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Replication protein A (RPA) is a heterotrimeric complex and the major single-strand DNA (ssDNA) binding protein in eukaryotes. It plays important roles in DNA replication, repair, recombination, telomere maintenance, and checkpoint signaling. Because RPA is essential for cell survival, understanding its checkpoint signaling function in cells has been challenging. Several RPA mutants have been reported previously in fission yeast. None of them, however, has a defined checkpoint defect. A separation-of-function mutant of RPA, if identified, would provide significant insights into the checkpoint initiation mechanisms. We have explored this possibility and carried out an extensive genetic screen for Rpa1/Ssb1, the large subunit of RPA in fission yeast, looking for mutants with defects in checkpoint signaling. This screen has identified twenty-five primary mutants that are sensitive to genotoxins. Among these mutants, two have been confirmed partially defective in checkpoint signaling primarily at the replication fork, not the DNA damage site. The remaining mutants are likely defective in other functions such as DNA repair or telomere maintenance. Our screened mutants, therefore, provide a valuable tool for future dissection of the multiple functions of RPA in fission yeast.

Using large-scale objective sleep data derived from body acceleration signals of 68,604 Japanese residents ranging from adolescents to the elderly (10–89 years old), we found significant age- and gender-related differences in sleep properties (timing, duration, and quality) in real-life settings. Time-in-bed and total sleep time (TST) showed a U-shaped association with age, indicating their decrease in adulthood following their increase in the elderly. There was a remarkable shift in sleep phase toward earlier bedtime and earlier wake time with increasing age (> 20 years), together with worsening of sleep quality, which is estimated by sleep efficiency (SE) and wake time after sleep onset. Gender comparisons showed that TST was shorter in women than in similarly aged men, which is much evident after the age of 30 years. This was associated with later bedtimes and greater age-related deterioration of sleep quality in women. Compared to men in the same age group, women over age 50 demonstrated a greater reduction in SE with aging, due mainly to increasing durations of nighttime awakening. These differences can be attributed to several intricately intertwined causes, including biological aging as well as socio-cultural and socio-familial factors in Japan. In conclusion, our findings provide valuable insights on the characteristics of Japanese sleep habits.

Telomerase is a reverse transcriptase complex that ensures stable maintenance of linear eukaryotic chromosome ends by overcoming the end replication problem, posed by the inability of replicative DNA polymerases to fully replicate linear DNA. The catalytic subunit TERT must be assembled properly with its telomerase RNA for telomerase to function, and studies in Tetrahymena have established that p65, a La-related protein 7 (LARP7) family protein, utilizes its C-terminal xRRM domain to promote assembly of the telomerase ribonucleoprotein (RNP) complex. However, LARP7-dependent telomerase complex assembly has been considered as unique to ciliates that utilize RNA polymerase III to transcribe telomerase RNA. Here we show evidence that fission yeast Schizosaccharomyces pombe utilizes the p65-related protein Pof8 and its xRRM domain to promote assembly of RNA polymerase II-encoded telomerase RNA with TERT. Furthermore, we show that Pof8 contributes to repression of the transcription of noncoding RNAs at telomeres. A functional telomerase complex requires that the catalytic TERT subunit be assembled with the template RNA TER1. Here the authors show that Pof8, a possible LARP7 family protein, is required for assembly of the telomerase complex, and repression of lncRNA transcripts at telomeres in S. pombe .

Hidewaki Nakagawa and colleagues report a comprehensive genome-wide mutational landscape of 300 liver cancers from Japanese individuals. They identify candidate driver mutations, including ones in noncoding regions, and structural mutations affecting the expression of nearby genes. Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes ( NEAT1 and MALAT1 ), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known ( CDKN2A , CCND1 , APC , and TERT ) and new ( ASH1L , NCOR1 , and MACROD2 ) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

CD44v9 is expressed in cancer stem cells (CSC) and stabilizes the glutamate‐cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species (ROS). This mechanism confers ROS resistance to CSC and CD44v9‐expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD44v9 and xCT in hepatocellular carcinoma (HCC) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization (HAIC) therapy with cisplatin (CDDP); and (ii) whether combination of CDDP with sulfasalazine (SASP), an inhibitor of xCT, was more effective on tumor cells than CDDP alone by inducing ROS‐mediated apoptosis. Twenty non‐pretreated HCC tissues and 7 HCC tissues administered HAIC therapy with CDDP before surgical resection were subjected to immunohistochemistry analysis of CD44v9 and xCT expression. Human HCC cell lines HAK‐1A and HAK‐1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. CD44v9 positivity was significantly higher in HAIC‐treated tissues (5/7) than in non‐pretreated tissues (2/30), suggesting the involvement of CD44v9 in the resistance to HAIC. xCT was significantly expressed in poorly differentiated HCC tissues. Combination treatment effectively killed the CD44v9‐harboring HAK‐1B cells through ROS‐mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the xCT inhibitor SASP augmented ROS‐mediated apoptosis in CDDP‐treated HCC cells, in which the CD44v9‐xCT system functioned. As CD44v9 is typically expressed in HAIC‐resistant HCC cells, combination treatment with SASP with CDDP may overcome such drug resistance. This study is the first to show high expression of CD44v9, a cancer stem cell marker, in chemoresistant hepatocellular carcinoma cells, which were previously exposed to chemotherapeutic agents through hepatic arterial infusion chemoembolization.

The posttranslational modifiers SUMO and ubiquitin critically regulate the DNA damage response (DDR). Important crosstalk between these modifiers at DNA lesions is mediated by the SUMO-targeted ubiquitin ligase (STUbL), which ubiquitinates SUMO chains to generate SUMO-ubiquitin hybrids. These SUMO-ubiquitin hybrids attract DDR proteins able to bind both modifiers, and/or are degraded at the proteasome. Despite these insights, specific roles for SUMO chains and STUbL in the DDR remain poorly defined. Notably, fission yeast defective in SUMO chain formation exhibit near wild-type resistance to genotoxins and moreover, have a greatly reduced dependency on STUbL activity for DNA repair. Based on these and other data, we propose that a critical role of STUbL is to antagonize DDR-inhibitory SUMO chain formation at DNA lesions. In this regard, we identify a SUMO-binding Swi2/Snf2 translocase called Rrp2 (ScUls1) as a mediator of the DDR defects in STUbL mutant cells. Therefore, in support of our proposal, SUMO chains attract activities that can antagonize STUbL and other DNA repair factors. Finally, we find that Taz1TRF1/TRF2-deficiency triggers extensive telomeric poly-SUMOylation. In this setting STUbL, together with its cofactor Cdc48p97, actually promotes genomic instability caused by the aberrant processing of taz1Δ telomeres by DNA repair factors. In summary, depending on the nature of the initiating DNA lesion, STUbL activity can either be beneficial or harmful.

The purpose of this study was to examine neural network properties at separate time-points during recovery from traumatic brain injury (TBI) using graph theory. Whole-brain analyses of the topological properties of the fMRI signal were conducted in 6 participants at 3 months and 6 months following severe TBI. Results revealed alterations of network properties including a change in the degree distribution, reduced overall strength in connectivity, and increased \"small-worldness\" from 3 months to 6 months post injury. The findings here indicate that, during recovery from injury, the strength but not the number of network connections diminishes, so that over the course of recovery, the network begins to approximate what is observed in healthy adults. These are the first data examining functional connectivity in a disrupted neural system during recovery.

The efficacy of preoperative neoadjuvant chemoradiotherapy (NAC) in cases of pancreatic cancer with extremely poor prognoses has been reported. In this study, we aimed to identify novel biomarkers that reflect prognoses following chemoradiotherapy using tertiary lymphoid organs (TLO) expressed in the tumor microenvironment. Resected tumor specimens were obtained from 140 pancreatic cancer patients. We retrospectively investigated the clinical relevance of TLO by categorizing patients into those who underwent upfront surgery (surgery first [SF]) and those who received NAC. The immunological elements within TLO were analyzed by immunohistochemistry (IHC). In the IHC analysis, the proportions of CD8+ T lymphocytes, PNAd+ high endothelial venules, CD163+ macrophages and Ki‐67+ cells within the TLO were higher in the NAC group than in the SF group. In contrast, the proportion of programmed cell death‐1+ immunosuppressive lymphocytes within TLO was lower in the NAC group than in the SF group. The NAC group demonstrated favorable prognoses compared with the SF group. In the multivariate analysis, the TLO/tumor ratio was determined as an independent predictive prognostic factor. In conclusion, the administration of preoperative chemoradiotherapy may influence the immunological elements in the tumor microenvironment and result in favorable prognoses in pancreatic ductal adenocarcinoma patients. The administration of preoperative chemoradiotherapy may influence the immunological elements in the tumor microenvironment and result in favorable prognoses in pancreatic ductal adenocarcinoma patients.

Sleep disturbance is a major contributor to future health and occupational issues. Mobile health can provide interventions that address adverse health behaviors for individuals in a vulnerable health state in real-world settings (just-in-time adaptive intervention). This study aims to identify a subpopulation with vulnerable sleep state in daily life (study 1) and, immediately afterward, to test whether providing mobile health intervention improved habitual sleep behaviors and psychological wellness in real-world settings by conducting a microrandomized trial (study 2). Japanese workers (n=182) were instructed to collect data on their habitual sleep behaviors and momentary symptoms (including depressive mood, anxiety, and subjective sleep quality) using digital devices in a real-world setting. In study 1, we calculated intraindividual mean and variability of sleep hours, midpoint of sleep, and sleep efficiency to characterize their habitual sleep behaviors. In study 2, we designed and conducted a sleep just-in-time adaptive intervention, which delivered objective push-type sleep feedback messages to improve their sleep hours for a subset of participants in study 1 (n=81). The feedback messages were generated based on their sleep data measured on previous nights and were randomly sent to participants with a 50% chance for each day (microrandomization). In study 1, we applied hierarchical clustering to dichotomize the population into 2 clusters (group A and group B) and found that group B was characterized by unstable habitual sleep behaviors (large intraindividual variabilities). In addition, linear mixed-effect models showed that the interindividual variability of sleep hours was significantly associated with depressive mood (β=3.83; P=.004), anxiety (β=5.70; P=.03), and subjective sleep quality (β=-3.37; P=.03). In study 2, we found that providing sleep feedback prolonged subsequent sleep hours (increasing up to 40 min; P=.01), and this effect lasted for up to 7 days. Overall, the stability of sleep hours in study 2 was significantly improved among participants in group B compared with the participants in study 1 (P=.001). This is the first study to demonstrate that providing sleep feedback can benefit the modification of habitual sleep behaviors in a microrandomized trial. The findings of this study encourage the use of digitalized health intervention that uses real-time health monitoring and personalized feedback.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, drug discovery for PDAC treatment has proven complicated, leading to stagnant therapeutic outcomes. Here, we identify Glycogen synthase kinase 3 (GSK3) as a therapeutic target through a whole‐body genetic screening utilizing a ‘4‐hit’ Drosophila model mimicking the PDAC genotype. Reducing the gene dosage of GSK3 in a whole‐body manner or knocking down GSK3 specifically in transformed cells suppressed 4‐hit fly lethality, similar to Mitogen‐activated protein kinase kinase (MEK), the therapeutic target in PDAC we have recently reported. Consistently, a combination of the GSK3 inhibitor CHIR99021 and the MEK inhibitor trametinib suppressed the phosphorylation of Polo‐like kinase 1 (PLK1) as well as the growth of orthotopic human PDAC xenografts in mice. Additionally, reducing PLK1 genetically in 4‐hit flies rescued their lethality. Our results reveal a therapeutic vulnerability in PDAC that offers a treatment opportunity for patients by inhibiting multiple targets. In this study, we found that GSK3 and MEK are therapeutic targets in PDAC. Co‐targeting of these two kinases provides a therapeutic opportunity for PDAC patients.