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Objectives The purpose of this study was to improve the previously developed Eulerian path-based water pipe network operation program. Methods Dynamic programming, integer programming, genetic algorithms, and harmonic search methods were reviewed to overcome memory limitations for program execution. However, it was found that the application of existing optimization techniques has limitations. Therefore, as an alternative method, a minimum hydraulic gradient method based on physical theory was introduced to establish a sequential pipes removal algorithm. Results and Discussion The excellence and the effectiveness of this program were proven through the existing pipe network and optimal path analysis using the EPANET2 input file of the test-bed Y_area. According to the results of the optimal path analysis, in the case of the Y_ area pipe network, 66 pipes and 6,465 m pipe length were analyzed to be possible for removal or maintenance, which was found to be 18.3% of the total pipe length. Conclusion According to the results of the optimal pipe network analysis derived by the minimum hydraulic gradient method, there was little change in the minimum pressure head, and it was evaluated that there was no effect on water supply from a hydraulic perspective. In particular, in terms of water quality, the minimum residual chlorine concentration was found to increase by 0.011 mg/L due to a decrease in residence time and pipe length, which was analyzed to improve water quality.

Since February 2022, the Ukrainian refugee crisis has been highlighting mental health problems associated with trauma and distress. This study aimed to evaluate the mental health status of twenty-seven refugee minors (10 to 18 years old) who fled Ukraine and temporarily settled in the Republic of Korea (ROK). This cross-sectional survey study aimed to evaluate the mental health status of ethnic Korean Ukrainian refugee minors. The Child and Adolescent Trauma Screen—Youth Report (CATS), generalized anxiety disorder seven-item scale (GAD-7), and subjective unit of distress scale (SUDs) were used for assessment. A preliminary analysis indicated that 77% Ukrainian refugee minors were exposed to and experienced war-related trauma. They are at a relatively low risk of trauma symptoms, anxiety, and distress due to stable family and visa status and a comparably better environment in the ROK. Meanwhile, refugee teenagers showed higher rates of psychological distress compared with refugee children. This finding suggests that an early psychological interventions in a host country may be beneficial to prevent mental health issues in refugee minors.

The bluetongue virus (BTV) is a significant animal pathogen with economic implications in the ruminant industry. Despite global reports on BTV detection and epidemiologic investigations, limited studies have focused on the virus in the ROK. In this study, BTV epidemiological research was conducted on blood samples from cattle and goat farms across nine regions during 2013–2014. The results showed that 3.33% of bovine blood samples (194/5824) and 0.19% of goat blood samples (2/1075) tested positive for BTV antibodies using ELISA. In Jeju-do, BTV RNA amplification occurred in 51 of 422 samples (12.1%) using real-time reverse transcription (RT-qPCR). The isolation of one sample revealed it as serotype 3, as indicated by the sequence of segments 2 (Seg-2) and 6 (Seg-6), associated with the eastern BTV topotype. However, based on Seg-1, -3, -4, -5, -7, -8, -9, and -10 analyses, the BTV-3/JJBB35 strain is more closely related to distinct BTV strains. These findings imply BTV circulation and that the Korean-isolated BTV might originate from Asian BTV strains due to multiple reassortment events. This study provides foundational data for ongoing BTV monitoring and disease-control policies in the ROK.

PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.

The objective of this study was to evaluate whether D-allulose has teratogenic effects on rats. A prenatal developmental toxicity test was conducted in SD rats in compliance with modified OECD guidelines test number 414, prenatal developmental toxicity study. Pregnant female rats received repeated doses of 1250, 2500, or 5000 mg/kg body weight D-allulose, or a vehicle control by gavage on GD 6–15. On GD 20, one day prior to the expected day of delivery, pregnant rats were weighed and anesthetized, and laparotomized to remove the uterine and its content were weighed. Fetuses were examined macroscopically for any soft tissue and skeletal changes. The evaluation indicators included general sign observation, body weight, food consumption, animal death, corpora lutea, numbers of embryonic or fetal deaths, and viable fetuses including live birth rate, fetal resorption rate, and stillbirth rate, as well as sex, body weights, and skeletal and soft tissue alterations of fetuses. No treatment-related abnormalities were observed in prenatal developmental toxicity and fetal malformation parameters, indicating that D-allulose had no teratogenic effects on pregnant rats and fetuses. From the findings of this prenatal developmental toxicity study, the NOAEL of D-allulose was estimated to be 5000 mg/kg/day in pregnant SD rats.

Background Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.Methods PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.Results In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.Conclusions We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.

Abstract There is an unmet need for new influenza vaccine strategies that compensate for impaired vaccine responses in elderly individuals. Here, we evaluated the effectiveness of a single-stranded RNA (ssRNA) as an adjuvant to enhance the efficacy of inactivated influenza vaccine (IIV) in mouse models. Immunization with the ssRNA along with IIV reduced viral titers as well as pathological and inflammatory scores in the lungs after influenza challenge in aged mice. ssRNA induced balanced Th1/Th2 responses with an increase in IgA titers. Moreover, the ssRNA adjuvant markedly increased the frequency of influenza HA-specific T cells and IFN-γ production along with the expression of genes related to innate and adaptive immune systems that could overcome immunosenescence in aged mice. Our findings indicate that ssRNA is an efficient vaccine adjuvant that boosts cellular and humoral immunity in aged mice, demonstrating its potential as a novel adjuvant for currently available influenza virus vaccines for elderly individuals.

Abstract Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies have shown that histone demethylases are implicated in osteoblastogenesis; however, little is known about the role of histone demethylases in osteoclast formation. Here, we identified KDM4B as an epigenetic regulator of osteoclast differentiation. Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency. Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. Using genome-wide chromatin immunoprecipitation (ChIP)-sequencing, we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation. We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure (euchromatinization) near the promoters of osteoclast-related genes through H3K9 demethylation, leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65. Finally, small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target for osteoporosis.

Glioblastomas (GBM) are frequently resistant to immune checkpoint blockade therapy. Here the authors show that treatment with an agonistic anti-GITR antibody converts tumor infiltrating regulatory T cells to effector cells, overcoming resistance to PD1 blockade in preclinical models of GBM.

d-Psicose, a rare sugar, not only has very low caloric value but possesses anti-adipogenic properties. Here, we identified target genes in adipose tissue affected by d-psicose by transcriptomic analysis and provided mechanistic explanations for the anti-adipogenic effect. C57BL/6J ob/ob mice were fed with a control or 5% d-psicose diet for 12 weeks. d-Psicose decreased final body weight, adipose tissue mass, adipocyte size, and serum total cholesterol levels. We identified 103 differentially expressed genes involved in inflammatory response, molecular transport, and lipid metabolism consequent to d-psicose administration. Genes related to inflammation and adipo/lipogenesis were significantly down-regulated, whereas those associated with β-oxidation were up-regulated by d-psicose. Our data suggest that Fos, Mmp3, Fgf21, and Abcd2 might be key target genes associated with d-psicose-induced changes in lipid metabolism and subsequent chronic inflammatory responses. d-Psicose is thus a promising sugar substitute possessing a direct gene-regulatory function related to the suppression of body fat deposition.

Summary: Follicular regulatory T (TFR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3+ TFR cells is essential for TFR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in TFR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of TFR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient TFR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated TFR homing into the GC. These findings uncover a Blimp1-dependent TFR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry. : Wang et al. identify Blimp1 as a critical transcription factor for the proper positioning and stable expression of the suppressive activity of TFR cells that control GC responses. In the absence of Blimp1, unstable TFR cells prematurely migrate into the GC and differentiate into TFH-like cells to promote dysregulated GC responses. Keywords: humoral tolerance, regulatory T cells, follicular regulatory T cells, follicular helper T cells, germinal center response, germinal center positioning, Blimp1, TFR lineage stability

Summary: PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients. : Ding et al. show that PARP inhibition in Brca1-deficient tumors elicits strong antitumor immunity involving activation of both innate and adaptive immune responses, a process that is dependent on STING pathway activation. In addition, they show that addition of PD-1 blockade augments the therapeutic efficacy of PARP inhibitor treatment. Keywords: PARP inhibition, BRCA deficiency, STING, immune response, PD-1 blockade, ovarian cancer, targeted therapy, immunotherapy, GEMM

The effectiveness of vaccines is enhanced by adding adjuvants. Furthermore, the selection of an inoculation route depends on the type of adjuvant used and is important for achieving optimum vaccine efficacy. We investigated the immunological differences between two types of vaccines—spike protein from the Middle East respiratory syndrome virus and inactivated influenza virus vaccine, in combination with a single-stranded RNA adjuvant—administered through various routes (intramuscular, intradermal, and intranasal) to BALB/c mice. Intramuscular immunization with the RNA adjuvant-formulated spike protein elicited the highest humoral immune response, characterized by IgG1 and neutralizing antibody production. Although intranasal immunization did not elicit a humoral response, it showed extensive T-cell activation through large-scale induction of interferon-γ- and interleukin-2-secreting cells, as well as CD4+ T-cell activation in mouse splenocytes. Moreover, only intranasal immunization induced IgA production. When immunized with the inactivated influenza vaccine, administration of the RNA adjuvant via all routes led to protection after viral challenge, regardless of the presence of a vaccine-specific antibody. Therefore, the inoculation route should depend on the type of immune response needed; i.e., the intramuscular route is suitable for eliciting a humoral immune response, whereas the intranasal route is useful for T-cell activation and IgA induction.

Adjuvants enhance the efficacy of vaccines by stimulating immune response-related gene expression and pathways. Although some adjuvants have been approved for commercial use in human vaccines (e.g., Alum, MF59, and AS03), they might elicit adverse side effects, such as autoimmune diseases. Recently, we developed a novel single-stranded RNA (ssRNA) nano-structure adjuvant, which can stimulate both Th1 and Th2 responses. In this study, we evaluated the safety and toxicological profiles of this ssRNA nano-structure adjuvant in vitro and in vivo. Mice were intramuscularly immunized with the ssRNA nano-structure adjuvant three times, once every 2 weeks. The results indicate no significant differences in hematological and serum biochemistry parameters between the ssRNA-treated groups and the control group. From a histopathological perspective, no evidence of tissue damage was found in any group. The levels of IgE and anti-nuclear antibodies, which are markers of autoimmune disease, were not different between the ssRNA-treated groups and the control group. The findings of this study suggest that the ssRNA nano-structure can be used as a safe adjuvant to increase vaccine efficacies.

LRRK2 (leucine-rich repeat kinase 2) has been identified as agene corresponding to PARK8, an autosomal-dominant genefor familial Parkinson’s disease (PD). LRRK2 pathogenicspecificmutants induce neurotoxicity and shorten neurites. Toelucidate the mechanism underlying LRRK2 expression, weconstructed the LRRK2-promoter-luciferase reporter and used itfor promoter analysis. We found that the glucocorticoid receptor(GR) transactivated LRRK2 in a ligand-dependent manner.Using quantitative RT-PCR and Western analysis, we furthershowed that treatment with dexamethasone, a synthetic GRligand, induced LRRK2 expression at both the transcriptionaland translational levels, in dopaminergic MN9D cells. Dexamethasonetreatment also increased expression of α-synuclein,another PD causative gene, and enhanced transactivation ofthe α-synuclein promoter-luciferase reporter. In addition, dexamethasonetreatment to MN9D cells weakly induced cytotoxicitybased on an LDH assay. Because glucocorticoidhormones are secreted in response to stress, our data suggestthat stress might be a related factor in the pathogenesis of PD.[BMB Reports 2013; 46(9): 454-459]

Developing thymocytes undergo a rigorous selection process to ensure that the mature T cell population expresses a T cell receptor (TCR) repertoire that can functionally interact with major histocompatibility complexes (MHC). Over 90% of thymocytes fail this selection process and die. A small number of macrophages within the thymus are responsible for clearing the large number of dying thymocytes that must be continuously cleared. We studied the capacity of thymic macrophages to clear apoptotic cells under acute circumstances. This was done by synchronously inducing cell death in the thymus and then monitoring the clearance of apoptotic thymocytes. Interestingly, acute cell death was shown to recruit large numbers of CD11b(+) cells into the thymus. In the absence of a minor CSF-1 dependent population of macrophages, the recruitment of these CD11b(+) cells into the thymus was greatly reduced and the clearance of apoptotic cells was disrupted. To assess a possible role for the CD11b(+) cells in the clearance of apoptotic cells, we analyzed mice deficient for eosinophils and mice with defective trafficking of neutrophils. Failure to attract either eosinophils or neutrophils to the thymus resulted in the impaired clearance of apoptotic cells. These results suggested that there is crosstalk between cells of the innate immune system that is necessary for maximizing the efficiency of apoptotic cell removal.

Background: Data-driven digital learning could improve the diagnostic performance of novice students for thyroid nodules. Objective: To evaluate the efficacy of digital self-learning and artificial intelligence-based computer-assisted diagnosis (AI-CAD) for inexperienced readers to diagnose thyroid nodules. Methods: Between February and August 2023, a total of 26 readers (less than 1 year of experience in thyroid US from various departments) from 6 hospitals participated in this study. Readers completed an online learning session comprising 3,000 thyroid nodules annotated as benign or malignant independently. They were asked to assess a test set consisting of 120 thyroid nodules with known surgical pathology before and after a learning session. Then, they referred to AI-CAD and made their final decisions on the thyroid nodules. Diagnostic performances before and after self-training and with AI-CAD assistance were evaluated and compared between radiology residents and readers from different specialties. Results: AUC (area under the receiver operating characteristic curve) improved after the self-learning session, and it improved further after radiologists referred to AI-CAD (0.679 vs 0.713 vs 0.758, p<0.05). Although the 18 radiology residents showed improved AUC (0.7 to 0.743, p=0.016) and accuracy (69.9% to 74.2%, p=0.013) after self-learning, the readers from other departments did not. With AI-CAD assistance, sensitivity (radiology 70.3% to 74.9%, others 67.9% to 82.3%, all p<0.05) and accuracy (radiology 74.2% to 77.1%, others 64.4% to 72.8%, all p <0.05) improved in all readers. Conclusion: While AI-CAD assistance helps improve the diagnostic performance of all inexperienced readers for thyroid nodules, self-learning was only effective for radiology residents with more background knowledge of ultrasonography. [ABSTRACT FROM AUTHOR]

Ectopic breast tissue can develop along the mammary ridge from the axilla to the groin, and the most common site is the axillae. Primary carcinoma of ectopic breast tissue is extremely rare. We report a rare case of a 61-year-old woman with a palpable mass in her left axilla who had a history of surgical excision of accessory breast tissue in the same area. Mammography (MMG), including axillary tail view, ultrasound (US), and breast MRI were performed. We evaluated the extent and characteristics of the microcalcifications in the axillary tail view. A US-guided biopsy was done, and histopathology revealed an invasive ductal carcinoma. Enhanced abdominal CT revealed multiple hepatic masses consistent with metastases, and the patient received palliative chemotherapy. Herein, we present a rare case of breast cancer arising from accessory breast tissue in the axilla, best appreciated on the axillary tail view of the patient's MMG. [ABSTRACT FROM AUTHOR]

Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses. [ABSTRACT FROM AUTHOR]