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The objective of our project was to identify the sex attractant pheromone of queens of the slave-making ant Polyergus samurai, which was characterized as a blend of methyl 6-methylsalicylate and methyl 3-ethyl-4-methylpentanoate. Both compounds were identified in volatiles collected from squashed heads of queens, and in field trials, a blend of the two compounds was highly attractive to males. In contrast, males were not attracted to a blend of methyl 6-methylsalicylate with 3-ethyl-4-methylpentanol. Thus, the pheromone blend of this species is analogous to that of species in the Polyergus lucidus complex from eastern North America, rather than that of the Polyergus breviceps complex from western North America and the European species P. rufescens. These results are discussed in the context of speciation within the genus.

IntroductionGastric outlet obstruction caused by upper tract urothelial carcinoma is rare.Case presentationA 78-year-old man presented to the hospital with nausea and vomiting. No hematuria was observed. Computed tomography revealed a tumor in the right renal pelvis and duodenal stenosis. Gastrojejunostomy was performed to treat the symptoms of the gastric outlet obstruction so that the patient could resume oral intake and outpatient chemotherapy. Chemotherapy was unsuccessful, and the patient died 9 months after the gastrojejunostomy. Histological assessment of an autopsy specimen revealed plasmacytoid urothelial carcinoma with direct infiltration of the duodenal wall, which caused the stenosis.ConclusionAutopsy revealed a right renal pelvis cancer causing gastric outlet obstruction. Early gastrojejunostomy enabled oral intake and outpatient visits.

Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid progenitor cells unaffected. Thus, the proposed modeling strategy can be employed as a general procedure to identify cell type-specific parameters and to recommend treatment strategies for the selective targeting of specific cell types.

Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.

Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.

Both subjective and objective evaluations are essential for the treatment of insomnia. Lemborexant has been shown to be effective in the long-term based solely on a subjective basis, and no long-term objective measures have been evaluated under natural sleep conditions. Small, lightweight sleep electroencephalogram (EEG) monitor was used, instead of polysomnography, to objectively evaluate sleep at home 4 and 12 weeks after lemborexant treatment. Adults and elderly subjects with insomnia disorder, per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were enrolled in this open-label, single-arm, single-center trial. Objective and subjective measures of sleep were prospectively assessed. Sleep disturbance, excessive sleepiness, and depressive symptoms were assessed using questionnaires. A total of 45 subjects were screened, of which 33 were enrolled. Paired t-tests were conducted to evaluate changes in sleep variables and compared with the baseline; subjects showed significant improvements in objective sleep efficiency (SE) and subjective sleep parameters at weeks 4 and 12 following treatment with lemborexant. When baseline values were taken into account, a repeated-multivariate analysis of variance (MANOVA) revealed statistically significant changes in the objective measures. Sleep disturbance, excessive sleepiness, and depressive symptoms improved after three months of lemborexant treatment. Furthermore, lemborexant therapy improved nocturnal sleep, when measured objectively using sleep EEG monitoring at home, and improved daytime sleepiness and depressive symptoms in older adults with insomnia disorder.

The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, and the number of patients presenting with respiratory failure is rapidly increasing in Japan. An international meta-analysis has been conducted to identify genetic factors associated with the onset and severity of COVID-19, but these factors have yet to be fully clarified. Here, we carried out genomic analysis based on a genome-wide association study (GWAS) in Japanese COVID-19 patients to determine whether genetic factors reported to be associated with the onset or severity of COVID-19 in the international meta-GWAS are replicated in the Japanese population, and whether new genetic factors exist. Although no significant genome-wide association was detected in the Japanese GWAS, an integrated analysis with the international meta-GWAS identified for the first time the involvement of the IL17A/IL17F gene in the severity of COVID-19. Among nine genes reported in the international meta-GWAS as genes involved in the onset of COVID-19, the association of FOXP4-AS1 , ABO , and IFNAR2 genes was replicated in the Japanese population. Moreover, combined analysis of ABO and FUT2 genotypes revealed that the presence of oral AB antigens was significantly associated with the onset of COVID-19. FOXP4-AS1 and IFNAR2 were also significantly associated in the integrated analysis of the Japanese GWAS and international meta-GWAS when compared with severe COVID-19 cases and the general population. This made it clear that these two genes were also involved in not only the onset but also the severity of COVID-19. In particular, FOXP4-AS1 was not found to be associated with the severity of COVID-19 in the international meta-GWAS, but an integrated analysis with the Japanese GWAS revealed an association with severity. Individuals with the SNP risk allele found between IL17A and IL17F had significantly lower mRNA expression levels of IL17F, suggesting that activation of the innate immune response by IL17F may play an important role in the severity of SARS-CoV-2 infection.

Introduction In the treatment of insomnia, both subjective and objective evaluations are essential. The orexin receptor antagonist, lemborexant, has a favorable profile in terms of efficacy, acceptability, and tolerability for adults diagnosed with insomnia. To date, the long-term efficacy of lemborexant has been evaluated solely on a subjective basis, with no long-term objective measures under natural sleeping conditions. Therefore, a small, lightweight sleep electroencephalograph monitor was used to evaluate sleep objectively at home after 4 and 12 weeks of lemborexant treatment. Methods Adults and elderly subjects with insomnia disorder per DSM-5 were enrolled in an open-label, single-arm, single-center trial. Participants took lemborexant (5/10 mg) at bedtime for 12 weeks. In addition, they underwent a home-based sleep study at baseline and weeks 4 and 12. Sleep ­efficiency (SE), total sleep time (TST), latency to persistent sleep (LPS), and wake after sleep onset (WASO) were ­evaluated at home. Sleep disturbance (Pittsburgh sleep quality index: PSQI), ­sleepiness (Epworth sleepiness scale: ESS), and depressive symptoms (Beck depression index: BDI) were examined. Results 31 subjects completed the 4-week and 29 completed the 12-week assessments. Subjects showed significant improvements in objective SE at weeks 4 and 12 of treatment compared to untreated baseline. Objective TST tended to increase with the treatment at week 12. Mixed-effects linear analysis revealed that the poorer the sleep measures (SE, TST, LPS, and WASO) were at baseline, the more these measures improved with lemborexant. Scores of PSQI, ESS, and BDI significantly decreased (improved) with lemborexant treatment compared to those at baseline. Conclusion The findings from the analyses demonstrate objective improvement of SE with lemborexant treatment across 12 weeks and support the previously reported benefit of lemborexant using polysomnography. Support (if any)

Insomnia is a common disorder worldwide. Growing evidence has revealed that the microbiota-gut-brain axis contributes to the regulation of sleep continuity and duration, both directly and indirectly. Although lemborexant is effective in treating insomnia, its effect on the gut microbiota remains unclear. Here, we investigated the relationship between the gut microbiota and hypnotic use in insomnia. We enrolled 29 adults with insomnia and performed sleep electroencephalography and stool analyses at baseline and after 4 and 12 weeks of open-label lemborexant treatment. Changes in gut microbiota were analyzed using 16S rRNA sequencing and metabolite analysis was performed to assess short-chain fatty acids (SCFAs). Beta diversity (Jaccard dissimilarity) and Firmicutes/Bacteroidetes ratio significantly increased after administration of lemborexant for 12 weeks (p < 0.05). Seven genera were significantly different (p < 0.05). Among these, decreased significantly after 12 weeks of lemborexant treatment (p = 0.013), even after correcting for false discovery rates. was strongly negatively correlated with sleep efficiency (r = -0.754, p = 0.0003). showed opposite correlations with latency to persistent sleep and sleep efficiency after 12 weeks of lemborexant treatment (r = 0.523, p = 0.018, r = -0.516, p = 0.020, respectively). There were no significant differences in SCFAs during the treatment period. Our findings suggest that prolonged lemborexant treatment in individuals with insomnia may induce notable shifts in gut microbiota composition, including a significant reduction in underscoring the potential interaction between hypnotic use and gut microbial balance.