The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Preconditioning-Induced Facilitation of Lactate Release from Astrocytes Is Essential for Brain Ischemic Tolerance.

A sublethal ischemic episode [termed preconditioning (PC)] protects neurons in the brain against a subsequent severe ischemic injury. This phenomenon is known as brain ischemic tolerance and has received much attention from researchers because of its robust neuroprotective effects. We have previously reported that PC activates astrocytes and subsequently upregulates P2X7 receptors, thereby leading to ischemic tolerance. However, the downstream signals of P2X7 receptors that are responsible for PC-induced ischemic tolerance remain unknown. Here, we show that PC-induced P2X7 receptor-mediated lactate release from astrocytes has an indispensable role in this event. Using a transient focal cerebral ischemia model caused by middle cerebral artery occlusion, extracellular lactate levels during severe ischemia were significantly increased in mice who experienced PC; this increase was dependent on P2X7 receptors. In addition, the intracerebroventricular injection of lactate protected against cerebral ischemic injury. In in vitro experiments, although stimulation of astrocytes with the P2X7 receptor agonist BzATP had no effect on the protein levels of monocarboxylate transporter (MCT) 1 and MCT4 (which are responsible for lactate release from astrocytes), BzATP induced the plasma membrane translocation of these MCTs via their chaperone CD147. Importantly, CD147 was increased in activated astrocytes after PC, and CD147-blocking antibody abolished the PC-induced facilitation of astrocytic lactate release and ischemic tolerance. Taken together, our findings suggest that astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release.

Changes in social norms during the early stages of the COVID-19 pandemic across 43 countries.

The emergence of COVID-19 dramatically changed social behavior across societies and contexts. Here we study whether social norms also changed. Specifically, we study this question for cultural tightness (the degree to which societies generally have strong norms), specific social norms (e.g. stealing, hand washing), and norms about enforcement, using survey data from 30,431 respondents in 43 countries recorded before and in the early stages following the emergence of COVID-19. Using variation in disease intensity, we shed light on the mechanisms predicting changes in social norm measures. We find evidence that, after the emergence of the COVID-19 pandemic, hand washing norms increased while tightness and punishing frequency slightly decreased but observe no evidence for a robust change in most other norms. Thus, at least in the short term, our findings suggest that cultures are largely stable to pandemic threats except in those norms, hand washing in this case, that are perceived to be directly relevant to dealing with the collective threat.

Central administered xenin induced Fos expression in nesfatin-1 neurons in rats.

Xenin is a 25-amino acid peptide identified in human gastric mucosa, which is widely expressed in peripheral and central tissues. It is known that the central or peripheral administration of xenin decreases food intake in rodents. Nesfatin-1/NUCB2 (nesfatin-1) has been identified as an anorexic neuropeptide, it is often found co-localized with many peptides in the central nervous system. After the intracerebroventricular administration of xenin on nesfain-1-like immunoreactivity (LI) neurons, we examined its effects on food intake and water intake in rats. As a result, Fos-LI neurons were observed in the organum vasculosum of the laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the supraoptic nucleus (SON), the paraventricular nucleus (PVN), the arcuate nucleus (Arc), the lateral hypothalamic area (LHA), the central amygdaloid nucleus (CAN), the dorsal raphe nucleus (DR), the locus coeruleus (LC), the area postrema (AP) and the nucleus of the solitary tract (NTS). After the administration, the number of Fos-LI neurons was significantly increased in the LC and the OVLT, the MnPO, the SFO, the SON, the PVN, the Arc, the LHA, the CAN, the DR, the AP and the NTS, compared with the control group. After the administration of xenin, we conducted double immunohistochemistry for Fos and nesfatin-1, and found that the number of nesfatin-1-LI neurons expressing Fos were significantly increased in the SON, the PVN, the Arc, the LHA, the CAN, the DR, the AP and the NTS, compared with the control group. The pretreatment of nesfatin-1 antisense significantly attenuated this xenin-induced feeding suppression, while that of nesfatin-1 missense showed no improvement. These results indicate that central administered xenin may have anorexia effects associated with activated central nesfatin-1 neurons.

Future-oriented thinking promotes positive attitudes toward the "Help Mark" in Japan.

The "Help Mark," created in Japan, is worn by people who need help in public settings. It is designed to induce help from others for those in need of help because of their hidden disabilities or health conditions. Several attempts have been made to publicize the meaning and implications of this wearable sign through various media. However, it is difficult to assert whether there is sufficient awareness regarding this sign in the Japanese society. The purpose of this study was to examine the type of messages that are more effective in promoting the "Help Mark" system (Study 1). Additionally, based on the data obtained in Study 1, we presented a newly designed poster to promote the "Help Mark" sign and attempted to empirically examine the effect of this poster (Study 2). The results suggest that a message that reflects that the "Help Mark" is for "everyone," based on future-oriented thinking, is more effective. Furthermore, it was indicated that people who saw the poster containing a message implying that the "Help Mark" is "for everyone" reported increased positive attitudes toward the "Help Mark" system. These results indicate that encouraging future-oriented thinking may lead to positive attitudes regarding the "Help Mark" system.

Effects of a novel hepatitis B anti-viral drug E-CFCP in renal organic acid transporters.

Currently, the emergence of drug resistance is an important issue in the treatment of hepatitis B virus (HBV). Recently, our collaborating group developed a novel long-acting anti-HBV drug, E-CFCP. However, until this study, the effects of E-CFCP in the kidney have remained unclarified. Using cell viability and uptake assays, we examined the effects of E-CFCP on the function of renal organic anion transporters (OATs). No cytotoxicity was shown related to the E-CFCP in the renal OATs in either assay. Thus, this study suggested that E-CFCP may be a novel, excellent candidate drug for the treatment of drug-resistant HBV.

Targeting L-type amino acid transporter 1 in urological malignancy: Current status and future perspective.

Amino acid transporters are responsible for the uptake of amino acids, critical for cell proliferation. L-type amino acid transporters play a major role in the uptake of essential amino acids. L-type amino acid transporter 1 (LAT1) exerts its functional properties by forming a dimer with 4F2hc. Utilizing this cancer-specificity, research on diagnostic imaging and therapeutic agents for malignant tumors targeting LAT1 progresses in various fields. In hormone-sensitive prostate cancer, the up-regulation of L-type amino acid transporter 3 (LAT3) through the androgen receptor (AR) has been identified. On the other hand, in castration-resistant prostate cancer, the negative regulation of LAT1 through AR has been determined. Furthermore, 4F2hc: a binding partner of LAT1, was identified as the specific downstream target of Androgen Receptor Splice Variant 7: AR-V7. LAT1 has been suggested to contribute to acquiring castration resistance in prostate cancer, making LAT1 a completely different therapeutic target from anti-androgens and taxanes. Increased expression of LAT1 has also been found in renal and bladder cancers, suggesting a contribution to acquiring malignancy and progression. In Japan, clinical trials of LAT1 inhibitors for solid tumors are in progress, and clinical applications are now underway. This article will summarize the relationship between LAT1 and urological malignancies.

Solicitation matters: Cultural differences in solicited and unsolicited support provision.

Two studies aimed to examine cultural differences in social support provision, with or without solicitation, in Japan and the United States (US). In Study 1, we replicated a previous study with Japanese university students. We found that the Japanese participants did not provide social support when it was not solicited, as compared with when it was solicited. Furthermore, in Study 2, participants were asked to respond to a questionnaire regarding a hypothetical stressful situation experienced by a close other and to indicate their willingness to provide support. We confirmed our hypothesis that Japanese participants hesitate to provide unsolicited support to close others (such as family members or close friends), even when they recognize that the close others are in need, whereas the American participants do not hesitate to provide such support. Contrastingly, regarding solicited support, the Japanese and Americans were equally ready to provide support, as hypothesized. The cultural difference in social support resides in the provision of unsolicited support. These results suggest that differences in culturally appropriate responses to needy people are responsible for the difference in the provision of unsolicited vs. solicited social support.

Potential influence of decision time on punishment behavior and its evaluation.

Previous studies on whether punishers are rewarded by reputational gains have yielded conflicting results. Some studies have argued that punitive behaviors potentially result in a positive evaluation, while others have found the opposite. This study aims to clarify the conditions that lead to the positive evaluation of costly punishment. Study 1 utilized one-round and repeated public goods game (PGG) situations and manipulated decision time for participants' punitive behavior toward the non-cooperative person in the situation. We also asked participants to report their impression evaluations of punitive behavior toward non-cooperative people. Moreover, utilizing the second- and third-party punishment games, Study 2 manipulated the decision time of participants' punitive behavior toward the self-interested person and asked them to evaluate the punitive behavior. The results showed that those who punished intuitively were not likely to be evaluated positively. However, punishers were rewarded when the decision to punish was made after deliberation or made by those who were not direct victims. These findings extend previous research on the evaluation of punitive behavior and reveal that deliberative punishment is evaluated positively occasionally.

Willingness to be the recipient during the dictator game.

OBJECTIVE: Researchers have investigated human altruism toward strangers for decades, using economic games such as the dictator game (DG) in their experiments. However, factors that cause the allocating behavior exhibited by those participants willing to be recipients in the DG have not been identified and the psychological mechanism of avoiding decision-making in economic games has not been widely addressed in previous studies. This study aimed to replicate previous findings regarding the number of people who are willing to be assigned the role of recipient and their allocation behavior and to explore why they share more than people who are willing to be dictators. RESULTS: We demonstrate that there are people willing to be assigned the role of the recipient, rather than the role of the dictator during the dictator game. In addition, we find evidence indicating that people who are willing to be recipients behave more altruistically in the dictator game than those who prefer to be dictators. Based on our results, we argue that willingness to be a recipient, in relation to the psychological unwillingness to assume responsibility and reputational concerns, is a strategic consideration.

Fickle Judgments in Moral Dilemmas: Time Pressure and Utilitarian Judgments in an Interdependent Culture.

In the trolley problem, a well-known moral dilemma, the intuitive process is believed to increase deontological judgments, while deliberative reasoning is thought to promote utilitarian decisions. Therefore, based on the dual-process model, there seems to be an attempt to save several lives at the expense of a few others in a deliberative manner. This study examines the validity of this argument. To this end, we manipulate decision-making time in the standard trolley dilemma to compare differences among 119 Japanese female undergraduates under three conditions: intuitive judgment, deliberative judgment, and judgment after a group discussion. The current results demonstrate that utilitarian judgments decreased from 52.9% in the intuition condition to 43.7% in the deliberation condition and 37.0% after the discussion. Additional analysis suggests that the decrease in utilitarian judgments may be related to psychological unwillingness to assume responsibility for the lives of others rather than to an increase in deontological judgments. Finally, these results are discussed from an adaptationist perspective.

Suppression of Cortical Microtubule Reorientation and Stimulation of Cell Elongation in Arabidopsis Hypocotyls under Microgravity Conditions in Space.

How microgravity in space influences plant cell growth is an important issue for plant cell biology as well as space biology. We investigated the role of cortical microtubules in the stimulation of elongation growth in Arabidopsis (Arabidopsis thaliana) hypocotyls under microgravity conditions with the Resist Tubule space experiment. The epidermal cells in the lower half of the hypocotyls of wild-type Columbia were longer in microgravity than at on-orbit 1 g, which precipitated an increase in the entire hypocotyl length. In the apical region, cortical microtubules adjacent to the outer tangential wall were predominantly transverse to the long axis of the cell, whereas longitudinal microtubules were predominant in the basal region. In the 9th to 12th epidermal cells (1 to 3 mm) from the tip, where the modification of microtubule orientation from transverse to longitudinal directions (reorientation) occurred, cells with transverse microtubules increased, whereas those with longitudinal microtubules decreased in microgravity, and the average angle with respect to the transverse cell axis decreased, indicating that the reorientation was suppressed in microgravity. The expression of tubulin genes was suppressed in microgravity. These results suggest that under microgravity conditions, the expression of genes related to microtubule formation was downregulated, which may cause the suppression of microtubule reorientation from transverse to longitudinal directions, thereby stimulating cell elongation in Arabidopsis hypocotyls.

Collegial Organizational Climate Alleviates Japanese Schoolteachers' Risk for Burnout.

The purpose of the current study was to examine the influence of individuals' help-seeking preference (HSP) and their collective perception of the organizational climate in school on teachers' mental health. Previous studies demonstrated that HSP was negatively associated with risk of burnout, suggesting that teachers who hesitate to seek help from their colleagues are more likely to have mental health problems. Thus, the current study hypothesized that a collegial organizational climate would be negatively associated with burnout. To test this hypothesis, we developed a scale to measure schoolteachers' collective perception of their organizational climate (Study 1), and the newly developed scale was used to assess its relationship with HSP and teachers' burnout risk (Study 2). The results demonstrated that younger teachers, a low level of help-seeking, and a less collaborative climate increased the risk of burnout. The results also showed a significant interaction effect, indicating that HSP was less closely associated with teachers' burnout risk if their organization was perceived as having a collegial climate. These findings clearly show how the social environment of a school's organizational climate can affect schoolteachers' mental health in Japan.

Investigation of Nostoc sp. HK-01, Cell Survival over Three Years during the Tanpopo Mission.

The survival of the terrestrial cyanobacterium Nostoc sp. HK-01 was tested as part of the Tanpopo mission experiment, which was conducted both outside and inside the International Space Station (ISS). The selection of Nostoc sp. HK-01 was based on the results of on-ground experiments that demonstrated that the cyanobacterium can survive simulated space environments. This study verified cell survival after exposure to the outside environment in low Earth orbit (LEO). We examined the cellular tolerance of Nostoc sp. HK-01 simultaneously outside and inside of the ISS over a 3-year period. After the experiments were conducted, we confirmed cell viability by fluorescein diacetate (FDA). Cell growth abilities for 3 years without sunlight in space-vacuum-exposed cells were not significantly different from those of cells kept in the dark of control cells in the ISS and on the ground. Though a few light-exposed cells in space vacuum survived outside the ISS after 3 years as judged by FDA staining assay, the survival could not be verified by testing the growth ability due to an insufficient number of cells. To the best of our knowledge, this is the first pure strain of Nostoc sp. HK-01 that survived in a space environment on the inside and outside of the ISS with and without sunlight for more than 3 years (1126 days).

Creating a positive perception toward inclusive education with future-oriented thinking.

OBJECTIVE: The purpose of this study was to examine the ways that encouraged people to develop positive attitudes and perceptions toward inclusive education. The Japanese special needs education system for students with disabilities has been shifting from a segregated model to a more inclusive form which is the major challenge facing educational systems around the world. While support for inclusive practices has grown rapidly in Japan, their implementation requires more attention. Considering these situations, in the current study, we experimentally manipulated future-oriented thinking and examined whether positive perceptions about inclusive education was enhanced if people acknowledged and realized that an inclusive society may improve the long-term welfare of not only people with disabilities but also people without disabilities or functional limitations. RESULTS: Our results partially confirmed that future-oriented thinking encouraged positive perceptions of inclusive education. It increased only when participants thought about the future employment of people with/without disabilities. No significant effects were found for the present orientation or control conditions.

Space Exposure of Amino Acids and Their Precursors during the Tanpopo Mission.

Amino acids have been detected in extraterrestrial bodies such as carbonaceous chondrites (CCs), which suggests that extraterrestrial organics could be the source of the first life on Earth, and interplanetary dust particles (IDPs) or micrometeorites (MMs) are promising carriers of extraterrestrial organic carbon. Some amino acids found in CCs are amino acid precursors, but these have not been well characterized. The Tanpopo mission was conducted in Earth orbit from 2015 to 2019, and the stability of glycine (Gly), hydantoin (Hyd), isovaline (Ival), 5-ethyl-5-methylhydantoin (EMHyd), and complex organics formed by proton irradiation from CO, NH3, and H2O (CAW) in space were analyzed by high-performance liquid chromatography and/or gas chromatography/mass spectrometry. The target substances showed a logarithmic decomposition over 1-3 years upon space exposure. Recoveries of Gly and CAW were higher than those of Hyd, Ival, and EMHyd. Ground simulation experiments showed different results: Hyd was more stable than Gly. Solar ultraviolet light was fatal to all organics, and they required protection when carried by IDPs/MMs. Thus, complex amino acid precursors (such as CAW) were possibly more robust than simple precursors during transportation to primitive Earth. The Tanpopo 2 mission is currently being conducted to expose organics to more probable space conditions.

Mutation Analysis of the rpoB Gene in the Radiation-Resistant Bacterium Deinococcus radiodurans R1 Exposed to Space during the Tanpopo Experiment at the International Space Station.

To investigate microbial viability and DNA damage, dried cell pellets of the radiation-resistant bacterium Deinococcus radiodurans were exposed to various space environmental conditions at the Exposure Facility of the International Space Station (ISS) as part of the Tanpopo mission. Mutation analysis was done by sequencing the rpoB gene encoding RNA polymerase ß-subunit of the rifampicin-resistant mutants. Samples included bacteria exposed to the space environment with and without exposure to UV radiation as well as control samples held in the ISS cabin and at ground. The mutation sites of the rpoB gene obtained from the space-exposed and ISS/ground control samples were similar to the rpoB mutation sites previously reported in D. radiodurans. Most mutations were found at or near the rifampicin binding site in the RNA polymerase ß-subunit. Mutation sites found in UV-exposed samples were mostly shared with non-exposed and ISS/ground control samples. These results suggest that most mutations found in our experiments were induced during procedures that were applied across all treatments: preparation, transfer from our laboratory to the ISS, return from the ISS, and storage before analysis. Some mutations may be enhanced by specific factors in the space experiments, but the mutations were also found in the spontaneous and control samples. Our experiment suggests that the dried cells of the microorganism D. radiodurans can travel without space-specific deterioration that may induce excess mutations relative to travel at Earth's surface. However, upon arrival at a recipient location, they must still be able to survive and repair the general damage induced during travel.

Four-Year Operation of Tanpopo: Astrobiology Exposure and Micrometeoroid Capture Experiments on the JEM Exposed Facility of the International Space Station.

The Tanpopo experiment was the first Japanese astrobiology mission on board the International Space Station. It included exposure experiments of microbes and organic compounds as well as a capture experiment of hypervelocity impacting microparticles. We deployed three Exposure Panels, each consisting of 20 Exposure Units that contained microbes, organic compounds, an alanine UV dosimeter or an ionizing radiation dosimeter. The three Exposure Panels were situated on the zenith face of the Exposed Experiment Handrail Attachment Mechanism (ExHAM) that was pointing in zenith direction toward space, which was attached on a handrail of the Japanese Experiment Module (Kibo) Exposed Facility (JEM-EF) outside the International Space Station. The three Exposure Panels were one by one retrieved and returned to the ground after approximately 1, 2, and 3 years of exposure to the space environment. Capture Panels, each of which contained one or two blocks of amorphous silica aerogel, were exposed to collect hypervelocity impact microparticles. Possible captured particles may include micrometeoroids, human-made orbital debris, and natural terrestrial particles. Each year, Capture Panels containing from 11 to 12 aerogel blocks were attached to the three faces of the ExHAM (pointing to zenith, ram, and port); they remained in place for about 1 year and were then returned to the laboratory. This process was repeated three times, in total, during 2015-2018. Additional exposure of a Capture Panel facing ram was conducted between 2018 and 2019. Once the aerogel blocks were returned to the laboratory, they were encapsulated in dedicated transparent plastic cases and optically inspected by a specially designed microscopic system. Once located and recorded, hypervelocity impact signatures were excavated one by one and distributed for further detailed analyses. The apparatus, operation, and environmental factors of all the Tanpopo experiments are summarized in this article.

Space Radiation Dosimetry at the Exposure Facility of the International Space Station for the Tanpopo Mission.

Radiation dosimetry was carried out at the exposure facility (EF) and the pressurized module (PM) of the Japanese Kibo module installed in the International Space Station as one study on environmental monitoring for the Tanpopo mission. Three exposure panels and three references including biological and organic samples and luminescence dosimeters were launched to obtain data for different exposure durations during 3 years from May 2015 to July 2018. The dosimeters were equipped with additional shielding materials (0.55, 2.95, and 6.23 g/cm2 mass thickness). The relative dose variation, as a function of shielding mass thickness, was observed and compared with Monte Carlo simulations with respect to galactic cosmic rays (GCRs) and typical solar energetic particles (SEPs). The mean annual dose rates were DEF = 231 ± 5 mGy/year at the EF and DPM = 82 ± 1 mGy/year at the PM during the 3 years. The PM is well shielded, and the GCR simulation indicated that the measured mean dose reduction ratio inside the module (DPM/DEF = 0.35) required ∼26 g/cm2 additional shielding mass thickness. Observed points of the dose reduction tendency could be explained by the energy ranges of protons (10-100 MeV), where the protons passed through, or were absorbed in, the shielding materials of different mass thickness that surrounded dosimeters.