogen on ESR1 and PTGS2 expression. cAMP had no effect whereas PMA further up-regulated PTGS2 expression and prevented decline of OXTR expression. Conclusion: Human myometrial tissue in culture undergoes culture-induced gene expression changes consistent with transition toward a laboring phenotype. Changes in ESR1, PTGS2 and OXTR expression could not be controlled simultaneously. Until optimal culture conditions are determined, results of in vitro experiments with myometrial tissues should be interpreted with caution.

Successful pregnancy necessitates that the uterus is maintained in a relaxed, quiescent state for the majority of pregnancy, before being transformed to a contractile and excitable phenotype to facilitate parturition. There is now a substantial body of evidence highlighting key upstream regulators involved in this transformation. Despite our rapidly advancing knowledge of myometrial biology, the exact mechanisms that regulate parturition are not yet understood. Further work is necessary to define the complex interactions that form the key regulatory pathways controlling uterine quiescence, contractility, and the transition between the two states. Furthermore, new evidence continues to emerge implicating novel mechanisms that regulate uterine activity during normal and preterm birth. This review examines current evidence pertaining to key upstream regulators that have been implicated in human parturition over the past decades and surveys recent findings that are yet to be integrated into the paradigm of uterine regulation.

Positive-sum behaviour arises when people expect a benefit from cooperation. This article argues that positive-sum behaviours give rise to a fairer, more civilized society; however, adoption of these behaviours is impeded by their complexity. For example, others’ actions may seem unpredictable, while individual benefit may seem intangible. Consequently, adoption of positive-sum behaviours could be encouraged by explicit instructions. This article proposes guidelines and outcomes for healthy collaboration, which is a positive-sum behaviour.

Background The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Objective Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. Study Design We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor–targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor–targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Results Oxytocin receptor–targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor–targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor–targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor–targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. Conclusion Our results demonstrate that oxytocin receptor–targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus.

Prostaglandins are key components of the parturition cascade; however, the mechanisms that regulate prostaglandin concentrations in the uterus during pregnancy are largely unknown. The purpose of this study was to determine the intrauterine expression of the chief prostaglandin-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase (PGDH), during gestation and labor in the guinea pig, an animal model in which the endocrine control of pregnancy and parturition is analogous to that of women. PGDH messenger RNA (mRNA) abundance decreased significantly in the visceral yolk sac membrane (VYS, the anatomical equivalent of the human chorion laeve) and the amnion throughout the last third of pregnancy. PGDH protein was robustly expressed in the VYS epithelium and mesoderm, correlated strongly with PGDH mRNA levels and exhibited a nadir at term prior to labor onset. PGDH protein was not detected in the amnion. PGDH mRNA and protein levels in the placenta and myoendometrium were variable throughout late gestation. In the placenta, PGDH protein was concentrated in the parietal yolk sac membrane (PYS) lining the placental surface and in placental blood vessels. We observed strong expression of PGDH protein in the endometrial epithelium with comparably little expression in the myometrium. These data indicate that metabolic inactivation of prostaglandins in the pregnant guinea pig uterus takes place in the VYS, PYS, and endometrium. Decreased PGDH expression in the fetal membranes may contribute to the increase in intrauterine prostaglandin concentrations at term, stimulating the onset of labor.

The objective of this study is to describe the fetal phenotype in utero and its associations with maternal pre-pregnancy weight and gestational weight gain. This prospective longitudinal cohort included 179 Australian women with singleton pregnancies. Serial ultrasound measurements were performed at 19, 25, 30 and 36 (±1) weeks gestation and maternal anthropometry were collected concurrently. The ultrasound scans included the standard fetal biometry of head circumference, biparietal diameter, abdominal circumference, and femur length, and body composition at the abdomen and mid-thigh, including fat and lean mass cross-sectional areas. Maternal gestational weight gain was compared to current clinical guidelines. The participants had an average of 3.7 ± 0.8 scans and birth data were available for 165 neonates. Fifty four per cent of the cohort gained weight in excess of current recommendations, according to pre-pregnancy body mass index (BMI). Maternal gestational weight positively predicted fetal abdominal circumference (P 0.029) and lean abdominal mass area (P 0.046) in linear mixed model regression analysis, adjusted for known and potential confounders. At any pre-pregnancy BMI gaining weight above the current recommendations resulted in a larger fetus according to standard biometry, because of significantly larger lean muscle mass at the abdomen (P 0.024) and not due to an increase in fat mass (P 0.463). We have demonstrated the importance of maternal weight gain, independent of pre-pregnancy BMI, to support the growth of a large but lean fetus. Prenatal counselling should focus on achieving a healthy BMI prior to conception so that gestational weight gain restrictions can be minimised.

Estrogens are key mediators of increased uterine contractility at labor. We sought to determine whether membrane-associated estrogen receptors, such as the recently described seven-transmembrane receptor G protein-coupled receptor 30 (GPR30), mediated some of this effect. Using human myometrium obtained at term cesarean section before or after the onset of labor, we demonstrated the presence of GPR30 mRNA and protein using quantitative RT-PCR and Western blotting. GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. Using the specific estrogen membrane receptor agonist G-1 and myometrial explants, we showed that membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27. Using myometrial strips incubated with G-1 or vehicle we demonstrated that estrogen membrane receptor activation increased the myometrial contractile response to oxytocin. These data suggest that activation of the plasma membrane estrogen receptor GPR30 likely participates in the physiology of the human myometrium during pregnancy and identifies it as a potential target to modify uterine activity.

Progesterone plays a crucial role in maintaining pregnancy by promoting myometrial quiescence. The withdrawal of progesterone action signals the end of pregnancy and, in most mammalian species, this is achieved by a rapid fall in progesterone concentrations. However, in humans circulating progesterone concentrations remain high up to and during labour. Efforts to understand this phenomenon led to the ‘functional progesterone withdrawal’ hypothesis, whereby the pro-gestation actions of progesterone are withdrawn, despite circulating concentrations remaining elevated. The exact mechanism of functional progesterone withdrawal is still unclear and in recent years has been the focus of intense research. Emerging evidence now indicates that epigenetic regulation of progesterone receptor isoform expression may be the crucial mechanism by which functional progesterone withdrawal is achieved, effectively precipitating human labour despite high concentrations of circulating progesterone. This review examines current evidence that epigenetic mechanisms play a role in determining whether the pro-gestation or pro-contractile isoform of the progesterone receptor is expressed in the pregnant human uterus. We explore the mechanism by which these epigenetic modifications are achieved and, importantly, how these underlying epigenetic mechanisms are influenced by known regulators of uterine physiology, such as prostaglandins and oestrogens, in order to phenotypically transform the pregnant uterus and initiate labour.

Mammalian spermatozoa must become `capacitated' in the female reproductive tract before they gain the ability to fertilize the oocyte. The attainment of a capacitated state has been correlated with a number of biochemical changes, the most notable of which is a dramatic increase in the tyrosine phosphorylation status of these cells. Despite its biological importance, the mechanisms responsible for initiating this tyrosine phosphorylation cascade in vivo are unknown. Here, we report that this signalling pathway can be elicited in a rapid, dose-dependent and lectin-specific manner by wheat germ agglutinin (WGA), but none of 18 other lectins assessed. This response was abrogated by prior enzymatic cleavage of either sialic acid or GlcNAc residues from the sperm surface and by treatment with a range of pharmacological inhibitors directed against protein kinase A, protein tyrosine kinases and intermediates including Src. Proteomic analysis of the WGA-binding sites on the sperm surface identified the putative cognate receptor as platelet cell adhesion molecule 1 (PECAM-1/CD31). This conclusion was supported by the following evidence: (i) anti-PECAM-1 antibodies identified a molecule of the correct molecular mass in human spermatozoa, (ii) PECAM-1 could be isolated from a pool of sperm surface proteins using WGA immobilized on a solid phase support, (iii) PECAM-1 and WGA co-localized to the sperm surface and (iv) anti-PECAM-1 antibodies could completely block the ability of WGA to stimulate tyrosine phosphorylation in these cells. Collectively, these data provide the first evidence that a receptor-mediated signal transduction pathway triggers human sperm capacitation and identifies PECAM-1 as the probable initiator of this second messenger cascade.

Employers rarely utilise their employees’ capacity to assess the collegiality and productivity of their own work unit, yet they are determinants of employee retention and profitability. One reason is the lack of a reliable, valid survey instrument to measure collaboration viability (CoVi), which we postulate is the construct that employees use to implicitly assess their work unit. Inherent weaknesses of own-perception and peer-assessment instruments prevent them reliably measuring CoVi. A novel method overcoming respective deficiencies by combining the strengths of both approaches is proposed that we term peer’s-perception. It is contended that such an instrument may be improved through formulation in accordance with a universal model of collaboration. The model chosen is PILAR as it encapsulates a variety of social and organisational psychology theories. Prospects, involved, liked, agency and respect constitute five Pillars of collaboration (Heslop, Bailey, et al., 2017). Based on this review, we propose a peer’s-perception instrument (Pillar-PP) and that this instrument be formally evaluated.

Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action potential that also possesses an initial spike followed by prolonged depolarization. Here we show that hERG channel proteins (α-conducting and β-inhibitory subunits) and hERG currents exist in isolated patch-clamped human myometrial cells. We show that hERG channel activity suppresses contraction amplitude and duration before labour, thereby facilitating quiescence. During established labour, expression of β-inhibitory protein is markedly enhanced, resulting in reduced hERG activity that is associated with an increased duration of uterine action potentials and contractions. Thus, changes in hERG channel activity contribute to electrophysiological mechanisms that produce contractions during labour. We also demonstrate that this system fails in women with elevated BMI, who have enhanced hERG activity as a result of low β-inhibitory protein expression, which likely contributes to the weak contractions and poor labour outcomes observed in many obese women necessitating caesarean delivery.

Throughout their evolution, animals have developed mechanisms which protect them against parasites or infections by detecting and destroying foreign biological material within their own bodies. These mechanisms for excluding “non-self” biological materials whilst at the same time maintaining the integrity of the “self” have evolved for hundreds of millions of years into a highly complex body system, the immune system (Bainbridge, 2000). Any disbalance or alteration of the mechanisms maintaining the dynamic equilibrium between the “self” and “non-self” recognition could translate into a pathological state (or condition) like autoimmune disease at one end of the scale or immunodeficiency at the other.

Human myometrium develops phasic contractions during labor. Phosphorylation of caldesmon (h-CaD) and extracellular signal-regulated kinase 1/2 (ERK 1/2) has been implicated in development of these contractions, however the phospho-regulation of these proteins is yet to be examined during periods of both contraction and relaxation. We hypothesized that protein phosphorylation events are implicated in the phasic nature of myometrial contractions, and aimed to examine h-CaD and ERK 1/2 phosphorylation in myometrium snap frozen at specific stages, including; (1) prior to onset of contractions, (2) at peak contraction and (3) during relaxation. We aimed to compare h-CaD and ERK 1/2 phosphorylation in vitro against results from in vivo studies that compared not-in-labor (NIL) and laboring (L) myometrium. Comparison of NIL (n = 8) and L (n = 8) myometrium revealed a 2-fold increase in h-CaD phosphorylation (ser-789; P = 0.012) during onset of labor in vivo, and was associated with significantly up-regulated ERK2 expression (P = 0.022), however no change in ERK2 phosphorylation was observed (P = 0.475). During in vitro studies (n = 5), transition from non-contracting tissue to tissue at peak contraction was associated with increased phosphorylation of both h-CaD and ERK 1/2. Furthermore, tissue preserved at relaxation phase exhibited diminished levels of h-CaD and ERK 1/2 phosphorylation compared to tissue preserved at peak contraction, thereby producing a phasic phosphorylation profile for h-CaD and ERK 1/2. h-CaD and ERK 1/2 are phosphorylated during myometrial contractions, however their phospho-regulation is dynamic, in that h-CaD and ERK 1/2 are phosphorylated and dephosphorylated in phase with contraction and relaxation respectively. Comparisons of NIL and L tissue are at risk of failing to detect these changes, as L samples are not necessarily preserved in the midst of an active contraction.

While the molecular basis of sperm-oolemma interaction is of considerable biological significance, the protein(s) involved in this process are yet to be identified. In particular, the point at which developing mammalian oocytes acquire the capacity to bind to, and fuse with, capacitated, acrosome-reacted spermatozoa is yet to be clearly defined. Previous reports suggested that mature metaphase II (MII) mouse oocytes possessed the capacity to bind and fuse with spermatozoa while, in contrast, immature germinal vesicle (GV) phase oocytes did not. In this study oocytes were cultured in α-MEM containing 5% fetal calf serum. For GV oocytes, α-MEM was also supplemented with 1 μM Milrinone to prevent GV breakdown. Standard murine IVF was performed in 100 μL α-MEM media droplets containing 10 to 15 oocytes and 2.5×104 capacitated spermatozoa. These studies found that no significant difference existed in the levels of sperm-oocyte binding or fusion between freshly isolated GV oocytes (14 sperm/egg bound, 7 sperm/egg fused), cultured arrested GV oocytes (16 sperm/egg bound, 7 sperm/egg fused) or cultured MII phase oocytes (17 sperm/egg bound, 8 sperm/egg fused). Interestingly, upon fusion MII oocytes commenced sperm nuclear decondensation whereas arrested GV oocytes did not. Comparison of biotinylated oolemmal surface proteins revealed markedly different protein profiles between the GV oolemma and the MII oolemma. The MII oolemma revealed a multitude of proteins ranging in size from approximately 20 to 200 kDa, whilst the GV oolemma revealed only six middle range molecular weight proteins ranging from approximately 50 to 90 kDa. The protein(s) implicated in sperm-egg interaction must be one or more of those proteins found in both oocyte populations. Comparison of these two profiles has greatly reduced the number of possible candidates, allowing possible identification of the proposed GPI-linked sperm receptor.

Acquisition of the ability to fertilise the egg is conferred on mammalian spermatozoa during their transit through the female reproductive tract. This process, termed capacitation, represents the culmination of a series of complex physiological and biochemical changes. Among the correlates of this process, the phosphorylation of tyrosine residues on multiple sperm proteins appears to be critically important for subsequent sperm-egg interaction. In this study, we report the novel finding that the binding of the lectin, wheat germ agglutinin (WGA) to human spermatozoa elicits a dose-dependent increase in tyrosine phosphorylation. Interestingly, this response appears to be specific to the WGA lectin, which possesses dual binding specificity for terminal N-acetylglucosamine (GlcNAc) and sialic acid residues. Other lectins, which possess binding specificities for either GlcNAc or sialic acid alone, were not capable of eliciting a similar response. In addition, this response appears to display some species specificity given that we were unable to elicit a similar effect in mouse spermatozoa. The mechanism through which WGA elicits an increase in tyrosine phosphorylation and the physiological significance of the process remains to be elucidated. However, preliminary evidence has led to the hypothesis that the lectin mimics a protein(s) present within the female reproductive tract. The binding of such a protein to human spermatozoa presumably induces an aggregation of a specific receptor(s) on the surface of these cells. This aggregation, in turn, activates a cyclic adenosine monophosphate (cAMP) dependent signal transduction cascade that involves Src family kinases. Future work will be directed to elucidating the identity of the sperm receptor(s) and the precise nature of the signal transduction pathway involved.