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.

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.

Effects of islatravir (4'-ethynyl-2-fluoro-2'-deoxyadenosine or EFdA) on renal tubular cells and islatravir's interactions with organic anion transporters.

Islatravir (ISL; 4'-ethynyl-2-fluoro-2'-deoxyadenosine or EFdA) is a novel reverse transcriptase translocation inhibitor and has a unique structure and high antiviral activity against wild-type and multidrug resistant HIV strains. In this study, we investigated whether islatravir (ISL) can cause kidney damage compared to tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). We also investigated interactions of these drugs with organic anion transporters (OATs). There is a large gap in ISL concentration between the pharmacological dose to proximal tubular cells and the clinical dose. ISL is unlikely to be taken up via OAT1 or OAT3; therefore, OAT1 and OAT3 may not be involved in the injury to tubular cells. Present data strongly suggests that ISL is not toxic to proximal tubules because blood levels of ISL are not high enough to cause kidney damage in the clinical setting.

Activation of central nesfatin-1/NucB2 after intraperitoneally administered cisplatin in rats.

Cisplatin, known as an anticancer drug, has been widely used; however, diverse disadvantageous side effects, including appetite loss, afflict patients. Nesfatin-1/NucB2, discovered as an anorexic neuropeptide, is broadly expressed in the central nervous system (CNS) and peripheral organ. In the present study, we examined the effects of intraperitoneally (i.p.) administered cisplatin on central nesfatin-1/NucB2. Saline, as control, or cisplatin (6 mg/kg dissolved in saline) was i.p. administered in adult male Wistar rats (180-220 g). Cumulative food intake was remarkably suppressed for at least 24 h and body weight was significantly smaller at 24 h after i.p. administration of cisplatin compared to control group. At 90 min after i.p. administration, they were perfused, followed by carrying out double-immunohistochemistry for Fos and nesfatin-1/NucB2. The percentage of nesfatin-1/NucB2 immunoreactive neurons expressing Fos was marked increased in the hypothalamus and brainstem after i.p. administration of cisplatin. Intracerebroventricularlly administered nesfatin-1/NucB2-antisense resulted in a significant attenuation of decreased food intake for 2 h after i.p. administration of cisplatin compared to nesfatin-1/NucB2-missense treated group. These results suggest that i.p. administration of cisplatin activated, at least in part, nesfatin-1/NucB2 neuron in the CNS and may exert anorexigenic effects in rats.

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition.

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders and obsessive-compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

Variations in atmospheric CO2 growth rates coupled with tropical temperature.

Previous studies have highlighted the occurrence and intensity of El Niño-Southern Oscillation as important drivers of the interannual variability of the atmospheric CO2 growth rate, but the underlying biogeophysical mechanisms governing such connections remain unclear. Here we show a strong and persistent coupling (r(2) ≈ 0.50) between interannual variations of the CO2 growth rate and tropical land-surface air temperature during 1959 to 2011, with a 1 °C tropical temperature anomaly leading to a 3.5 ± 0.6 Petagrams of carbon per year (PgC/y) CO2 growth-rate anomaly on average. Analysis of simulation results from Dynamic Global Vegetation Models suggests that this temperature-CO2 coupling is contributed mainly by the additive responses of heterotrophic respiration (Rh) and net primary production (NPP) to temperature variations in tropical ecosystems. However, we find a weaker and less consistent (r(2) ≈ 0.25) interannual coupling between CO2 growth rate and tropical land precipitation than diagnosed from the Dynamic Global Vegetation Models, likely resulting from the subtractive responses of tropical Rh and NPP to precipitation anomalies that partly offset each other in the net ecosystem exchange (i.e., net ecosystem exchange ≈ Rh - NPP). Variations in other climate variables (e.g., large-scale cloudiness) and natural disturbances (e.g., volcanic eruptions) may induce transient reductions in the temperature-CO2 coupling, but the relationship is robust during the past 50 y and shows full recovery within a few years after any such major variability event. Therefore, it provides an important diagnostic tool for improved understanding of the contemporary and future global carbon cycle.

Silica aerogel for capturing intact interplanetary dust particles for the Tanpopo experiment.

In this paper, we report the progress in developing a silica-aerogel-based cosmic dust capture panel for use in the Tanpopo experiment on the International Space Station (ISS). Previous studies revealed that ultralow-density silica aerogel tiles, comprising two layers with densities of 0.01 and 0.03 g/cm(3) developed using our production technique, were suitable for achieving the scientific objectives of the astrobiological mission. A special density configuration (i.e., box framing) aerogel with a holder was designed to construct the capture panels. Qualification tests for an engineering model of the capture panel as an instrument aboard the ISS were successful. Sixty box-framing aerogel tiles were manufactured in a contamination-controlled environment.

Rejection of unfair offers in the ultimatum game is no evidence of strong reciprocity.

The strong reciprocity model of the evolution of human cooperation has gained some acceptance, partly on the basis of support from experimental findings. The observation that unfair offers in the ultimatum game are frequently rejected constitutes an important piece of the experimental evidence for strong reciprocity. In the present study, we have challenged the idea that the rejection response in the ultimatum game provides evidence of the assumption held by strong reciprocity theorists that negative reciprocity observed in the ultimatum game is inseparably related to positive reciprocity as the two sides of a preference for fairness. The prediction of an inseparable relationship between positive and negative reciprocity was rejected on the basis of the results of a series of experiments that we conducted using the ultimatum game, the dictator game, the trust game, and the prisoner's dilemma game. We did not find any correlation between the participants' tendencies to reject unfair offers in the ultimatum game and their tendencies to exhibit various prosocial behaviors in the other games, including their inclinations to positively reciprocate in the trust game. The participants' responses to postexperimental questions add support to the view that the rejection of unfair offers in the ultimatum game is a tacit strategy for avoiding the imposition of an inferior status.

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line.

Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC.

A role of nesfatin-1/NucB2 in dehydration-induced anorexia.

Nesfatin-1/NucB2, an anorexigenic molecule, is expressed mainly in the hypothalamus, particularly in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN). Nesfatin-1/NucB2 is also expressed in the subfornical organ (SFO). Because the SON and PVN are involved in body fluid regulation, nesfatin-1/NucB2 may be involved in dehydration-induced anorexia. To clarify the effects of endogenous nesfatin-1/NucB2, we studied changes in nesfatin-1/NucB2 mRNA levels in the SFO, SON, and PVN in adult male Wistar rats after exposure to osmotic stimuli by using in situ hybridization histochemistry. Significant increases in nesfatin-1/NucB2 mRNA levels, ∼2- to 3-fold compared with control, were observed in the SFO, SON, and PVN following water deprivation for 48 h, consumption of 2% NaCl hypertonic saline in drinking water for 5 days, and polyethylene glycol-induced hypovolemia. In addition, nesfatin-1/NucB2 expression was increased in response to water deprivation in a time-dependent manner. These changes in nesfatin-1/NucB2 mRNA expression were positively correlated with plasma sodium concentration, plasma osmolality, and total protein levels in all of the examined nuclei. Immunohistochemistry for nesfatin-1/NucB2 revealed that nesfatin-1/NucB2 protein levels were also increased after 48 h of dehydration and attenuated by 24 h of rehydration. Moreover, intracerebroventricular administration of nesfatin-1/NucB2-neutralizing antibody after 48 h of water deprivation resulted in a significant increase in food intake compared with administration of vehicle alone. These results suggested that nesfatin-1/NucB2 is a crucial peptide in dehydration-induced anorexia.

Fluorescence imaging of microbe-containing particles shot from a two-stage Light-gas gun into an aerogel.

We have proposed an experiment (the Tanpopo mission) to capture microbes on the Japan Experimental Module of the International Space Station. An ultra low-density silica aerogel will be exposed to space for more than 1 year. After retrieving the aerogel, particle tracks and particles found in it will be visualized by fluorescence microscopy after staining it with a DNA-specific fluorescence dye. In preparation for this study, we simulated particle trapping in an aerogel so that methods could be developed to visualize the particles and their tracks. During the Tanpopo mission, particles that have an orbital velocity of ~8 km/s are expected to collide with the aerogel. To simulate these collisions, we shot Deinococcus radiodurans-containing Lucentite particles into the aerogel from a two-stage light-gas gun (acceleration 4.2 km/s). The shapes of the captured particles, and their tracks and entrance holes were recorded with a microscope/camera system for further analysis. The size distribution of the captured particles was smaller than the original distribution, suggesting that the particles had fragmented. We were able to distinguish between microbial DNA and inorganic compounds after staining the aerogel with the DNA-specific fluorescence dye SYBR green I as the fluorescence of the stained DNA and the autofluorescence of the inorganic particles decay at different rates. The developed methods are suitable to determine if microbes exist at the International Space Station altitude.

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.

The possible interplanetary transfer of microbes: assessing the viability of Deinococcus spp. under the ISS Environmental conditions for performing exposure experiments of microbes in the Tanpopo mission.

To investigate the possible interplanetary transfer of life, numerous exposure experiments have been carried out on various microbes in space since the 1960s. In the Tanpopo mission, we have proposed to carry out experiments on capture and space exposure of microbes at the Exposure Facility of the Japanese Experimental Module of the International Space Station (ISS). Microbial candidates for the exposure experiments in space include Deinococcus spp.: Deinococcus radiodurans, D. aerius and D. aetherius. In this paper, we have examined the survivability of Deinococcus spp. under the environmental conditions in ISS in orbit (i.e., long exposure to heavy-ion beams, temperature cycles, vacuum and UV irradiation). A One-year dose of heavy-ion beam irradiation did not affect the viability of Deinococcus spp. within the detection limit. Vacuum (10(-1) Pa) also had little effect on the cell viability. Experiments to test the effects of changes in temperature from 80 °C to -80 °C in 90 min (± 80 °C/90 min cycle) or from 60 °C to -60 °C in 90 min (± 60 °C/90 min cycle) on cell viability revealed that the survival rate decreased severely by the ± 80 °C/90 min temperature cycle. Exposure of various thicknesses of deinococcal cell aggregates to UV radiation (172 nm and 254 nm, respectively) revealed that a few hundred micrometer thick aggregate of deinococcal cells would be able to withstand the solar UV radiation on ISS for 1 year. We concluded that aggregated deinococcal cells will survive the yearlong exposure experiments. We propose that microbial cells can aggregate as an ark for the interplanetary transfer of microbes, and we named it 'massapanspermia'.

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.

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.

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.

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.