Development of a Communication Tool between Patients and Physicians for Recognizing COPD Exacerbations in Japan.

In Japan, exacerbations are underreported compared with other countries, possibly due in part to a failure to recognize them. This study aimed to create a simple chronic obstructive pulmonary disease (COPD) Exacerbation Recognition Tool (CERT-J) specifically for Japanese patients. Patients ≥40 years with confirmed COPD or asthma-COPD overlap were included. Focus groups were held to identify words and phrases used by patients to describe symptoms associated with an exacerbation, resulting in candidate items being identified. Following cognitive debriefing, the items were refined based on item frequency, level of endorsement and effect of demographic factors. Exploratory factor analysis (EFA) was then performed to inform an expert panel's choice of items to form the new tool. A total of 41 patients were included in the focus groups and nine patients performed the cognitive debrief. Following this, the expert panel identified 26 items for testing in a further 100 patients (mean age 72 years, forced expiratory volume in 1 s 54.8% predicted and 1.8 exacerbations in the preceding 12 months). Eleven items were associated with breathlessness or activity limitation and seven of these were the most frequently endorsed. EFA identified four factors, with one (breathlessness) being dominant. The expert panel recommended that the CERT-J should include six items: breathlessness and activity limitation (3 items), cough (1 item) and phlegm (2 items). The final CERT-J should benefit patients with COPD by providing them with an increased understanding and recognition of exacerbations.Clinical Trial Registration: GSK K.K (jRCT1080224526).

Constructive conflict resolution requires tailored responsiveness to specific needs.

Conflict affords an opportunity for relationship partners to demonstrate that they can be responsive to each other's needs. Understanding what constitutes responsiveness during conflict requires taking a dyadic perspective to identify how partners can tailor responses to address actors' specific needs. The present article reviews recent evidence showing that perceived responsiveness emerges from dyadic patterns involving how both partners and actors behave, and that partners' responsiveness during conflict involves different kinds of behaviors depending on actors' behavior and needs. These dyadic patterns emphasize that building tailored responsiveness to promote conflict resolution requires couples being able and willing to identify, communicate, and respond to each other's specific needs.

Feeling loved as a strong link in relationship interactions: Partners who feel loved may buffer destructive behavior by actors who feel unloved.

Feeling loved (loved, cared for, accepted, valued, understood) is inherently dyadic, yet most prior theoretical perspectives and investigations have focused on how actors feeling (un)loved shapes actors' outcomes. Adopting a dyadic perspective, the present research tested whether the established links between actors feeling unloved and destructive (critical, hostile) behavior depended on partners' feelings of being loved. Does feeling loved need to be mutual to reduce destructive behavior, or can partners feeling loved compensate for actors feeling unloved? In five dyadic observational studies, couples were recorded discussing conflicts, diverging preferences or relationship strengths, or interacting with their child (total N = 842 couples; 1,965 interactions). Participants reported how much they felt loved during each interaction and independent coders rated how much each person exhibited destructive behavior. Significant Actors' × Partners' Felt-Loved interactions revealed a strong-link/mutual felt-unloved pattern: partners' high felt-loved buffered the damaging effect of actors' low felt-loved on destructive behavior, resulting in actors' destructive behavior mostly occurring when both actors' and partners' felt-loved was low. This dyadic pattern also emerged in three supplemental daily sampling studies. Providing directional support for the strong-link/mutual felt-unloved pattern, in Studies 4 and 5 involving two or more sequential interactions, Actors' × Partners' Felt-Loved in one interaction predicted actors' destructive behavior within couples' subsequent conflict interactions. The results illustrate the dyadic nature of feeling loved: Partners feeling loved can protect against actors feeling unloved in challenging interactions. Assessing Actor × Partner effects should be equally valuable for advancing understanding of other fundamentally dyadic relationship processes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Actor and partner power are distinct and have differential effects on social behavior.

Interpersonal power involves how much actors can influence partners (actor power) and how much partners can influence actors (partner power). Yet, most theories and investigations of power conflate the effects of actor and partner power, creating a fundamental ambiguity in the literature regarding how power shapes social behavior. We demonstrate that actor and partner power are distinct and have differential effects on social behavior. Six studies (total N = 1,787) tested whether actor and partner power independently predicted behavioral inhibition (expressive suppression) and communal behavior (prioritization of partners' needs) within close relationships, including during couples' daily life (Study 1), lab-based social interactions (Studies 1-5; 1,012 dyadic interactions), and general responses during conflict (Studies 5 and 6). Actor power was negatively associated with behavioral inhibition, indicating that actors' low power prompts self-focused inhibition to prevent negative outcomes that low power actors are unable to control. Partner power was positively associated with actors' communal behavior, indicating that high partner power prompts other-focused behavior that prioritizes partners' needs and goals. These differential effects of actor and partner power replicated in work-based relationships with bosses/managers (Study 6). Unexpectedly, partner power was negatively associated with actors' behavioral inhibition within close relationships, consistent with a desire to prevent negative outcomes for low power partners. We present a framework that integrates the approach-inhibition and agentic-communal theories of power to account for the differential effects of actor and partner power. We describe the implications of this framework for understanding the effects of power in both close and hierarchical relationships. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Attenuation of Bone Formation through a Decrease in Osteoblasts in Mutant Mice Lacking the GM2/GD2 Synthase Gene.

The ganglioside GD1a has been reported to promote the differentiation of mesenchymal stem cells to osteoblasts in cell culture systems. However, the involvement of gangliosides, including GD1a, in bone formation in vivo remains unknown; therefore, we herein investigated their roles in GM2/GD2 synthase-knockout (GM2/GD2S KO) mice without GD1a. The femoral cancellous bone mass was analyzed using three-dimensional micro-computed tomography. A histomorphometric analysis of bone using hematoxylin and eosin (HE) and tartrate-resistant acid phosphatase was performed to examine bone formation and resorption, respectively. Calcein double labeling was also conducted to evaluate bone formation. Although no significant differences were observed in bone mass or resorption between GM2/GD2S KO mice and wild-type (WT) mice, analyses of the parameters of bone formation using HE staining and calcein double labeling revealed less bone formation in GM2/GD2S KO mice than in WT mice. These results suggest that gangliosides play roles in bone formation.

Income robustly predicts self-regard emotions.

There is robust evidence that higher income makes people evaluate their lives more favorably, but there is no consistent evidence on whether it makes people feel better. Analyzing data from five large surveys spanning 162 countries, we predicted and found the most comprehensive evidence to date that income reliably predicted greater positive self-regard emotions (e.g., pride) and lower negative self-regard emotions (e.g., anxiety). In contrast, its relationships with other-regard emotions (e.g., gratitude, anger) and global emotions (e.g., happiness) were weaker in magnitude and difficult to replicate. In addition, income predicted higher (lower) levels of positive (negative) self-regard emotions about 10 years later, controlling for the same self-regard emotions at baseline. Sense of control mediated the relationships between income and both positive and negative self-regard emotions. Income predicted self-regard emotions as strongly as it has been known to predict life evaluation. Hence, having more money makes people feel more proud, contented, and confident and less sad, afraid, and ashamed, but does not affect whether they feel grateful, caring, and angry. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A dyadic perspective of expressive suppression: Own or partner suppression weakens relationships.

In the current research, we apply a dyadic perspective of expressive suppression (ES) to test whether ES represents a weak link, such that either actors' or partners' ES is sufficient to undermine relationship satisfaction. Our primary aim was to test this weak-link pattern by modeling Actor × Partner ES interactions on relationship satisfaction. To maximize power, we conducted integrative data analyses across four existing dyadic samples (N = 427 couples) that included self-reports of habitual ES and relationship satisfaction. Our second aim was to examine the role of conflict resolution ability as one potential mechanism for the ES weak-link pattern on satisfaction. These integrative data analyses involved two dyadic samples (N = 242 couples) that included self-reports of conflict resolution ability. Significant Actor × Partner ES interactions revealed a weak-link pattern: greater actors' or partners' ES was associated with lower relationship satisfaction. Accordingly, actors' lower ES was associated with higher satisfaction only when partners' ES was also low. This ES weak-link pattern also emerged for conflict resolution ability, which provided evidence that reduced conflict resolution ability is one interpersonal process that contributes to the weak-link pattern on satisfaction. ES likely operates as a weak link because actors' or partners' ES interferes with the coordination, cooperation, and connection needed to manage relationship challenges and sustain healthy relationships. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Partners' Withdrawal When Actors Behave Destructively: Implications for Perceptions of Partners' Responsiveness and Relationship Satisfaction.

Growing evidence indicates that whether critical and hostile behavior harms relationships depends on how partners respond. The current studies test a key behavioral indicator of partners' responsiveness by examining whether partners' withdrawal when actors exhibit negative-direct behavior predicts within-person and longitudinal declines in perceived partner responsiveness and relationship satisfaction. Test of Actors' negative-direct × Partners' withdrawal interactions indicated that partners' withdrawal in the context of actors' negative-direct behavior when targeted for change during conflict discussions (Study 1, N = 162 dyads) and during daily interactions (Study 2, N = 151 dyads) predicted lower perceived partner responsiveness and relationship satisfaction. This Actor × Partner effect did not emerge when actors were pushing for change during conflict (Study 1) and was more consistent predicting perceived partner responsiveness. These results illustrate the importance of Actor × Partner effects and indicate that actors' own destructive behavior provides an important context to diagnose partners' responsiveness.

Development of A2G80 peptide-gene complex for targeted delivery to muscle cells.

Therapeutic strategies based on antisense oligonucleotides and therapeutic genes are being extensively investigated for the treatment of hereditary muscle diseases and hold great promise. However, the cellular uptake of these polyanions to the muscle cells is inefficient. Therefore, it is necessary to develop more effective methods of gene delivery into the muscle tissue. The A2G80 peptide (VQLRNGFPYFSY) from the laminin α2 chain has high affinity for α-dystroglycan (α-DG) which is expressed on the membrane of muscle cells. In this study, we designed a peptide-modified A2G80 with oligoarginine and oligohistidine (A2G80-R9-H8), and prepared peptide/plasmid DNA (pDNA) complex, to develop an efficient gene delivery system for the muscle tissue. The peptide/pDNA complex showed α-DG-dependent cellular uptake of the A2G80 sequence and significantly improved gene transfection efficiency mediated by the oligohistidine sequence in C2C12 myoblast cells. Further, the peptide/pDNA complex promoted efficient and sustained gene expression in the Duchenne muscular dystrophy mouse models. The A2G80-R9-H8 peptide has the potential for use as a specific carrier for targeting muscle in gene therapy in muscular dystrophy.

Alpha-dystroglycan binding peptide A2G80-modified stealth liposomes as a muscle-targeting carrier for Duchenne muscular dystrophy.

Safe and efficient gene therapy for the treatment of Duchenne muscular dystrophy (DMD), a genetic disorder, is required. For this, the muscle-targeting delivery system of genes and nucleic acids is ideal. In this study, we focused on the A2G80 peptide, which has an affinity for α-dystroglycan expressed on muscle cell membranes, as a muscle targeted nanocarrier for DMD and developed A2G80-modified liposomes. We also prepared A2G80-modified liposomes coated with long- and short-chain PEG, called A2G80-LSP-Lip, to improve the blood circulation of liposomes using microfluidics. The liposomes had a particle size of approximately 80 nm. A2G80-LSP-Lip showed an affinity for the muscle tissue section of mice by overlay assay. When the liposomes were administered to DMD model mice (mdx mice) via the tail vein, A2G80-LSP-Lip accumulated efficiently in muscle tissue compared to control liposomes. These results suggest that A2G80-LSP-Lip can function as a muscle-targeting liposome for DMD via systemic administration, and may be a useful tool for DMD treatment.

A Dyadic Perspective of Felt Security: Does Partners' Security Buffer the Effects of Actors' Insecurity on Daily Commitment?

Interdependence and attachment models have identified felt security as a critical foundation for commitment by orientating individuals towards relationship-promotion rather than self-protection. However, partners' security also signals the relative safety to commit to relationships. The current investigation adopted a dyadic perspective to examine whether partners' security acts as a strong link by buffering the negative effects of actors' insecurity on daily commitment. Across two daily diary studies (Study 1, N = 78 dyads and Study 2, N = 73 dyads), actors' X partners' daily felt security interactions revealed a strong-link pattern: lower actors' felt security on a given day predicted lower daily commitment, but these reductions were mitigated when partners reported higher levels of felt security that day. Actors' X partners' trait insecurity (attachment anxiety) interaction also showed this strong-link pattern in Study 1 but not Study 2. The results suggest that partners' felt security can help individuals experiencing insecurity overcome their self-protective impulses and feel safe enough to commit to their relationship on a daily basis.

Gratitude inhibits competitive behaviour in threatening interactions.

It is well established that gratitude favours prosocial tendencies in neutral and amicable social interactions. Less is clear, however, about the role of gratitude in threatening situations that breed competitive impulses. As gratitude inhibits self-centred impulses and motivates a communal orientation, we predict and demonstrate that gratitude reduces competitive behaviour in threatening interactions. In Study 1 (N = 171), after emotion induction, participants went through the classic Trucking game paradigm, whereby a bogus opponent behaved in a competitive manner (i.e. closing the gate on them). Gratitude, as compared to joy and a neutral mood state, reduced participants' competitive behaviour against the opponent. In Study 2 (N = 422), after losing to a bogus opponent on a self-relevant task, participants were given an opportunity to sabotage the opponent's chances of winning a lottery. Individuals induced to feel gratitude showed less sabotaging behaviour than those in a neutral mood state. Importantly, this effect was only observed against a highly competitive, but not a neutral, opponent, suggesting that gratitude inhibits competitive behaviour only under high threat. Our findings suggest that gratitude is instrumental in arresting the competitive cycles from developing in threatening social interactions.

Sex differences in vocalizations to familiar or unfamiliar females in mice.

Mice, both wild and laboratory strains, emit ultrasound to communicate. The sex differences between male to female (male-female) and female to female (female-female) ultrasonic vocalizations (USVs) have been discussed for decades. In the present study, we compared the number of USVs emitted to familiar and unfamiliar females by both males (male-female USVs) and females (female-female USVs). We found that females vocalized more to unfamiliar than to familiar females. By contrast, males exhibited more USVs to familiar partners. This sexually dimorphic behaviour suggests that mice change their vocal behaviour in response to the social context, and their perception of the context is based on social cognition and memory. In addition, because males vocalized more to familiar females, USVs appear to be not only a response to novel objects or individuals, but also a social response.

Chain-Shortened Myostatin Inhibitory Peptides Improve Grip Strength in Mice.

Inhibition of myostatin is a promising strategy for treatment of muscle atrophic disorders. We had already identified a 23-mer peptide (1) as a synthetic myostatin inhibitor, and structure-activity relationship studies with 1 afforded a potent 22-mer peptide derivative (3). Herein, we report the shortest myostatin inhibitory peptide so far. Among chain-shortened 16-mer peptidic inhibitors derived from the C-terminal region of 3, peptide inhibitor 8a with ß-sheet propensity was twice as potent as 22-mer inhibitor 3 and significantly increased not only muscle mass but also hind limb grip strength in Duchenne muscular dystrophic model mice. These results suggest that 8a is a promising platform for drug development treating muscle atrophic disorders.

PMO Delivery System Using Bubble Liposomes and Ultrasound Exposure for Duchenne Muscular Dystrophy Treatment.

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration, caused by nonsense or frameshift mutations in the dystrophin (DMD) gene. Antisense oligonucleotides can be used to induce specific exon skipping; recently, a phosphorodiamidate morpholino oligomer (PMO) has been approved for clinical use in DMD. However, an efficient PMO delivery strategy is required to improve the therapeutic efficacy in DMD patients. We previously developed polyethylene glycol (PEG)-modified liposomes containing ultrasound contrast gas, "Bubble liposomes" (BLs), and found that the combination of BLs with ultrasound exposure is a useful gene delivery tool. Here, we describe an efficient PMO delivery strategy using the combination of BLs and ultrasound exposure to treat muscles in a DMD mouse model (mdx). This ultrasound-mediated BL technique can increase the PMO-mediated exon-skipping efficiency, leading to significantly increased dystrophin expression. Thus, the combination of BLs and ultrasound exposure may be a feasible PMO delivery method to improve therapeutic efficacy and reduce the PMO dosage for DMD treatment.

Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification.

Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp21, rodent-specific Tyr27, and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on 1 and characterized a 3-fold more potent inhibitor 2 bearing a 2-naphthyloxyacetyl group at position 21. Herein, we performed 1-based SAR studies focused on all aliphatic residues and Ala32, discovering that the incorporations of Trp and Ile at positions 32 and 38, respectively, enhanced the inhibitory activity. Combining these findings with 2, a novel peptide 3d displayed an IC50 value of 0.32 µM, which is 11 times more potent than 1. The peptide 3d would have the potential to be a promising drug lead to develop better peptidomimetics.

Mammalian target of rapamycin (mTOR) complex 2 regulates filamin A-dependent focal adhesion dynamics and cell migration.

The serine/threonine kinase mTOR forms two distinct complexes, mTORC1 and mTORC2, and controls a number of biological processes, including proliferation, survival and autophagy. Although the function of mTORC1 has been extensively studied, the mTORC2 signaling pathway largely remains to be elucidated. Here, we have shown that mTORC2 phosphorylates filamin A, an actin cross-linking protein, at serine 2152 (S2152) both in vivo and in living cells. Treatment of HeLa cells with Torin1 (an mTORC1/mTORC2 inhibitor), but not rapamycin (an mTORC1 inhibitor), suppressed the phosphorylation of filamin A, which decreased the binding of filamin A with ß7-integrin cytoplasmic tail. Torin1 also inhibited focal adhesion formation and cell migration in A7 filamin A-replete melanoma cells but not in M2 filamin A-deficient cells, suggesting a pivotal role for mTORC2 in filamin A function. Finally, reduced focal adhesion formation in M2 cells was significantly rescued by expressing wild type but not S2152A nonphosphorylatable mutant of filamin A. Taken together, our results indicate that mTORC2 regulates filamin A-dependent focal adhesions and cell migration.

Graphiumins, new thiodiketopiperazines from the marine-derived fungus Graphium sp. OPMF00224.

Eight new thiodiketopiperazines, designated as graphiumins A to H (1-8), were isolated along with bisdethiobis(methylthio)-deacetylaranotin (9) and bisdethiobis(methylthio)-deacetylapoaranotin (10) from the culture broth of the marine-derived fungus Graphium sp. OPMF00224. The structures of the graphiumins were elucidated based on spectroscopic analyses (1D and 2D NMR data, ROESY correlations and CD data) and chemical methods. The absolute configuration of the common (3S)-3-hydroxy-octanoyl acid residue in 1, 3 and 4 was determined by hydrolysis, benzoyl derivatization and HPLC analysis using a chiral column. Five graphiumins moderately inhibited yellow pigment production by methicillin-resistant Staphylococcus aureus.