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Tob is a member of the anti‐proliferative protein family, which functions in transcription and mRNA decay. We have previously demonstrated that Tob is involved in the general mechanism of mRNA decay by mediating mRNA deadenylation through interaction with Caf1 and a general RNA‐binding protein, PABPC1. Here, we focus on the role of Tob in the regulation of specific mRNA. We show that Tob binds directly to a sequence‐specific RNA‐binding protein, cytoplasmic polyadenylation element‐binding protein 3 (CPEB3). CPEB3 negatively regulates the expression of a target by accelerating deadenylation and decay of its mRNA, which it achieves by tethering to the mRNA. The carboxyl‐terminal RNA‐binding domain of CPEB3 binds to the carboxyl‐terminal unstructured region of Tob. Tob then binds Caf1 deadenylase and recruits it to CPEB3 to form a ternary complex. The CPEB3‐accelerated deadenylation was abrogated by a dominant‐negative mutant of either Caf1 or Tob. Together, these results indicate that Tob mediates the recruitment of Caf1 to the target of CPEB3 and elicits deadenylation and decay of the mRNA. Our results provide an explanation of how Tob regulates specific biological processes. Shortening of the 3′ poly(A) tail by deadenylation promotes mRNA decay. Here, the authors show that the anti‐proliferative protein Tob binds to the cytoplasmic polyadenylation element‐binding protein CPEB3 and recruits the deadenylase Caf1 to target mRNAs to promote deadenylation and mRNA turnover.

Many genes responsible for Malignant mesothelioma (MM) have been identified as tumor suppressor genes and it is difficult to target these genes directly at a molecular level. We searched for the gene which showed synthetic lethal phenotype with LATS2, one of the MM causative genes and one of the kinases in the Hippo pathway. Here we showed that knockdown of SMG6 results in synthetic lethality in LATS2-inactivated cells. We found that this synthetic lethality required the nuclear translocation of YAP1 and TAZ. Both are downstream factors of the Hippo pathway. We also demonstrated that this synthetic lethality did not require SMG6 in nonsense-mediated mRNA decay (NMD) but in regulating telomerase reverse transcriptase (TERT) activity. In addition, the RNA-dependent DNA polymerase (RdDP) activity of TERT was required for this synthetic lethal phenotype. We confirmed the inhibitory effects of LATS2 and SMG6 on cell proliferation in vivo. The result suggests an interaction between the Hippo and TERT signaling pathways. We also propose that SMG6 and TERT are novel molecular target candidates for LATS2-inactivated cancers such as MM.

Shugoshin 1 (SGO1) is required for accurate chromosome segregation during mitosis and meiosis; however, its other functions, especially at interphase, are not clearly understood. Here, we found that downregulation of SGO1 caused a synergistic phenotype in cells overexpressing MYCN. Downregulation of SGO1 impaired proliferation and induced DNA damage followed by a senescence-like phenotype only in MYCN-overexpressing neuroblastoma cells. In these cells, SGO1 knockdown induced DNA damage, even during interphase and this effect was independent of cohesin. Furthermore, MYCN-promoted SGO1 transcription and SGO1 expression tended to be higher in MYCN- or MYC-overexpressing cancers. Together, these findings indicate that SGO1 plays a role in the DNA damage response in interphase. Therefore, we propose that SGO1 represents a potential molecular target for treatment of MYCN -amplified neuroblastoma.

Liver fibrosis progression and regression are dynamic processes involving diverse hepatic and immune cell populations. Here, we utilize single-cell fixed RNA profiling (FLEX) of a TAA-induced mouse liver cirrhosis model, with and without a recovery phase, to depict the cellular landscape and molecular mechanisms of fibrosis resolution. The regression phase was characterized by the emergence of pericentral hepatocytes enriched in detoxification and antioxidant genes (e.g., Cyp2e1, Txn1), which secreted Rarres2 to modulate hepatic stellate cell (HSC) function. This was accompanied by the upregulation of scar-resolving genes (Mmp14, Ctsl), restoration of fenestrae in liver sinusoidal endothelial cells, anti-inflammatory phenotypes of Kupffer cells, a decrease in fibrogenic cholangiocyte subsets, and recovery-associated signatures in NK/T cells, B cells, and neutrophils. In contrast, SEMA4D secreted by monocyte-derived macrophages during fibrosis progression activated Plxnb2⁺ HSCs, and its blockade attenuated fibrosis in vivo. Furthermore, LMCD1 was identified as a novel marker for HSC activation and regulation. This single-cell atlas reveals key transcriptional programs and intercellular signaling pathways dependent on the fibrotic condition, offering new therapeutic targets for liver cirrhosis.

Behavioral and neuroscientific studies explore two pathways through which internalized social norms promote prosocial behavior. One pathway involves internal control of impulsive selfishness, and the other involves emotion-based prosocial preferences that are translated into behavior when they evade cognitive control for pursuing self-interest.Wemeasured 443 participants’ overall prosocial behavior in four economic games. Participants’ predispositions [social value orientation (SVO)] were more strongly reflected in their overall game behavior when they made decisions quickly than when they spent a longer time. Prosocially (or selfishly) predisposed participants behaved less prosocially (or less selfishly) when they spent more time in decision making, such that their SVO prosociality yielded limited effects in actual behavior in their slow decisions. The increase (or decrease) in slower decision makers was prominent among consistent prosocials (or proselfs) whose strong preference for prosocial (or proself) goals would make it less likely to experience conflict between prosocial and proself goals. The strong effect of RT on behavior in consistent prosocials (or proselfs) suggests that conflict between prosocial and selfish goals alone is not responsible for slow decisions. Specifically, we found that contemplation of the risk of being exploited by others (social risk aversion) was partly responsible for making consistent prosocials (but not consistent proselfs) spend longer time in decision making and behave less prosocially. Conflict between means rather than between goals (immediate versus strategic pursuit of self-interest) was suggested to be responsible for the time-related increase in consistent proselfs’ prosocial behavior. The findings of this study are generally in favor of the intuitive cooperation model of prosocial behavior.

Human prosociality has been traditionally explained in the social sciences in terms of internalized social norms. Recent neuroscientific studies extended this traditional view of human prosociality by providing evidence that prosocial choices in economic games require cognitive control of the impulsive pursuit of self-interest. However, this view is challenged by an intuitive prosociality view emphasizing the spontaneous and heuristic basis of prosocial choices in economic games. We assessed the brain structure of 411 players of an ultimatum game (UG) and a dictator game (DG) and measured the strategic reasoning ability of 386. According to the reflective norm-enforcement view of prosociality, only those capable of strategically controlling their selfish impulses give a fair share in the UG, but cognitive control capability should not affect behavior in the DG. Conversely, we support the intuitive prosociality view by showing for the first time, to our knowledge, that strategic reasoning and cortical thickness of the dorsolateral prefrontal cortex were not related to giving in the UG but were negatively related to giving in the DG. This implies that the uncontrolled choice in the DG is prosocial rather than selfish, and those who have a thicker dorsolateral prefrontal cortex and are capable of strategic reasoning (goal-directed use of the theory of mind) control this intuitive drive for prosociality as a means to maximize reward when there are no future implications of choices.

Hydrogen storage properties and reactivity for hydrogenation of acetylene in a series of CeNi5-xGax (x = 0, 0.5, 0.75, 1, 1.25, 1.5) alloys and Mg2Ni were determined and compared. The structure of CeNi5 (CaCu5 type) was maintained up to CeNi3.5Ga1.5 when Ni was replaced by Ga. The replacement facilitated hydrogenation absorption by creating larger interstitial spaces through expansion of the lattice, allowing CeNi4.25Ga0.75 to absorb the greatest proportion of hydrogen atoms among the alloys under the same conditions. The results showed that the absorbed hydrogen in CeNi3.75Ga1.25 improved reactivity. In contrast, Mg2Ni formed a hydride upon hydrogenation of acetylene and thus possessed much lower activity. The difference of the activity of absorbed hydrogen between CeNi5-xGax and Mg2Ni was confirmed from transient response tests under reaction gases alternately containing He and H2.

Trust attitude is a social personality trait linked with the estimation of others’ trustworthiness. Trusting others, however, can have substantial negative effects on mental health, such as the development of depression. Despite significant progress in understanding the neurobiology of trust, whether the neuroanatomy of trust is linked with depression vulnerability remains unknown. To investigate a link between the neuroanatomy of trust and depression vulnerability, we assessed trust and depressive symptoms and employed neuroimaging to acquire brain structure data of healthy participants. A high depressive symptom score was used as an indicator of depression vulnerability. The neuroanatomical results observed with the healthy sample were validated in a sample of clinically diagnosed depressive patients. We found significantly higher depressive symptoms among low trusters than among high trusters. Neuroanatomically, low trusters and depressive patients showed similar volume reduction in brain regions implicated in social cognition, including the dorsolateral prefrontal cortex (DLPFC), dorsomedial PFC, posterior cingulate, precuneus, and angular gyrus. Furthermore, the reduced volume of the DLPFC and precuneus mediated the relationship between trust and depressive symptoms. These findings contribute to understanding social- and neural-markers of depression vulnerability and may inform the development of social interventions to prevent pathological depression.

Classic electrocardiographic (ECG) voltage indexes have been applied to screen for left ventricular (LV) hypertrophy in hypertrophic cardiomyopathy (HC). However, it is unclear whether low ECG voltage reflects deteriorated electrical forces because of replacement of the myocardium by fibrotic tissues in HC. We investigated correlations between classic ECG voltage indexes (Cornell, total QRS voltage, and Sokolow-Lyon) and cardiac magnetic resonance (CMR) parameters focusing on the impact of low ECG voltage on the LV ejection fraction (LVEF) and myocardial fibrosis in HC. We studied 108 consecutive patients with HC who underwent CMR imaging with late gadolinium enhancement (LGE). Nineteen patients with complete right or left bundle branch block were excluded, leaving 89 patients for analysis (age 61.0 ± 13.9 years; 58 men). Of the 3 voltage indexes, the total QRS voltage and Sokolow-Lyon indexes were positively correlated with LVEF. For discriminating patients with end-stage HC (LVEF <50%) from patients with HC and preserved LVEF (≥50%), receiver-operating characteristic analysis revealed an excellent area under the curve of 0.87 for the total QRS voltage index and 0.90 for the Sokolow-Lyon index, whereas the area under the curve for the Cornell index was only 0.54 (p <0.01). Moreover, these 2 voltage indexes were negatively correlated with the extent of LGE-determined myocardial fibrosis when adjusted by the LV maximal wall thickness. In conclusion, low ECG voltage indexes may reflect increased myocardial fibrosis in patients with HC.

The aims of this study were (1) to determine whether the accumulation of coronary plaque burden assessed with coronary computed tomography angiography (CCTA) can predict future events and (2) to estimate the onset and progression of coronary atherosclerosis in patients with familial hypercholesterolemia (FH). Consecutive 101 Japanese patients with heterozygous FH (men = 52, mean age 56 ± 16 years, mean low-density lipoprotein cholesterol 264 ± 58 mg/dl) who underwent 64-detector row CCTA without known coronary artery disease were retrospectively evaluated by assigning a score (0 to 5) to each of 17 coronary artery segments according to the Society of Cardiovascular Computed Tomography guidelines. Those scores were summed and subsequently natural log transformed. The periods to major adverse cardiac events (MACE) were estimated using multivariable Cox proportional hazards models. During the follow-up period (median 941 days), 21 MACE had occurred. Receiver operating characteristic curve analyses identified a plaque burden score of 3.35 (raw score 28.5) as the optimal cutoff for predicting a worse prognosis. Multivariate Cox regression analysis identified the presence of a plaque score ≥3.35 as a significant independent predictor of MACE (hazard ratio = 3.65; 95% confidence interval 1.32 to 25.84, p <0.05). The regression equations were Y = 0.68X − 15.6 (r = 0.54, p <0.05) in male and Y = 0.74X − 24.8 (r = 0.69, p <0.05) in female patients with heterozygous FH. In conclusion, coronary plaque burden identified in a noninvasive, quantitative manner was significantly associated with future coronary events in Japanese patients with heterozygous FH and that coronary atherosclerosis may start to develop, on average, at age 23 and 34 years in male and female patients with heterozygous FH, respectively.