CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids.

The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis. Aberrant HH signaling can lead to congenital malformations and diseases including cancer. Although cholesterol and several oxysterol lipids have been shown to play crucial roles in HH activation, the molecular mechanisms governing their regulation remain unresolved. Here, we identify Canopy4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that modulates levels of membrane sterol lipids. Cnpy4-/- embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway in vitro and elevates membrane levels of accessible sterol lipids, such as cholesterol, an endogenous ligand involved in HH activation. Our data demonstrate that CNPY4 is a negative regulator that fine-tunes HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition.

Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.

Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.

Dealing with loss in the face of disasters and crises: Integrating interpersonal theories of couple adaptation and functioning.

The COVID-19 pandemic has highlighted the significant and varied losses that couples can experience during times of global and regional disasters and crises. What factors determine how couples navigate their close relationships during times of loss? In this paper, we elaborate and extend on one of the most influential frameworks in relationship science-the Vulnerability Stress Adaptation Model (VSAM, Karney and Bradbury, 1995)-to enhance the model's power to explain relationships during loss-themed disasters/crises. We do so by elaborating on attachment theory and integrating interdependence theory (emphasizing partner similarities and differences). Our elaboration and extension to the VSAM provides a comprehensive framework to guide future research and inform practice and policy in supporting relationships during and beyond loss-themed disasters/crises.

Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization.

Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

Commitment strength versus commitment bolstering: Uncertainty undermines and promotes relationship success.

Little research has examined factors that might weaken or strengthen commitment effects on relationship outcomes. The current research integrates attitude strength and investment model perspectives to identify uncertainty as a new moderator of commitment's predictive ability. Consistent with an attitude strength perspective, having doubt associated with commitment undermines commitment's predictive power. However, uncertainty can motivate uncertainty reduction achieved by acting in line with commitment. Therefore, uncertainty amplifies commitment effects on relationship maintenance, but only when behaviors are perceived to have implications for uncertainty. Across studies, certainty was found to moderate the link between commitment and relationship outcomes. Whether uncertainty weakened or strengthened commitment's predictive power depends on an individual's focus (implication-focused or not) when making relationship judgments.

Seeking and Ensuring Interdependence: Desiring Commitment and the Strategic Initiation and Maintenance of Close Relationships.

The current research offers and examines the concept of commitment desirability, defined as the subjective desire to be involved in a committed romantic relationship at a given time. In pursuing their desire for a committed romance, how do individuals high in commitment desirability strategically ensure success? We suggest that high perceived partner commitment is sought by individuals who themselves desire to be involved in a committed relationship. In three studies involving individuals both currently involved and not involved in a relationship, we found support for the hypothesized interactive effect of commitment desirability and perceived partner commitment, such that greater commitment desirability was associated with more positive relationship outcomes, especially when partners were perceived to be high in commitment. The present research suggests that commitment desirability is a meaningful predictor of relationship attitudes and behaviors. Implications for understanding relationship commitment as well as future research directions are discussed.

The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region.

The homeodomain-interacting protein kinase (HIPK) family is comprised of four nuclear protein kinases, HIPK1-4. HIPK proteins phosphorylate a diverse range of transcription factors involved in cell proliferation, differentiation, and apoptosis. HIPK2, thus far the best-characterized member of this largely understudied family of protein kinases, plays a role in the activation of p53 in response to DNA damage. Despite this tumor-suppressor function, HIPK2 is also found overexpressed in several cancers, and its hyperactivation causes chronic fibrosis. There are currently no structures of HIPK2 or of any other HIPK kinase. Here, we report the crystal structure of HIPK2's kinase domain bound to CX-4945, a casein kinase 2α (CK2α) inhibitor currently in clinical trials against several cancers. The structure, determined at 2.2 Å resolution, revealed that CX-4945 engages the HIPK2 active site in a hybrid binding mode between that seen in structures of CK2α and Pim1 kinases. The HIPK2 kinase domain crystallized in the active conformation, which was stabilized by phosphorylation of the activation loop. We noted that the overall kinase domain fold of HIPK2 closely resembles that of evolutionarily related dual-specificity tyrosine-regulated kinases (DYRKs). Most significant structural differences between HIPK2 and DYRKs included an absence of the regulatory N-terminal domain and a unique conformation of the CMGC-insert region and of a newly defined insert segment in the αC-ß4 loop. This first crystal structure of HIPK2 paves the way for characterizing the understudied members of the HIPK family and for developing HIPK2-directed therapies for managing cancer and fibrosis.

Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.

Commitment Readiness and Relationship Formation.

The concept of being ready for a relationship is pervasive in popular culture, but theoretical and empirical research on readiness is lacking. We offer a conceptualization of commitment readiness and provide some of the first empirical work examining readiness among single individuals-specifically how this construct shapes various aspects of relationship formation. Using data from five independent samples of individuals not involved in romantic relationships, we first establish that commitment readiness is associated with more interest in developing a close romantic relationship (Studies 1a, 1b, 2) and with active pursuit of relationship initiation (Study 2). We then test whether readiness among single individuals longitudinally predicts both the likelihood of later entering a relationship and, ultimately, how committed individuals are to a future relationship (Studies 3a, 3b, 3c). Implications of commitment readiness specifically, and perceived personal timing more generally, for the social psychology of relationships are discussed.

Contraceptive Method Choice Among Young Adults: Influence of Individual and Relationship Factors.

Because decisions related to contraceptive behavior are often made by young adults in the context of specific relationships, the relational context likely influences use of contraceptives. Data presented here are from in-person structured interviews with 536 Black, Hispanic, and White young adults from East Los Angeles, California. We collected partner-specific relational and contraceptive data on all sexual partnerships for each individual, on four occasions, over one year. Using three-level multinomial logistic regression models, we examined individual and relationship factors predictive of contraceptive use. Results indicated that both individual and relationship factors predicted contraceptive use, but factors varied by method. Participants reporting greater perceived partner exclusivity and relationship commitment were more likely to use hormonal/long-acting methods only or a less effective method/no method versus condoms only. Those with greater participation in sexual decision making were more likely to use any method over a less effective method/no method and were more likely to use condoms only or dual methods versus a hormonal/long-acting method only. In addition, for women only, those who reported greater relationship commitment were more likely to use hormonal/long-acting methods or a less effective method/no method versus a dual method. In summary, interactive relationship qualities and dynamics (commitment and sexual decision making) significantly predicted contraceptive use.

The ebbs and flows of attachment: Within-person variation in attachment undermine secure individuals' relationship wellbeing across time.

Although attachment security is relatively stable over time, individuals do experience significant within-person variation in their attachment security across time. No research to date, however, has assessed the relational consequences of within-person variation (fluctuations) in attachment security toward a specific attachment figure. Study 1 (N = 409) first examined whether attachment security was associated with individuals' expectations that their current intimate relationship would be stable and consistent over time (vs. inconsistent and unstable). Studies 2 and 3 extended this by examining the prevalence and consequences of actual within-person variation (fluctuations) in relationship-specific attachment security toward an intimate partner in 2 multiwave longitudinal studies that assessed individuals (Study 2, N = 324) and couples (Study 3, N = 171 dyads). The results indicate that secure individuals (those low in attachment anxiety or attachment avoidance) expect their current relationship to remain relatively stable and consistent over time (Study 1). However, Studies 2 and 3 demonstrated that most individuals do experience fluctuations in their relationship-specific attachment security. Moreover, greater fluctuations predict declines in relationship satisfaction (Studies 2 and 3) and increases in relationship distress (Study 3) over time, but primarily for secure individuals (those low in baseline attachment anxiety or attachment avoidance). This set of findings highlight the importance of examining within-person fluctuations in attachment security, which are associated with declines in trajectories of relationship wellbeing, particularly for secure individuals who anticipate greater stability in their relationships. (PsycINFO Database Record

Switching on BTK-One Domain at a Time.

BTK kinase activity is controlled by multiple inhibitory domains, whose coordinated mechanism of action is poorly understood. In this issue of Structure,Joseph et al. (2017) use solution-based approaches to characterize conformational changes associated with the binding of each inhibitory tether, revealing a multi-step activation process and a previously unknown C-terminal autoinhibitory latch.

Relational underpinnings of condom use: Findings from the project on partner dynamics.

OBJECTIVE: To examine how relational qualities, including commitment to a sexual partner, are associated with condom use among young heterosexual adults at increased risk for sexually transmitted infections. Guided by the investment model of commitment processes, we hypothesized that sexual partner commitment is a function of satisfaction with, alternatives to, and investments in the relationship. Commitment to a sexual partner is, in turn, associated with reduced perceptions of vulnerability to sexually transmitted infection acquisition, which results in lowered condom use intentions and use. METHOD: We tested the hypothesized model using data from the Project on Partner Dynamics (POPD), a 4-wave, 1-year longitudinal study featuring a Time 1 sample of 538 African American, Hispanic, and White young adult from East Los Angeles, California, who provided data on all their sexual relationships over the year. RESULTS: Findings from hierarchical path models supported the hypotheses, with relational qualities significantly linked to condom use via commitment, perceived vulnerability to harm from partner and intentions to use. CONCLUSION: These findings have implications for improving the health of high-risk individuals, including suggesting the importance of raising awareness of relational qualities that may give rise to unsafe sexual practices. (PsycINFO Database Record

EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms.

Heteromeric interactions between the catalytically impaired human epidermal growth factor receptor (HER3/ERBB3) and its catalytically active homologs EGFR and HER2 are essential for their signaling. Different ligands can activate these receptor pairs but lead to divergent signaling outcomes through mechanisms that remain largely unknown. We used stochastic optical reconstruction microscopy (STORM) with pair-correlation analysis to show that EGF and neuregulin (NRG) can induce different extents of HER3 clustering that are dependent on the nature of the coexpressed HER receptor. We found that the presence of these clusters correlated with distinct patterns and mechanisms of receptor phosphorylation. NRG induction of HER3 phosphorylation depended on the formation of the asymmetric kinase dimer with EGFR in the absence of detectable higher-order oligomers. Upon EGF stimulation, HER3 paralleled previously observed EGFR behavior and formed large clusters within which HER3 was phosphorylated via a noncanonical mechanism. HER3 phosphorylation by HER2 in the presence of NRG proceeded through still another mechanism and involved the formation of clusters within which receptor phosphorylation depended on asymmetric kinase dimerization. Our results demonstrate that the higher-order organization of HER receptors is an essential feature of their ligand-induced behavior and plays an essential role in lateral cross-activation of the receptors. We also show that HER receptor ligands exert unique effects on signaling by modulating this behavior.

Can Young Adults Accurately Report Sexual Partnership Dates? Factors Associated With Interpartner and Dyad Agreement.

BACKGROUND: Sexual partnership dates are critical to sexually transmitted infection/HIV research and control programs, although validity is limited by inaccurate recall and reporting. METHODS: We examined data from 302 heterosexual adults (151 index-partner dyads) to assess reliability of reporting. Dates of first sex and last sex were collected through individual interviews and joint dyad questionnaires, which were completed together with their partners. We compared index- and partner-reported dates to estimate interpartner agreement. We used log-linear regression to model associations between interpartner differences and partnership characteristics. To assess validity, we compared individually reported dates with those from joint dyad questionnaires. RESULTS: Most partnerships (66.2%) were 2 years or less in duration, and many (36.2%) were nonmonogamous. Interpartner agreement to within 1, 30, and 365 days was, respectively, 5.6%, 43.1%, and 81.3% for first sex, and 32.9%, 94.5%, and 100.0% for last sex. In adjusted models, longer relationship duration was associated with disagreement on first sex dates; partnership nonmonogamy was associated with disagreement on dates of first sex and last sex. Within dyads, several participant characteristics were associated with reporting dates closer to joint dyad responses (e.g., for first sex date, female sex [54.7%], having fewer sex partners [58.5%], and greater relationship commitment [57.3%]). However, percent agreement to within 30, 60, and 90 days was similar for all groups for both first and last sex dates. CONCLUSIONS: Agreement was high on date of last sex but only moderate on date of first sex. Methods to increase accuracy of reporting of dates of sex may improve STI research.

Ease of Retrieval Effects on Relationship Commitment: The Role of Future Plans.

How do perceptions of future romantic plans affect close relationships? In three studies, we examined the effects of ease of retrieval of future plans on romantic relationship commitment. We hypothesized that greater ease of retrieval would be associated with greater relationship commitment among those who were high in need for cognition. Study 1 participants listed either two or 10 future plans and completed a measure assessing need for cognition. Results showed that high need for cognition individuals asked to list two instead of 10 future plans reported greater commitment, but those low in need for cognition showed the opposite pattern. Study 2 replicated this effect while controlling for plan substitutability. Study 3 examined the mediational role of commitment doubt. Those high in need for cognition listing more plans had more doubts and reported lower commitment. These findings suggest that perceptions of future plans can influence relationship commitment under specific conditions.

Association of perceived partner non-monogamy with prevalent and incident sexual concurrency.

OBJECTIVES: Concurrency is suggested as an important factor in sexually transmitted infection transmission and acquisition, though little is known regarding factors that may predict concurrency initiation. We examined the association between perception of a partner's non-monogamy (PPNM) and simultaneous or subsequent concurrency among at-risk heterosexual young adults in the Los Angeles area. METHODS: We used Poisson regression models to estimate the relationship between PPNM and incident concurrency among 536 participants participating in a cohort study, interviewed at 4-month periods during 1 year. Concurrency was defined as an overlap in reported sexual partnership dates; PPNM was defined as believing a partner was also having sex with someone else. RESULTS: Participants (51% female; 30% non-Hispanic white, 28% non-Hispanic black, 27% Hispanic/Latino) had a mean age of 23 years and lifetime median of nine sex partners. At each interview (baseline, 4-month, 8-month and 12-month), 4-month concurrency prevalence was, respectively, 38.8%, 27.4%, 23.1% and 24.5%. Four-month concurrency incidence at 4, 8 and 12 months was 8.5%, 10.6% and 17.8%, respectively. Participants with recent PPNM were more likely to initiate concurrency (crude 4-month RR=4.6; 95% CI 3.0, 7.0; adjusted 4-month RR=4.0, 95% CI 2.6 to 6.1). CONCLUSIONS: Recent PPNM was associated with incident concurrency. Among young adults, onset of concurrency may be stimulated, relatively quickly, by the PPNM. Programmes which promote relationship communication skills and explicit monogamy expectations may help reduce concurrency.

Concurrent sexual partnerships among young heterosexual adults at increased HIV risk: types and characteristics.

BACKGROUND: The impact of concurrency on sexually transmitted infection transmission depends on coital frequency, condom use, duration of relationship overlap, and number of partners. Previous research has identified distinct concurrency types; however, little is known about their risk characteristics. METHODS: Men (n = 261) and women (n = 275) aged 18 to 30 years at increased risk for acquiring HIV were recruited from community locations in Los Angeles. Participants completed 4 in-person interviews for 12 months. Partnership data were used to characterize the prevalence of 4 types of concurrency: transitional (2 overlapping relationships in which the first relationship ended before the second), single day (a second relationship of 1 day's duration during the course of another relationship), contained (a second relationship >1 day began and ended during the course of another), and multiple (≥3 overlapping relationships). Multilevel random intercept models were used to estimate mean coital frequency, proportion of condom-protected acts, total duration of overlap, and lifetime sex partners. RESULTS: At baseline, 47% of male and 32% of female participants reported any type of concurrency in the previous 4 months, and 26% of men and 10% of women reported multiple concurrencies. Condom use ranged from 56% to 64%, with the highest use in transitional concurrency (61% for men, 68% for women) and the lowest in contained (52% for men, 54% for women). Coital frequency, total overlap, and lifetime sex partners also varied by concurrency type. CONCLUSIONS: Inconsistent condom use and repeated opportunities for exposure characterize common types of concurrency among high-risk young adults.

Relational consequences of personal goal pursuits.

Individuals balance tasks necessary to fulfill personal goals and to maintain their interpersonal relationships. In the current studies, we examined the impact of personal goal pursuits on how individuals process and respond to events in their romantic relationships. In 5 experiments, we examined consequences of motivationally active personal goals for relationships. Results indicated that when individuals focused on pursuing a personal goal, they processed relationship information in an evaluatively polarized (Study 1), one-sided (Study 2) fashion. Relative to those deliberating about a personal goal, those focused on a personal goal reported less willingness to engage in some kinds of pro-relationship behaviors (Study 3) and were more likely to forego an opportunity to improve their relationship (Study 4). We attribute this pattern of findings to processing that shielded the personal goal from goal-irrelevant influence (Study 5). These findings provide a greater understanding of how pursuing a personal goal can undermine relationships.

Effect of time on perceived gains from an undergraduate research program.

The current study examines the trajectories of student perceived gains as a result of time spent in an undergraduate research experience (URE). Data for the study come from a survey administered at three points over a 1-yr period: before participation in the program, at the end of a Summer segment of research, and at the end of the year. Repeated-measures analysis of variance was used to examine the effect of time on perceived gains in student research skills, research confidence, and understanding of research processes. The results suggest that the students experienced different gains/benefits at developmentally different stages of their UREs. Participants reported gains in fewer areas at the end of the Summer segment compared with the end of the yearlong experience, thus supporting the notion that longer UREs offer students more benefit.