Role of Prefrontal Cortex Circuitry in Maintaining Social Homeostasis.

Homeostasis is a fundamental concept in biology and ensures the stability of life by maintaining the constancy of physiological processes. Recent years have witnessed a surge in research interest in these physiological processes, with a growing focus on understanding the mechanisms underlying social homeostasis. This shift in focus underscores our increasing understanding of the importance of social interactions and their impact on individual well-being. In this review, we explore the interconnected research across three primary categories: understanding the neural mechanisms influencing set-points, defining contemporary factors that can disrupt social homeostasis, and identifying the potential contributions of social homeostatic failure in the development of psychiatric diseases. We also delve into the role of the prefrontal cortex and its circuitry in regulating social behavior, decision-making processes, and the manifestation of neuropsychiatric disorders such as depression and anxiety. Finally, we examine the influence of more recent factors such as growing social media exposure and the COVID-19 pandemic on mental health, highlighting their disruptive effects. We also identify gaps in current literature through the analysis of research trends and propose future research directions to advance our understanding of social homeostasis, with implications for mental health interventions.

DNA barcoding reveals a taxonomic fraud: Note on validity of Propomacrusmuramotoae (Coleoptera, Scarabaeidae).

Until the early 2000s, the genus Propomacrus was known to comprise two species, occurring in the Eastern Mediterranean and Southeast China. The discovery of Propomacrusmuramotoae Fujioka in Tibet and subsequently in Bhutan and Nepal, might play a crucial role in bridging the geographical distribution gap of the Euchirini tribe between the Mediterranean and Central China, offering profound insights into its evolution and biogeography. However, all specimens, including the holotype specimen, were sourced from a single insect vendor, with no further specimens found or catalogued in museum collections thereafter. During our examination of a P.muramotoae specimen from a private collection in South Korea, we found its COI gene sequence to be identical to that of P.bimucronatus (Pallas) from Turkey, a species known for its wide distribution and genetic variability across regional populations. This overlap in genetic identity raised significant doubts, further compounded by our detection of deliberate modifications in essential diagnostic features during morphological examination. All three specimens we examined showed crude modifications, including staining and artificial grinding. Despite our inability to access the P.muramotoae type specimens for direct examination-a challenge we attempted to overcome through various means-it is evident that significant fraudulent tampering has occurred with the P.muramotoae specimens. Therefore, a new synonymy is proposed: Propomacrusbimucronatus Pallas, 1781 = P.muramotoae Fujioka, 2007 (syn. nov.). We also advocate for a straightforward verification of the type specimen through molecular analysis of the COI barcode region and morphological re-examination under a microscope for those who have access to the type specimens.

New Paradigm of Identifiable General-response Cognitive Diagnostic Models: Beyond Categorical Data.

Cognitive diagnostic models (CDMs) are a popular family of discrete latent variable models that model students' mastery or deficiency of multiple fine-grained skills. CDMs have been most widely used to model categorical item response data such as binary or polytomous responses. With advances in technology and the emergence of varying test formats in modern educational assessments, new response types, including continuous responses such as response times, and count-valued responses from tests with repetitive tasks or eye-tracking sensors, have also become available. Variants of CDMs have been proposed recently for modeling such responses. However, whether these extended CDMs are identifiable and estimable is entirely unknown. We propose a very general cognitive diagnostic modeling framework for arbitrary types of multivariate responses with minimal assumptions, and establish identifiability in this general setting. Surprisingly, we prove that our general-response CDMs are identifiable under Q -matrix-based conditions similar to those for traditional categorical-response CDMs. Our conclusions set up a new paradigm of identifiable general-response CDMs. We propose an EM algorithm to efficiently estimate a broad class of exponential family-based general-response CDMs. We conduct simulation studies under various response types. The simulation results not only corroborate our identifiability theory, but also demonstrate the superior empirical performance of our estimation algorithms. We illustrate our methodology by applying it to a TIMSS 2019 response time dataset.

Monodispersed mesoscopic star-shaped gold particles via silver-ion-assisted multi-directional growth for highly sensitive SERS-active substrates.

Surface-enhanced Raman scattering (SERS) exploits localized surface plasmon resonances in metallic nanostructures to significantly amplify Raman signals and perform ultrasensitive analyses. A critical factor for SERS-based analysis systems is the formation of numerous electromagnetic hot spots within the nanostructures, which represent regions with highly concentrated fields emerging from excited localized surface plasmons. These intense hotspot fields can amplify the Raman signal by several orders of magnitude, facilitating analyte detection at extremely low concentrations and highly sensitive molecular identification at the single-nanoparticle level. In this study, mesoscopic star-shaped gold particles (gold mesostars) were synthesized using a three-step seed-mediated growth approach coupled with the addition of silver ions. Our study confirms the successful synthesis of gold mesostars with numerous sharp tips via the multi-directional growth effect induced by the underpotential deposition of silver adatoms (AgUPD) onto the gold surfaces. The AgUPD process affects the nanocrystal growth kinetics of the noble metal and its morphological evolution, thereby leading to intricate nanostructures with high-index facets and protruding tips or branches. Mesoscopic gold particles with a distinctive star-like morphology featuring multiple sharp projections from the central core were synthesized by exploiting this phenomenon. Sharp tips of the gold mesostars facilitate intense localized electromagnetic fields, which result in strong SERS enhancements at the single-particle level. Electromagnetic fields can be further enhanced by interparticle hot spots in addition to the intraparticle local field enhancements when arranged in multilayered arrays on substrates, rendering these arrays as highly efficient SERS-active substrates with improved sensitivity. Evaluation using Raman-tagged analytes revealed a higher SERS signal intensity compared to that of individual mesostars because of interparticle hot spots enhancements. These substrates enabled analyte detection at a concentration of 10- 9 M, demonstrating their remarkable sensitivity for trace analysis applications.

Differential Impact of Subcutaneous and Visceral Fat on Bone Changes after Gastrectomy.

Background: Osteoporosis and fragility fractures are crucial musculoskeletal complications in long-term survivors of gastric cancer. However, the relationship between changes in body composition after gastrectomy and bone loss has not been investigated. Therefore, this study aimed to explore whether computed tomography (CT)-derived body composition parameters are associated with bone loss after gastrectomy in patients with gastric cancer. Methods: We retrospectively reviewed medical records and abdomen CT scans of patients who underwent gastrectomy at Yonsei University Severance Hospital between 2009 and 2018. Patients with non-metastatic gastric adenocarcinoma and preoperative and postoperative non-contrast CT scans were analyzed. Section area of skeletal muscle (SMA), visceral fat (VFA), and subcutaneous fat (SFA) were assessed using semi-automatic segmentation software. Changes in trabecular bone attenuation of L1 mid-vertebra level (L1 Hounsfield units [HU]) were measured. Results: Fifty-seven patients (mean age, 65.5±10.6; 70.2% males) were analyzed, and the median duration was 31 months. Fortyseven patients (82.5%) lost weight after gastrectomy. Baseline SMA and VFA did not differ between the bone loss and preserved groups; however, baseline SFA was significantly higher in the bone preserved group than in the bone loss group (P=0.020). In a multivariable linear regression model adjusted for confounding factors, one standard deviation higher VFA at baseline was associated with greater annualized L1 HU loss (%) (P=0.034). However, higher preoperative SFA was associated with protection against bone loss after gastrectomy (P=0.025). Conclusion: Higher preoperative SFA exhibited a protective effect against bone loss after gastrectomy in patients with non-metastatic gastric cancer, whereas VFA exhibited a negative effect.

Molecular phylogeny reveals Varroa mites are not a separate family but a subfamily of Laelapidae.

Varroa mites, notorious for parasitizing honeybees, are generally classified as Varroidae. Their extremely modified morphologies and behaviors have led to debates regarding their phylogenetic position and classification as an independent family. In this study, two different datasets were employed to reconstruct the phylogenies of Varroa mites and related Laelapidae species: (1) 9257 bp from the whole 13 mitochondrial protein-coding genes of 24 taxa, (2) 3158 bp from 113 taxa using Sanger sequencing of four nuclear loci. Both mitochondrial and nuclear analyses consistently place Varroa mites within the Laelapidae. Here we propose to place Varroa mites in the subfamily Varroinae stat. nov., which represents a highly morphologically adapted group within the Laelapidae. Ancestral state reconstructions reveal that bee-associated lifestyles evolved independently at least three times within Laelapidae, with most phoretic traits originating from free-living ancestors. Our revised classification and evolutionary analyses will provide new insight into understanding the Varroa mites.

[Pediatric Hip Disorders]. / 소아 ê³ ê´€ì ˆ 질환.

Developmental dysplasia of the hip is a condition characterized by hip joint instability due to acetabular dysplasia in infancy, necessitating precise ultrasound examination. Legg-Calvé-Perthes disease is caused by a temporary disruption in blood flow to the femoral head during childhood, progressing through avascular, fragmentation, re-ossification, and residual stages. Slipped capital femoral epiphysis is a condition where the femoral head shifts medially along the epiphyseal line during adolescence due to stress, such as weight-bearing. Differentiating between transient hip synovitis and septic arthritis may require joint fluid aspiration. Osteomyelitis can be associated with soft tissue edema and osteolysis. When multiple lesions are present, it is essential to distinguish between Langerhans cell histiocytosis and metastatic neuroblastoma. This review will introduce imaging techniques and typical findings for these conditions.

Building Resilience and Social-Emotional Competencies in Elementary School Students through a Short-Term Intervention Program Based on the SEE Learning Curriculum.

This study explored the positive effects of a six-week Social-Emotional and Ethical Learning® (SEE Learning) program on resilience and social and emotional competences, adapted for elementary students in Daegu, South Korea, a region strongly affected by the first outbreak of COVID-19. A total of 348 third- and fourth-grade students from 15 elementary schools participated, and the curriculum was tailored, emphasizing key areas such as resilience, attention, kindness, attention training, and compassion. Repeated measures analysis of variance (RMANOVA) tests showed statistically significant improvements between pre- and post-tests in resilience and its subscales, including self-efficacy, tolerance of negative affect, positive support relations, power of control, and spontaneity, as well as in social and emotional competencies, including emotional regulation, social skills, empathy, and social tendencies. Despite a lack of maintenance in all areas, at follow-up, the mean scores for self-efficacy, tolerance of negative affect, and positive support relations, as well as emotional regulation, social skills, empathy, and social tendency, remained higher than pre-test levels, suggesting some lasting benefits. The findings underscore the potential of the SEE Learning program integrated with resilience, mindfulness, compassion, and ethical practices to enhance students' resilience and social and emotional well-being. This study contributes to the growing body of evidence supporting the use of mindfulness and compassion-based SEL programs to mitigate the adverse effects of traumatic events on children's mental health.

Generation of an induced pluripotent stem cell line from a patient with arrhythmogenic right ventricular cardiomyopathy harboring a TMEM43 splice-site variant.

Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.

Low-iodine-dose computed tomography coupled with an artificial intelligence-based contrast-boosting technique in children: a retrospective study on comparison with conventional-iodine-dose computed tomography.

BACKGROUND: Low-iodine-dose computed tomography (CT) protocols have emerged to mitigate the risks associated with contrast injection, often resulting in decreased image quality. OBJECTIVE: To evaluate the image quality of low-iodine-dose CT combined with an artificial intelligence (AI)-based contrast-boosting technique in abdominal CT, compared to a standard-iodine-dose protocol in children. MATERIALS AND METHODS: This single-center retrospective study included 35 pediatric patients (mean age 9.2 years, range 1-17 years) who underwent sequential abdominal CT scans-one with a standard-iodine-dose protocol (standard-dose group, Iobitridol 350 mgI/mL) and another with a low-iodine-dose protocol (low-dose group, Iohexol 240 mgI/mL)-within a 4-month interval from January 2022 to July 2022. The low-iodine CT protocol was reconstructed using an AI-based contrast-boosting technique (contrast-boosted group). Quantitative and qualitative parameters were measured in the three groups. For qualitative parameters, interobserver agreement was assessed using the intraclass correlation coefficient, and mean values were employed for subsequent analyses. For quantitative analysis of the three groups, repeated measures one-way analysis of variance with post hoc pairwise analysis was used. For qualitative analysis, the Friedman test followed by post hoc pairwise analysis was used. Paired t-tests were employed to compare radiation dose and iodine uptake between the standard- and low-dose groups. RESULTS: The standard-dose group exhibited higher attenuation, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) of organs and vessels compared to the low-dose group (all P-values < 0.05 except for liver SNR, P = 0.12). However, noise levels did not differ between the standard- and low-dose groups (P = 0.86). The contrast-boosted group had increased attenuation, CNR, and SNR of organs and vessels, and reduced noise compared with the low-dose group (all P < 0.05). The contrast-boosted group showed no differences in attenuation, CNR, and SNR of organs and vessels (all P > 0.05), and lower noise (P = 0.002), than the standard-dose group. In qualitative analysis, the contrast-boosted group did not differ regarding vessel enhancement and lesion conspicuity (P > 0.05) but had lower noise (P < 0.05) and higher organ enhancement and artifacts (all P < 0.05) than the standard-dose group. While iodine uptake was significantly reduced in low-iodine-dose CT (P < 0.001), there was no difference in radiation dose between standard- and low-iodine-dose CT (all P > 0.05). CONCLUSION: Low-iodine-dose abdominal CT, combined with an AI-based contrast-boosting technique exhibited comparable organ and vessel enhancement, as well as lesion conspicuity compared to standard-iodine-dose CT in children. Moreover, image noise decreased in the contrast-boosted group, albeit with an increase in artifacts.

Shear wave elastography and dispersion imaging for hepatic veno-occlusive disease prediction after pediatric hematopoietic stem cell transplantation: a feasibility study.

BACKGROUND: Non-invasive imaging modalities are warranted for diagnosing and monitoring veno-occlusive disease because early diagnosis and treatment improve the prognosis. OBJECTIVE: To evaluate the usefulness of liver shear wave elastography (SWE) and shear wave dispersion (SWD) imaging in diagnosing and monitoring veno-occlusive disease in pediatric patients. MATERIALS AND METHODS: We conducted a prospective cohort study at a single tertiary hospital from March 2021 to April 2022. The study protocol included four ultrasound (US) sessions: a baseline US and three follow-up US after hematopoietic stem cell transplantation. Clinical criteria, including the European Society for Blood and Marrow Transplantation criteria, were used to diagnose veno-occlusive disease. We compared clinical factors and US parameters between the veno-occlusive disease and non-veno-occlusive disease groups. The diagnostic performance of US parameters for veno-occlusive disease was assessed by plotting receiver operating characteristic (ROC) curves. We describe temporal changes in US parameters before and after veno-occlusive disease diagnosis. RESULTS: Among the 38 participants (mean age 10.7 years), eight developed veno-occlusive disease occurring 17.0 ± 5.2 days after hematopoietic stem cell transplantation. Liver stiffness, as measured by SWE (15.0 ± 6.2 kPa vs. 5.8 ± 1.8 kPa; P<0.001), and viscosity, as assessed with SWD (17.7 ± 3.1 m/s/kHz vs. 14.3 ± 2.8 m/s/kHz; P=0.015), were significantly higher in the veno-occlusive disease group compared to the non-veno-occlusive disease group at the time of diagnosis. Liver stiffness demonstrated the highest area under the ROC (AUROC) curves at 0.960, with an optimal predictive value of >6.5 kPa, resulting in sensitivity and specificity of 100% and 83.3%, respectively. Viscosity demonstrated an AUROC of 0.783, with an optimal cutoff value of 13.9 m/s/kHz for predicting veno-occlusive disease, with a sensitivity of 100% and specificity of 53.3%, respectively. Liver stiffness increased with disease severity and decreased during post-treatment follow-up. CONCLUSION: SWE may be a promising technique for early diagnosis and severity prediction of veno-occlusive disease. Furthermore, liver viscosity assessed by SWD may serve as an additional marker of veno-occlusive disease.

Association of sodium-glucose cotransporter 2 inhibitor use with risk of osteoporotic fracture among older women: A nationwide, population-based cohort study.

INTRODUCTION: We investigated the relationship between sodium-glucose cotransporter-2 inhibitor (SGLT2i) and fracture in elderly women diagnosed with type 2 diabetes mellitus (T2DM) and newly prescribed antidiabetic medications (ADMs). MATERIAL AND METHODS: We used the population-based cohort study data from the National Health Insurance Service of Korea (2013-2020). Women ≥65 years old with T2DM, who were newly prescribed ADMs other than glucagon-like peptide-1 receptor agonists and thiazolidinedione, and who had comprehensive health check-up data were included. RESULTS: A total of 1,333 SGLT2i users were matched in a 1:2 ratio with 2,626 non-SGLT2i users. After propensity score matching, mean age, body mass index, number of ADMs, and other covariates were well-balanced between SGLT2i users and non-SGLT2i users. During the follow-up period, a higher incidence of vertebral fractures in SGLT2i users than in non-SGLT2i users (incidence rate 19.2 vs. 13.8 per 1,000 person-years; hazard ratio 1.40, 95 % confidence interval 1.00-1.96, p = 0.049). No significant difference was noted in other types of fracture. CONCLUSION: SGLT2i use showed an increased risk of vertebral fracture than non-SGLT2i use in elderly women. Although further validation is required, SGLT2i should be cautiously prescribed in older women due to the potential association with fracture risk.

Caudal Agenesis: Classification Based on the Pathoembryogenesis of the Spinal Cord.

BACKGROUND AND OBJECTIVES: Caudal agenesis (CA) is a congenital disease characterized by lower vertebral bone defects. Previous classifications for CA were based on the levels of bony defects or the conus medullaris. We created a new pathoembryogenic classification that takes into account the level of conus, considering both its shape and filum. We evaluated its accuracy in reflecting the neurological status and the need for untethering. METHODS: Patients with radiologic studies available on our institute's electronic image view system between 1985 and 2019 were reviewed. Our classification categorized patients with CA into 3 groups: the failure of formation (a conus level > L1 or normal level conus with a blunt shape), the failure of regression (a conus level < L3 or normal level conus with a thickened filum or a filar lipoma), and the normal (a normal level conus without specific abnormalities). We analyzed which of the following 3 classifications better reflects the neurological status and the probability of recommending untethering: classifications based on (1) bony defect level, (2) conus level, and (3) pathoembryogenic mechanism. RESULTS: A total of 89 patients were included in this study. The pathoembryogenic classification revealed more significant differences in motor or sensory deficits compared with other classifications (failure of formation: 42%; failure of regression: 16%; and normal: 0%, P = .039). In addition, the pathoembryogenic classification emerged as a significant or suggestive predictive factor for motor and sensory deficits (motor: odds ratio 11.66, P = .007; sensory: odds ratio 5.44, P = .066). Notably, only the pathoembryogenic classification exhibited a significant difference in the probabilities of recommending untethering between groups (failure of formation: 42%; failure of regression: 81%; and normal 12%, P < .001). CONCLUSION: The correlation between bony classification and spinal cord abnormalities was exaggerated. Our new pathoembryogenic classification was valuable in prognosticating neurological status and identifying the patient group more likely to require untethering among patients with CA.

Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/ß-catenin signal pathway.

AIMS: Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. METHODS AND RESULTS: We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy (DCM) and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites-D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with ß-catenin. As a result, Wnt reporter activity, and Wnt target gene expression collectively indicate a decrease in Wnt/ß-catenin signaling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. CONCLUSIONS: Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.

CMOS-Integrated Ternary Content Addressable Memory using Nanocavity CBRAMs for High Sensing Margin.

The development of data-intensive computing methods imposes a significant load on the hardware, requiring progress toward a memory-centric paradigm. Within this context, ternary content-addressable memory (TCAM) can become an essential platform for high-speed in-memory matching applications of large data vectors. Compared to traditional static random-access memory (SRAM) designs, TCAM technology using non-volatile resistive memories (RRAMs) in two-transistor-two-resistor (2T2R) configurations presents a cost-efficient alternative. However, the limited sensing margin between the match and mismatch states in RRAM structures hinders the potential of using memory-based TCAMs for large-scale architectures. Therefore, this study proposes a practical device engineering method to improve the switching response of conductive-bridge memories (CBRAMs) integrated with existing complementary metal-oxide-semiconductor (CMOS) transistor technology. Importantly, this work demonstrates a significant improvement in memory window reaching 1.87 × 107 by incorporating nanocavity arrays and modifying electrode geometry. Consequently, TCAM cells using nanocavity-enhanced CBRAM devices can exhibit a considerable increase in resistance ratio up to 6.17 × 105, thereby closely approximating the sensing metrics observed in SRAM-based TCAMs. The improved sensing capability facilitates the parallel querying of extensive data sets. TCAM array simulations using experimentally verified device models indicate a substantial sensing margin of 65× enabling a parallel search of 2048 bits.

Optimizing Ultrathin 2D Transistors for Monolithic 3D Integration: A Study on Directly Grown Nanocrystalline Interconnects and Buried Contacts.

The potential of monolithic 3D integration technology is largely dependent on the enhancement of interconnect characteristics which can lead to thinner stacks, better heat dissipation, and reduced signal delays. Carbon materials such as graphene, characterized by sp2 hybridized carbons, are promising candidates for future interconnects due to their exceptional electrical, thermal conductivity and resistance to electromigration. However, a significant challenge lies in achieving low contact resistance between extremely thin semiconductor channels and graphitic materials. To address this issue, an innovative wafer-scale synthesis approach is proposed that enables low contact resistance between dry-transferred 2D semiconductors and the as-grown nanocrystalline graphitic interconnects. A hybrid graphitic interconnect with metal doping reduces the sheet resistance by 84% compared to an equivalent thickness metal film. Furthermore, the introduction of a buried graphitic contact results in a contact resistance that is 17 times lower than that of bulk metal contacts (>40 nm). Transistors with this optimal structure are used to successfully demonstrate a simple logic function. The thickness of active layer is maintained within sub-7 nm range, encompassing both channels and contacts. The ultrathin transistor and interconnect stack developed here, characterized by a readily etchable interlayer and low parasitic resistance, leads to heterogeneous integration of future 3D integrated circuits (ICs).

Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.

BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.

Cancer-associated fibroblast-derived Dickkopf-1 suppresses NK cell cytotoxicity in breast cancer.

Breast cancer is poorly immunogenic, hence able to evade T cell recognition and respond poorly to immune checkpoint blockade. Breast cancer cells can also evade NK cell-mediated immune surveillance, but the mechanism remains enigmatic. Dickkopf-1 (DKK1) is a Wnt/b-catenin inhibitor, whose levels are increased in breast cancer patients and correlate with reduced overall survival. DKK1 is expressed by cancer-associated fibroblasts (CAFs) in orthotopic breast tumors and patient samples, and at higher levels by bone cells. While bone-derived DKK1 contributes to the systemic elevation of DKK1 in tumor-bearing mice, CAFs represent the primary source of DKK1 at the tumor site. Systemic or bone-specific DKK1 targeting reduces primary tumor growth. Intriguingly, specific deletion of CAF-derived DKK1 also limits breast cancer progression, regardless of its elevated levels in circulation and in the bone. DKK1 does not support tumor proliferation directly but rather suppresses the activation and tumoricidal activity of NK cells. Importantly, increased DKK1 levels and reduced number of cytotoxic NK cells are detected in breast cancer patients with progressive bone metastases compared to those with stable disease. Our findings indicate that DKK1 creates a tumor-supporting environment through the suppression of NK cells in breast cancer.