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Highlights: [•] Iron–platinum arsenides Ca10(Pt n As8)(Fe2−xPt x As2)5 (n =3, 4) have been grown and characterized. [•] Due to modest electromagnetic anisotropy, resistive transition shows broadening. [•] Magneto-optical imaging confirm homogeneous superconducting states. [•] Proton irradiation into n =3 compound leads to T c suppression by ∼2K and J c enhancement by a factor of three. [ABSTRACT FROM AUTHOR]

Background: This study aimed to clarify the situation and evaluate the communication on anticancer treatment discontinuation from the viewpoint of a bereaved family, in reference to the concept of nudges., Methods: A multi-center questionnaire survey was conducted involving 350 bereaved families of patients with cancer admitted to palliative care units in Japan., Results: The following explanations were rated as essential or very useful: (i) treatment would be a physical burden to the patient (42.9%), (ii) providing anticancer treatment was impossible (40.5%), (iii) specific disadvantages of receiving treatment (40.5%), (iv) not receiving treatment would be better for the patient (39.9%) and (v) specific advantages of not receiving treatment (39.6%). The factors associated with a high need for improvement of the physician's explanation included lack of explanation on specific advantages of not receiving treatment (β = 0.228, P = 0.001), and lack of explanation of 'If the patient's condition improves, you may consider receiving the treatment again at that time.' (β = 0.189, P = 0.008)., Conclusions: Explaining the disadvantages of receiving treatment and the advantages of not receiving treatment, and presenting treatment discontinuation as the default option were effective in helping patients' families in making the decision to discontinue treatment. In particular, explanation regarding specific advantages of not receiving treatment was considered useful, as they caused a lower need for improvement of the physicians' explanation., (© The Author(s) 2024. Published by Oxford University Press.)

Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2 VHL - or CRL4 CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4-PROTAC-CRL2 VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors., (© 2024. The Author(s).)

OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis., (© 2024 Takeda et al.)

Ubiquitin regulates various cellular functions by posttranslationally modifying substrates with diverse ubiquitin codes. Recent discoveries of new ubiquitin chain topologies, types of bonds, and non-protein substrates have substantially expanded the complexity of the ubiquitin code. Here, we describe the ubiquitin system covering the basic principles and recent discoveries related to mechanisms, technologies, and biological importance., (© 2024 Akizuki et al.)

K63-linked ubiquitin chains attached to plasma membrane proteins serve as tags for endocytosis and endosome-to-lysosome sorting. USP8 is an essential deubiquitinase for the maintenance of endosomal functions. Prolonged depletion of USP8 leads to cell death, but the major effects on cellular signaling pathways are poorly understood. Here, we show that USP8 depletion causes aberrant accumulation of K63-linked ubiquitin chains on endosomes and induces immune and stress responses. Upon USP8 depletion, two different decoders for K63-linked ubiquitin chains, TAB2/3 and p62, were recruited to endosomes and activated the TAK1-NF-κB and Keap1-Nrf2 pathways, respectively. Oxidative stress, an environmental stimulus that potentially suppresses USP8 activity, induced accumulation of K63-linked ubiquitin chains on endosomes, recruitment of TAB2, and expression of the inflammatory cytokine. The results demonstrate that USP8 is a gatekeeper of misdirected ubiquitin signals and inhibits immune and stress response pathways by removing K63-linked ubiquitin chains from endosomes., (© 2024 Endo et al.)

Background: It has been said that physicians should provide their patients with accurate evidence in terms of information on treatment options. However, in some cases, although the physician provides accurate and sufficient information, the patient still chooses the medically not-recommended treatment. The purpose of this research is to clarify how patients' decisions differ when a physician changes the frame of an explanation when he/she provides information about cancer treatment., Methods: An online questionnaire survey was conducted in March 2017. Through the aid of a survey company, we emailed questionnaires to 1,360 cancer patients who received treatment within the last 2 years. We randomly assigned participants to 6 hypotheticals scenario of a terminal cancer patient, and presented hypothetical evidence in different ways. Subsequently, we asked survey participants whether they would choose to receive additional anti-cancer treatment., Results: Although there was no statistically significant difference between scenarios, the "social burden" groups showed a lower rate of patients who preferred to continue a medically ineffective anti-cancer treatment than the control group, at a 10% significance level. The scenario significantly affected the patients' sense of abandonment [F(5, 1,354)=5.680, P<0.001], sense of distress [F(5, 1,354)=3.920, P=0.002], and necessity of improvement [F(5, 1,354)=2.783, P=0.017]., Conclusions: Nudges were not shown to be effective in situations where discontinuation of anticancer treatment was being considered. On the other hand, some nudges were found to be invasive and should be used with caution.

Teachers in Japanese schools employ alphabetical surname lists that call students sooner, with surnames appearing early on these lists. We conducted Internet surveys nearly every month from March 2020 to September 2022 with the same participants, wherein we asked participants where the alphabetical columns of their childhood and adult surnames were located. We aimed to identify how surname order is important for the formation of noncognitive skills. During the data collection period, the COVID-19 vaccines became available; Japanese people could receive their third dose starting in December 2021. The 19th wave of the survey was conducted in January 2022. Therefore, to examine how a surname's alphabetical order could influence intention to revaccinate, we used a subsample of data from December 2021 to September 2022. The major findings were as follows. Women with early surnames had an approximately 4% stronger likelihood of having such intentions than men with early surnames. Early name order was more strongly correlated with revaccination intention among women than among men. The surname effect for women was larger when a mixed-gender list was used compared with when it was not used. This effect was only observed for childhood surnames and not for adult surnames., (© 2024. The Author(s).)

The number of people with mental disorders (PMD) living in the community is increasing; however, it is unclear how home-visiting nurses (HVNs) supporting them in the community acquire their support skills. This study aimed to reveal the process of how HVNs learn support skills for PMD. Semi-structured interviews were conducted with 14 HVNs supporting PMD living in the community. The grounded theory approach was used for data analysis. As a result, two stages were present: "Explore the personal recovery of PMD" and "Believe in the potential of PMD and accompanying them". The first stage is further divided into two themes: "Overlapping the worlds of PMD and HVNs", and "Easing difficulty in living for PMD". In the first stage, HVNs gained a better understanding of PMD and obtained insight into the support they needed in their daily lives. In the second stage, HVNs became to provide the support that PMD truly needed. HVNs gained a deeper understanding of the reality of PMD through their support. After HVNs found the support PMD required, they sought to provide it, ultimately resulting in finding ways to facilitate the personal recovery of PMD.

The proteasome plays a central role in intracellular protein degradation. Age-dependent decline in proteasome activity is associated with cellular senescence and organismal aging; however, the mechanism by which the proteasome plays a role in senescent cells remains elusive. Here, we show that nuclear foci that contain the proteasome and exhibit liquid-like properties are formed in senescent cells. The formation of senescence-associated nuclear proteasome foci (SANPs) is dependent on ubiquitination and RAD23B, similar to previously known nuclear proteasome foci, but also requires proteasome activity. RAD23B knockdown suppresses SANP formation and increases mitochondrial activity, leading to reactive oxygen species production without affecting other senescence traits such as cell-cycle arrest and cell morphology. These findings suggest that SANPs are an important feature of senescent cells and uncover a mechanism by which the proteasome plays a role in senescent cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vaccination has been promoted to mitigate the spread of the coronavirus disease 2019 (COVID-19). Vaccination is expected to reduce the probability of and alleviate the seriousness of COVID-19 infection. Accordingly, this might significantly change an individual's subjective well-being and mental health. We observed the same individuals on a monthly basis from March 2020 to September 2021 in all parts of Japan. Then, large sample panel data (N = 54,007) were independently constructed. Using the data, we compared the individuals' perceptions of COVID-19, subjective well-being, and mental health before and after vaccination. Furthermore, we compared the effect of vaccination on the perceptions of COVID-19 and mental health for females and males. We used the fixed-effects model to control for individual time-invariant characteristics. The major findings were as follows: First, the vaccinated people perceived the probability of getting infected and the seriousness of COVID-19 to be lower than before vaccination. This was observed not only when we used the whole sample but also when we used subsamples of males and a subsample of females. Second, subjective well-being and mental health improved. The same results were also observed using the subsample of females, whereas the improvements were not observed when using a subsample of males. This implies that females' quality of life was more likely to be improved by vaccination than males' one. The novelty of the work is to show the gender difference in the vaccination effects.

The coronavirus (COVID-19) vaccine is key to reducing the probability of contracting COVID-19. The vaccine is generally known to prevent severe illness, death, and hospitalization as a result of the disease and for considerably reduce COVID-19 infection risk. Accordingly, this might significantly change an individual's perceived risk of altering everyday behaviors. For instance, the proliferation of vaccination is anticipated to reduce preventive behaviors such as staying at home, handwashing, and wearing a mask. We corresponded with the same individuals monthly for 18 months from March 2020 (early stage of COVID-19) to September 2021 in Japan to independently construct large sample panel data (N = 54,007), with a participation rate of 54.7%. We used a fixed effects model, controlling for key confounders, to determine whether vaccination was associated with a change in preventive behaviors. The major findings are as follows. Contrary to the prediction, (1) based on the whole sample, being vaccinated against COVID-19 led people to stay at home; however, it did not change the habit of handwashing and wearing a mask. Especially after the second shot, respondents were likelier to stay at home by 0.107 (95% CIs: 0.059-0.154) points on a 5-point scale compared to before the vaccination. Dividing the entire sample into young and old, (2) those aged ≤ 40 years were more likely to go out after being vaccinated, and (3) people over 40 years of age were more likely to stay at home (similar to the first result). Preventive behaviors impact all individuals during the current pandemic. Informal social norms motivate people to increase or maintain preventive behaviors even after being vaccinated in societies where these behaviors are not enforced.

Targeted protein degradation through chemical hijacking of E3 ubiquitin ligases is an emerging concept in precision medicine. The ubiquitin code is a critical determinant of the fate of substrates. Although two E3s, CRL2 VHL and CRL4 CRBN , frequently assemble with proteolysis-targeting chimeras (PROTACs) to attach lysine-48 (K48)-linked ubiquitin chains, the diversity of the ubiquitin code used for chemically induced degradation is largely unknown. Here we show that the efficacy of cIAP1-targeting degraders depends on the K63-specific E2 enzyme UBE2N. UBE2N promotes degradation of cIAP1 induced by cIAP1 ligands and subsequent cancer cell apoptosis. Mechanistically, UBE2N-catalyzed K63-linked ubiquitin chains facilitate assembly of highly complex K48/K63 and K11/K48 branched ubiquitin chains, thereby recruiting p97/VCP, UCH37 and the proteasome. Degradation of neo-substrates directed by cIAP1-recruiting PROTACs also depends on UBE2N. These results reveal an unexpected role for K63-linked ubiquitin chains and UBE2N in degrader-induced proteasomal degradation and demonstrate the diversity of the ubiquitin code used for chemical hijacking., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The role of social ties, other-regarding preferences, and cultural traits in boosting community resilience and minimizing citizens' vulnerability to crises such as COVID-19 is increasingly being recognized. However, little is presently known about the possible routes through which such personal preferences and cultural norms pertinent to social behaviors are formulated. Thus, in this paper, factors that can be potentially associated with individuals to self-regulate strict hand hygiene practices before the pandemic, during the state of emergency, and after the state of emergency was lifted in Japan are investigated. Focus is given to the handwashing education in primary school, a cultural practice originating from the old Shinto tradition, and individuals' reciprocal inclinations. As people in Japan are known to be highly conscious of hygiene in all aspects of their daily life and are less likely to contract an infection, evidence obtained in this specific context could contribute to the better understanding of individuals' health-related behaviors in general, and during crises in particular., Methods: Using the data derived from a four-wave nationwide longitudinal online survey, we examined the extent to which elementary school education, childhood cultural experiences at shrines, and individual other-regarding preferences are associated with self-regulating hand hygiene practices prior to the pandemic and people's efforts to comply with the government-imposed measures aimed at preventing the spread of COVID-19 infection during the state of emergency. We also investigated the long-term trends in the relationships among these factors (i.e., after the abolishment of the state of emergency) using panel data., Results: Our findings reveal that childhood education and cultural experiences related to handwashing practices, as well as reciprocal inclinations, are significantly associated with Japanese attitudes toward personal hygiene (beyond handwashing practices) prior to, during, and after the state of emergency. In recognition of the possible effects of recall bias and measurement errors, several important attempts to mitigate these issues were made to strengthen the value of our findings., Conclusions: The importance of school education received during childhood, as well as culture and other-regarding preferences, in the individual attitudes toward hand hygiene in adulthood highlighted in this study contributes to the better understanding of the role that these factors play in the variations in voluntary compliance with strict hand hygiene practices before and during an uncertain and prolonged crisis., (© 2022. The Author(s).)

Vaccination rates for human papillomavirus (HPV) in Japan are significantly lower than other countries, and Japanese people are reluctant to be vaccinated. Repeated daily reports of COVID-19 infections and restrictions have made people more health conscious and aware of the danger of infectious diseases. In this study, we used the health belief model (HBM) to examine perceived threats of cancer and infectious diseases and to ascertain whether the new COVID-19 vaccination in addition to these perceived threats would increase vaccination intention against cervical cancer. We conducted a cluster analysis to classify the segmentation regarding the perceived threat, and a logistic regression analysis to predict factors influencing people accepting vaccination. We received 1257 completed surveys during our research. We classified the participants into six clusters, and the logistic regression analysis indicated eight factors significantly associated with the willingness to get the HPV vaccine: reliable information sources such as doctors and social networking sites (SNS), the recognition of COVID-19 symptoms, the awareness of COVID-19 vaccination, the importance of HPV prevention through vaccination, one's own intention of COVID-19 vaccination, their intention of COVID-19 vaccination toward children, and benefits of HPV vaccination. Further research on HPV and COVID-19 vaccination is encouraged.

We asked experts from different fields-from genome maintenance and proteostasis to organelle degradation via ubiquitin and autophagy-"What does quality control mean to you?" Despite their diverse backgrounds, they converge on and discuss the importance of continuous quality control at all levels, context, communication, timing, decisions on whether to repair or remove, and the significance of dysregulated quality control in disease., Competing Interests: Declaration of interests Sonya Neal, Fumiaki Ohtake, Ursula Jakob, Michael Lazarou, Wendy V. Gilbert, Sharon A. Tooze, and Kylie J. Walters declare no competing interests. Ana Maria Cuervo, Ramanujan S. Hegde, Zhijian J. Chen, James E. Haber, and F. Ulrich Hartl are members of the Molecular Cell advisory board., (Copyright © 2022. Published by Elsevier Inc.)

Protein ubiquitylation regulates numerous pathways, and the diverse information encoded by various forms of ubiquitylation is known as the ubiquitin code. Recent studies revealed that branched ubiquitin chains are abundant in mammalian cells and regulate important pathways. They include proteasomal degradation of misfolded and disease-causing proteins, regulation of NF-κB signalling and apoptotic cell fate decisions. Targeted protein degradation through chemical degraders emerged as a transformative therapeutic paradigm aimed at inducing the disappearance of unwanted cellular proteins. To further improve the efficacy of target degradation and expand its applications, understanding the molecular mechanism of degraders' action from the view of ubiquitin code biology is required. In this review, I discuss the roles of the ubiquitin code in biological pathways and in chemically induced targeted protein degradation by focusing on the branched ubiquitin codes that we have characterized., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 ( 1 ) in complex with human VHL and BRD4 BD2 , we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 ( 1 ) could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, 2a-c and 3a-c , by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (2 or 1). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 ( 2a ), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 ( 1 ). Based on the structure of 2a , we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, 15a-15d , having a tert -butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 ( 15c ) retained a level of BRD4 depletion activity similar to that of 2a without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 ( 1 ). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications.

Vaccination promotion is a crucial strategy to end the COVID-19 pandemic; however, individual autonomy should also be respected. This study aimed to discover other-regarding information nudges that can reinforce people's intention to receive the COVID-19 vaccine without impeding their autonomous decision-making. In March 2021, we conducted an online experiment with 1595 people living throughout Japan, and randomly assigned them either of one control group and three treatment groups that received messages differently describing peer information: control, comparison, influence-gain, and influence-loss. We compared each message's effects on vaccination intention, autonomous decision-making, and emotional response. We found that the influence-gain nudge was effective in increasing the number of older adults who newly decided to receive the vaccine. The comparison and influence-loss nudges further reinforced the intention of older adults who had already planned to receive it. However, the influence-loss nudge, which conveys similar information to the influence-gain nudge but with loss-framing, increased viewers' negative emotion. These messages had no promoting effect for young adults with lower vaccination intentions at baseline. Based on the findings, we propose governments should use different messages depending on their purposes and targets, such as comparison instead of influence-loss, to encourage voluntary vaccination behavior., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Using a large sample of individual-level records in Japan speedboat racing where men and women racers participate, we investigated how racers' performance meets fans' pre-race expectations. To control for endogeneity bias, we measured the order of racers' attractiveness randomly determined in each race and then used this order as instrument for measuring racers' popularity. The fixed-effects IV estimations revealed the following. (1) Racers who are more attractive than their competitors tend to be more popular even after controlling for the condition of the race, racer ability, and other characteristics. (2) More popular men show better performance in the race even if the reward does not vary according to popularity; such tendency is not observed for women. This study contributes a novel setting for determining the expectation-enhancing effects of physical attractiveness., (© Japanese Economic Association 2020.)

To assess the promotion of life saving behaviors and determine the sustainability of nudge message effects, this paper examines nudges that promote evacuation during heavy rainfall, preventative COVID-19 infection behaviors, and COVID-19 vaccination. The results showed that altruistic gain messages may have more sustained effects than others in promoting both evacuation during heavy rainfall and contact reduction behaviors as a measure against COVID-19 infection. Specifically, social influence nudges that use a gain frame to convey that a person's behavior promotes the behavior of others are effective for both heavy rainfall evacuations and encouraging COVID-19 vaccination., Competing Interests: Conflict of interestWe declare no conflicts of interest., (© The Author(s) 2021.)

The most promising way to prevent the explosive spread of COVID-19 infection is to achieve herd immunity through vaccination. It is therefore important to motivate those who are less willing to be vaccinated. To address this issue, we conducted an online survey of 6232 Japanese people to investigate age- and gender-dependent differences in attitudes towards COVID-19 vaccination and the underlying psychological processes. We asked participants to read one of nine different messages about COVID-19 vaccination and rate their willingness to be vaccinated. We also collected their 17 social personality trait scores and demographic information. We found that males 10-20 years old were least willing to be vaccinated. We also found that prosocial traits are the driving force for young people, but the motivation in older people also depends on risk aversion and self-interest. Furthermore, an analysis of 9 different messages demonstrated that for young people (particularly males), the message emphasizing the majority's intention to vaccinate and scientific evidence for the safety of the vaccination had the strongest positive effect on the willingness to be vaccinated, suggesting that the "majority + scientific evidence" message nudges young people to show their prosocial nature in action., (© 2021. The Author(s).)

This study investigates how people in Japan perceived the severity of and probability of infection from coronavirus disease 2019 (COVID-19), and how their willingness to purchase a hypothetical vaccine depends on these perceptions and their risk attitudes. We conducted a large-scale panel survey three times between 13 March to 13 April 2020 in Japan. By analyzing the data, we found that the perception of COVID-19 became more serious. The estimation of the fixed effect model reveals that a person becomes more willing to pay for a vaccine as the person evaluates COVID-19 as a more severe disease, considers a higher probability of infection, and becomes more risk averse. Since the sensitivity of willingness to pay for the vaccine on risk aversion increased during the period, the change in risk attitude contributed to an increase in willingness through the sensitivity channel, while it decreased through the magnitude channel.

Notch-Delta signaling regulates many developmental processes, including tissue homeostasis and maintenance of stem cells. Upon interaction of juxtaposed cells via Notch and Delta proteins, intracellular domains of both transmembrane proteins are cleaved and translocate to the nucleus. Notch intracellular domain activates target gene expression; however, the role of the Delta intracellular domain remains elusive. Here, we show the biological function of Delta like 1 intracellular domain (D1ICD) by modulating its production. We find that the sustained production of D1ICD abrogates cell proliferation but enhances neurogenesis in the developing dorsal root ganglia (DRG), whereas inhibition of D1ICD production promotes cell proliferation and gliogenesis. D1ICD acts as an integral component of lateral inhibition mechanism by inhibiting Notch activity. In addition, D1ICD promotes neurogenesis in a Notch signaling-independent manner. We show that D1ICD binds to Erk1/2 in neural crest stem cells and inhibits the phosphorylation of Erk1/2. In summary, our results indicate that D1ICD regulates DRG development by modulating not only Notch signaling but also the MAP kinase pathway., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

There have been numerous studies in which the biological role of oxytocin in trusting behavior has been investigated. However, a link between oxytocin and trust in humans was discovered only in one early study. We hypothesized that there is a large interindividual variation in oxytocin sensitivity, and that such variation is one reason for the doubt surrounding the role of oxytocin in trusting behavior. Here, in a double-blind, prospective, case-control study, we administered intranasal oxytocin to participants of trust and risk games. We measured salivary oxytocin concentration, relating it to the amount of money transferred among participants (a proxy for trust) and the autism-spectrum quotient (AQ). A one-sided Fisher's exact test was performed to detect differences between the oxytocin and placebo groups in the proportions of investors who transferred the maximum amount of money. We discovered a tendency for participants who received oxytocin to transfer higher amounts of money to co-participants than those who received a placebo ( P = 0.04). We also revealed a high degree of interindividual variation in salivary oxytocin concentrations after oxytocin administration. After stratifying the samples with respect to oxytocin sensitivity, oxytocin-sensitive participants in the oxytocin group also transferred higher amounts of money than those in the placebo group ( P = 0.03), while such a tendency was not observed for oxytocin-insensitive participants ( P = 0.34). Participants with lower AQ scores (less severe autistic traits) exhibited a greater tendency toward trusting behavior after oxytocin administration than did those with higher AQ scores ( P = 0.02). A two-sample t -test that was performed to detect significant differences in the mean transfers between the oxytocin and placebo groups indicated no significant between-group difference in the mean transfers ( P = 0.08). There are two possible interpretations of these results: First, there is no effect of oxytocin on trust in humans; second, the effects of oxytocin on trust in humans is person-dependent. However, the results should be interpreted with caution as the effect size was not larger than the minimal detectable effect size and the results were not statistically significant ( P > 0.05) after Bonferroni corrections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kurokawa, Kinari, Okudaira, Tsubouchi, Sai, Kikuchi, Higashida and Ohtake.)

Targeted protein degradation is an emerging therapeutic paradigm. Small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) induce the degradation of neo-substrates by hijacking E3 ubiquitin ligases. Although ubiquitylation of endogenous substrates has been extensively studied, the mechanism underlying forced degradation of neo-substrates is less well understood. We found that the ubiquitin ligase TRIP12 promotes PROTAC-induced and CRL2 VHL -mediated degradation of BRD4 but is dispensable for the degradation of the endogenous CRL2 VHL substrate HIF-1α. TRIP12 associates with BRD4 via CRL2 VHL and specifically assembles K29-linked ubiquitin chains, facilitating the formation of K29/K48-branched ubiquitin chains and accelerating the assembly of K48 linkage by CRL2 VHL . Consequently, TRIP12 promotes the PROTAC-induced apoptotic response. TRIP12 also supports the efficiency of other degraders that target CRABP2 or TRIM24 or recruit CRBN. These observations define TRIP12 and K29/K48-branched ubiquitin chains as accelerators of PROTAC-directed targeted protein degradation, revealing a cooperative mechanism of branched ubiquitin chain assembly unique to the degradation of neo-substrates., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In the process of community building, it is important to create a place for multigenerational exchanges. To promote multigenerational exchanges in regional locations, it is essential to clarify whether such exchanges are related to government infrastructure, regional characteristics, and social capital, and how these exchanges contribute to community building., Methods: A cross-sectional questionnaire study was conducted with representatives from 455 Chiiki no Cha-no-Ma (literal translation "community living room," and hereafter "Cha-no-Ma") in Niigata City, Japan. Responses were received from 405 representatives (response rate: 89.0 %), and 401 agreed to participate (4 declined). The survey details included basic information (e.g., date each location was established, frequency of meetings, number of caretakers and participants, qualifications of the representative), activities reflecting local culture, a social capital scale, the effects of the Cha-no-Ma implemented by the representative (12 items), challenges for management (16 items), and the implementation of multigenerational exchanges., Results: Most of the age groups that participated in the Cha-no-Ma were elderly, and multigenerational exchanges took place in 125 locations (31.5 %). Items that had a significant connection to the implementation of multigenerational exchanges were "Frequency of meetings" (p < 0.001) and "Activities reflecting local culture" (p = 0.026). Binomial logistic regression analysis indicated that a high frequency of meetings was associated with the implementation of multigenerational exchanges (Odds ratio = 3.839). There was a significantly higher ratio of implementation of multigenerational exchanges when the effects were a "connection with the region" (p = 0.006) and "conversations with different generations" (p = 0.004), and when the challenge was "no support from residents" (p = 0.002)., Conclusions: Cha-no-Ma participation is low among young people. The following ideas can be considered in order to increase multigenerational exchanges in regional locations. These exchanges may be promoted by increasing the frequency of meetings with qualified personnel and by adding activities that reflect local culture, such as festivals and making local foods. This community-based study clearly indicates that implementing multigenerational exchanges is an important activity for community building because it is related to connection within the community.

Mind bomb 2 (MIB2) is an E3 ligase involved in Notch signalling and attenuates TNF-induced apoptosis through ubiquitylation of receptor-interacting protein kinase 1 (RIPK1) and cylindromatosis. Here we show that MIB2 bound and conjugated K48- and K63-linked polyubiquitin chains to a long-form of cellular FLICE-inhibitory protein (cFLIP L ), a catalytically inactive homologue of caspase 8. Deletion of MIB2 did not impair the TNF-induced complex I formation that mediates NF-κB activation but significantly enhanced formation of cytosolic death-inducing signalling complex II. TNF-induced RIPK1 Ser 166 phosphorylation, a hallmark of RIPK1 death-inducing activity, was enhanced in MIB2 knockout cells, as was RIPK1 kinase activity-dependent and -independent apoptosis. Moreover, RIPK1 kinase activity-independent apoptosis was induced in cells expressing cFLIP L mutants lacking MIB2-dependent ubiquitylation. Together, these results suggest that MIB2 suppresses both RIPK1 kinase activity-dependent and -independent apoptosis, through suppression of RIPK1 kinase activity and ubiquitylation of cFLIP L , respectively.

Nudge-based messages have been employed in various countries to encourage voluntary contact-avoidance and infection-prevention behaviors to control the spread of COVID-19. People have been repeatedly exposed to such messages; however, whether the messages keep exerting a significant impact over time remains unclear. From April to August 2020, we conducted a four-wave online survey experiment to examine how five types of nudge-based messages influence Japanese people's self-reported preventive behaviors. In particular, we investigate how their behaviors are affected by repeated displays over time. The analysis with 4241 participants finds that only a gain-framed altruistic message, emphasizing their behavioral adherence would protect the lives of people close to them, reduces their frequency of going out and contacting others. We do not find similar behavioral changes in messages that contain an altruistic element but emphasize it in a loss-frame or describe their behavioral adherence as protecting both one's own and others' lives. Furthermore, the behavioral change effect of the gain-framed altruistic message disappears in the third and fourth waves, although its impact of reinforcing intentions remains. This message has even an adverse effect of worsening the compliance level of infection-prevention behaviors for the subgroup who went out less frequently before the experiment. The study's results imply that when using nudge-based messages as a countermeasure for COVID-19, policymakers and practitioners need to carefully scrutinize the message elements and wording and examine to whom and how the messages should be delivered while considering their potential adverse and side effects., Competing Interests: Conflict of interestWe declare no conflicts of interest., (© The Author(s) 2021.)

Background: In Japan, a recent opinion poll in 2017 showed that 41.9% of the respondents wished to donate their organs, but only 12.7% declared their intention to donate or not do so. Therefore, it is important to explore measures to prompt more individuals to register their intention about organ donation., Methods: A field experimental questionnaire survey was conducted to confirm the effect of a prompt message for registering intentions for organ donation, which was communicated at a driver's license center. The study employed a prospective randomized control design. Seven thousand six hundred fifteen individuals visited the Tokyo Fuchu License Examination Center to update their driver's license and received leaflets including a message prompting organ donation registration and the questionnaire. Of the participants who received leaflets, 3224 respondents provided complete responses to the questionnaire (valid response rate: 42.3%). Subsequently, a questionnaire survey was conducted to assess the participants' willingness to register for organ donation. A control condition and the following types of messages were used: peer-framed, gain-framed, loss-framed, reciprocity-framed, and peer + reciprocity-framed., Results: The reciprocity message emerged as a significant predictor of increase in immediate decision response. The loss-framed message was a significant predictor of decrease in no intention to register., Conclusions: This study found that reciprocity and loss-framed messages promoted the readiness to register for organ donation among individuals from a Japanese urban area. Mandatory distribution of prompt messages at every driver's license centers in Japan would be recommended.

The identification of true substrates of an E3 ligase is biologically important but biochemically difficult. In recent years, several techniques for identifying substrates have been developed, but these approaches cannot exclude indirect ubiquitination or have other limitations. Here we develop an E3 ligase substrate-trapping strategy by fusing a tandem ubiquitin-binding entity (TUBE) with an anti-ubiquitin remnant antibody to effectively identify ubiquitinated substrates. We apply this method to one of the RBR-type ligases, Parkin, and to one of the RING-type ligases, TRIM28, and identify previously unknown substrates for TRIM28 including cyclin A2 and TFIIB. Furthermore, we find that TRIM28 promotes cyclin A2 ubiquitination and degradation at the G1/S phase and suppresses premature entry into S phase. Taken together, the results indicate that this method is a powerful tool for comprehensively identifying substrates of E3 ligases.