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Abstract Three-dimensional (3-D) analysis of intraepidermal nerve fibers (IENFs) is conducted to advance assessment methods for peripheral neuropathies and pruritic skin disorders. The skin-clearing technique was proven to be a reliable method for 3-D imaging of IENFs. Nonetheless, it still requires further improvement in the imaging process. The aim of this study was to standardize the 3-D evaluation method of IENFs and to suggest promising 3-D biomarkers for clinical application. A total of nine healthy individuals were prospectively enrolled. The newly adopted suction blister method was combined with the tissue-clearing technique. The detailed structure of the IENFs was reconstructed and quantified using the neuron tracing software. The suction blister method showed improved linear integrity of IENFs compared with those obtained from the previously used salt-split skin test. The 3-D parameters most significantly related to natural aging were the convex hull two-dimensional perimeter and the total length (both p = 0.020). The meaningful correlations were followed by total volume (p = 0.025), ends (p = 0.026), convex hull 3-D surface, and complexity (both p = 0.030). Thus, the 3-D parameters could be utilized as possible biomarkers to identify ambiguous pathologies of peripheral neuropathies and pruritic skin disorders.

Abstract Converging evidence suggests that oxytocin (OT) is associated with creative thinking (CT) and that release of OT depends on ADP ribosyl-cyclases (CD38 and CD157). Neural mechanisms of CT and OT show a strong association with dopaminergic (DA) pathways, yet the link between CT and CD38, CD157, dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) peripheral gene expression remain inconclusive, thus limiting our understanding of the neurobiology of CT. To address this issue, two principal domains of CT, divergent thinking (AUT), were assessed. In men, both AUT is associated with gene expression of CD38, CD157, and their interaction CD38 × CD157. There were no significant associations for DA expression (DRD2, COMT, DRD2 × COMT) on both CT measures. However, analysis of the interactions of OT and DA systems reveal significant interactions for AUT in men. The full model explained a sizable 39% of the variance in females for the total CT score. The current findings suggest that OT and DA gene expression contributed significantly to cognition and CT phenotype. This provides the first empirical foundation of a more refined understanding of the molecular landscape of CT.

Summary: Background: There have been mixed reports on the beneficial effects of meditation in cardiovascular disease (CVD), which is widely considered the leading cause of death worldwide. Methods: To clarify the role of meditation in modulating the heart-brain axis, we implemented an extreme phenotype strategy, i.e., Tibetan monks (BMI > 30) who practised 19.20 ± 7.82 years of meditation on average and their strictly matched non-meditative Tibetan controls. Hypothesis-free advanced proteomics strategies (Data Independent Acquisition and Targeted Parallel Reaction Monitoring) were jointly applied to systematically investigate and target the plasma proteome underlying meditation. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B) and lipoprotein (a) [Lp(a)] as the potential cardiovascular risk factors were evaluated. Heart rate variability (HRV) was assessed by electrocardiogram. Findings: Obesity, hypertension, and reduced HRV is offset by long-term meditation. Notably, meditative monks have blood pressure and HRV comparable to their matched Tibetan controls. Meditative monks have a protective plasma proteome, related to decreased atherosclerosis, enhanced glycolysis, and oxygen release, that confers resilience to the development of CVD. In addition, clinical risk factors in plasma were significantly decreased in monks compared with controls, including total cholesterol, LDL-C, Apo B, and Lp(a). Interpretation: To our knowledge, this work is the first well-controlled proteomics investigation of long-term meditation, which opens up a window for individuals characterized by a sedentary lifestyle to improve their cardiovascular health with an accessible method practised for more than two millennia. Funding: See the Acknowledgements section.

Abstract Background Whereas meditation training has been purported to support slower cellular aging, little work has explored the association among different facets of dispositional mindfulness, self-compassion, and cellular aging. The present study aimed to examine the relationship between leukocyte telomere length (LTL), an index of cellular aging, dispositional mindfulness, and self-compassion in a sample of Singaporean Chinese adults. Methods One hundred and fifty-eight Chinese adults (mean age = 27.24 years; 63.3% female) were recruited from the community and completed self-report measures assessing dispositional mindfulness, self-compassion, and psychological symptoms, as well as provided blood samples for analyses of LTL. Multiple regression analyses were conducted to examine the role of trait mindfulness and self-compassion in predicting LTL, taking into consideration potential covariates such as chronological age and psychological symptoms. Results Results showed that nonreactivity, one of the five facets of dispositional mindfulness, was significantly associated with LTL, after controlling for chronological age. There was also a trend for dispositional mindfulness, self-compassion, and their selected facets (i.e., nonjudging, common humanity, and de-identification) to each be associated with longer LTL. Conclusions Overall, the findings provide preliminary support for the association among aspects of dispositional mindfulness, self-compassion, and aging. In particular, individuals high on nonreactivity experience slower aging at the cellular level, likely through engaging in more adaptive coping mechanisms.

The use of tissue adhesives for the closure of wounds is of growing interest for surgery and trauma management. Here, the authors develop an adhesive that is biocompatible, enables tissue adhesion and also permits real-time imaging due to the presence of contrast agents for multiple modalities.

BackgroundCurrent minimally invasive fat reduction modalities use equipment that can cost thousands of U.S. dollars. Electrochemical lipolysis (ECLL), using low-cost battery and electrodes (approximately $10), creates acid/base within fat (width, approximately 3 mm), damaging adipocytes. Longitudinal effects of ECLL have not been studied. In this pilot study, the authors hypothesize that in vivo ECLL induces fat necrosis, decreases adipocyte number/viability, and forms lipid droplets.MethodsTwo female Yorkshire pigs (50 to 60 kg) received ECLL. In pig 1, 10 sites received ECLL, and 10 sites were untreated. In pig 2, 12 sites received ECLL and 12 sites were untreated. For ECLL, two electrodes were inserted into dorsal subcutaneous fat and direct current was applied for 5 minutes. Adverse effects of excessive pain, bleeding, infection, and agitation were monitored. Histology, live-dead (calcein, Hoechst, ethidium homodimer-1), and morphology (Bodipy and Hoechst) assays were performed on day 0 and postprocedure days 1, 2, 7, 14 (pig 1 and pig 2), and 28 (pig 2). Average particle area, fluorescence signal areas, and adipocytes and lipid droplet numbers were compared.ResultsNo adverse effects occurred. Live-dead assays showed adipocyte death on the anode on days 0 to 7 and the cathode on days 1 to 2 (not significant). Bodipy showed significant adipocyte loss at all sites ( P < 0.001) and lipid droplet formation at the cathode site on day 2 ( P = 0.0046). Histology revealed fat necrosis with significant increases in average particle area at the anode and cathode sites by day 14 (+277.3% change compared with untreated, P < 0.0001; +143.4%, P < 0.0001) and day 28 (+498.6%, P < 0.0001; +354.5%, P < 0.0001).ConclusionsIn vivo ECLL induces fat necrosis in pigs. Further studies are needed to evaluate volumetric fat reduction.Clinical relevance statementIn vivo ECLL induces adipocyte death and fat necrosis. ECLL has the potential to be utilized in body fat contouring.

Erwinia pyrifoliae is a gram-negative bacterial pathogen that commonly causes black shoot blight in pear and apple tree. Although the pathogenicity of this bacterial species is very similar to E. amylovora, there is no specific explanation of its pathogenic genes and mechanisms. In this study, our investigation into E. pyrifoliae pathogenicity involved generating seven YKB12327 mutant strains using Tn5 transposon mutagenesis. Observations revealed weakened growth rate and loss of pathogenicity in these mutants. Whole-genome sequencing and alignment analysis identified transposon insertions within the coding sequences of five strains and in the intergenic region of two strains. Annotation analysis elucidated genes directly or indirectly associated with pathogenicity. Notably, mutant strain MT16 displayed a transposon insertion mutation in the cyclic-di-GMP phosphodiesterase (pdeF) gene, a key player in bacterial signaling, governing microbial behavior and adaptation to environmental changes. Our findings provide insights into the genetic regulation of E. pyrifoliae pathogenicity, suggesting potential avenues for further research aimed at understanding and controlling this bacterial pathogen by targeting pdeF to mitigate apple black shoot blight disease.

Abstract Background Corynebacterium glutamicum is an attractive host for secretory production of recombinant proteins, including high-value industrial enzymes and therapeutic proteins. The choice of an appropriate signaling peptide is crucial for efficient protein secretion. However, due to the limited availability of signal peptides in C. glutamicum, establishing an optimal secretion system is challenging. Result We constructed a signal peptide library for the isolation of target-specific signal peptides and developed a highly efficient secretory production system in C. glutamicum. Based on the sequence information of the signal peptides of the general secretion-dependent pathway in C. glutamicum, a synthetic signal peptide library was designed, and validated with three protein models. First, we examined endoxylanase (XynA) and one potential signal peptide (C1) was successfully isolated by library screening on xylan-containing agar plates. With this C1 signal peptide, secretory production of XynA as high as 3.2 g/L could be achieved with high purity (> 80%). Next, the signal peptide for ⍺-amylase (AmyA) was screened on a starch-containing agar plate. The production titer of the isolated signal peptide (HS06) reached 1.48 g/L which was 2-fold higher than that of the well-known Cg1514 signal peptide. Finally, we isolated the signal peptide for the M18 single-chain variable fragment (scFv). As an enzyme-independent screening tool, we developed a fluorescence-dependent screening tool using Fluorescence-Activating and Absorption-Shifting Tag (FAST) fusion, and successfully isolated the optimal signal peptide (18F11) for M18 scFv. With 18F11, secretory production as high as 228 mg/L was achieved, which was 3.4-fold higher than previous results. Conclusions By screening a fully synthetic signal peptide library, we achieved improved production of target proteins compared to previous results using well-known signal peptides. Our synthetic library provides a useful resource for the development of an optimal secretion system for various recombinant proteins in C. glutamicum, and we believe this bacterium to be a more promising workhorse for the bioindustry.

Abstract Natural killer (NK) cells play a crucial role in immunotherapy for cancer due to their natural ability to target and destroy cancer cells. However, current methods to visualize NK cells’ activity against tumors in live organisms are limited. We introduce an imaging method that non-invasively tracks NK cell activation by cancer cells through the STAT1 protein. To achieve this, we modified NK cells to include a specific genetic sequence that binds to STAT1 when activated. These engineered NK cells (GAS-NK) demonstrate their functionality through various biological tests and analysis. Observations of changes in cancer environments and patient-derived cancer organoid models further confirm the effectiveness of this approach. Our method provides a way to monitor NK cell activity, which could improve the prediction and effectiveness of NK cell-based cancer therapies, contributing to advances in cancer treatment.

Objective This study aimed to evaluate the prevalence of urinary incontinence (UI) and its associated risk factors among pregnant Korean women, as UI significantly impacts their quality of life. Methods A cross-sectional study involving singleton pregnant women was conducted between April and December 2023. Data were collected using a questionnaire assessing demographic information and UI symptoms. The International Consultation on Incontinence Questionnaire-UI short form was used to diagnose UI. Results A total of 824 pregnant women from three centers participated, with an overall prenatal UI prevalence of 40.2% (331/824). Stress UI was most common (77.1%), followed by mixed UI (16.9%), and urgency UI (6.0%). Risk factors for UI included prior delivery mode, specifically vaginal delivery (adjusted odds ratio [aOR], 5.61; 95% confidence interval [CI], 1.40–22.50; P=0.015) and combined vaginal and cesarean delivery (aOR, 23.14; 95% CI, 1.77–302.74; P=0.017). Additionally, second trimester (aOR, 1.99; 95% CI, 1.19–3.32; P=0.009) and third trimester (aOR, 4.44; 95% CI, 2.65–7.40; P

Recently, neuromediators such as substance P (SP) have been found to be important factors in tendon homeostasis. Some studies have found SP to be the cause of inflammation and tendinopathy, whereas others have determined it to be a critical component of tendon healing. As demonstrated by these conflicting findings, the effects of SP on tendinopathy remain unclear. In this study, we hypothesized that the duration of SP exposure determines its effect on the tendons, with repetitive long-term exposure leading to the development of tendinopathy. First, we verified the changes in gene and protein expression using in vitro tenocytes with 10-day exposure to SP. SP and SP + Run groups were injected with SP in their Achilles tendon every other day for 14 days. Achilles tendons were then harvested for biomechanical testing and histological processing. Notably, tendinopathic changes with decreased tensile strength, as observed in the Positive Control, were observed in the Achilles in the SP group compared to the Negative Control. Subsequent histological analysis, including Alcian blue staining, also revealed alterations in the Achilles tendon, which were generally consistent with the findings of tendinopathy in SP and SP + Run groups. Immunohistochemical analysis revealed increased expression of SP in the SP group, similar to the Positive Control. In general, the SP + Run group showed worse tendinopathic changes. These results suggest that sustained exposure to SP may be involved in the development of tendinopathy. Future research on inhibiting SP is warranted to target SP in the treatment of tendinopathy and may be beneficial to patients with tendinopathy.

An amendment to this paper has been published and can be accessed via the original article.

Aluminum-induced crystallization (AIC) is one process which increases silicon grain size at low temperatures. In this study, we analyzed the effect of silicon crystallization according to the aluminum deposition conditions in the AIC process using silicon oxide. The initial aluminum layer was analyzed using a field emission-scanning electron microscopy (FE-SEM) after cutting the samples with a focused-ion-beam (FIB). Through FE-SEM, we observed that the aluminum grain size of the original aluminum layer increased in proportion to the aluminum deposition temperature. However, not only aluminum grain size but also surface roughness and porosity of the initial aluminum layer were increased. The initial aluminum layer, according to the deposition temperature, significantly affected the crystallized silicon grain size. The silicon grain size was decreased from 16.97 μm to 7.81 μm according to the increase of the aluminum deposition temperature. This was because the Si diffusion area was increased by the increase of the aluminum surface roughness.

PURPOSE:To investigate the difference between sonographic findings in extensor pollicis longus tendons rupture and other finger tendons rupture in patients sustaining hand and wrist trauma. METHODS:Twenty-four patients who presented with signs and symptoms clinically suspicious for tendon injury and surgically confirmed tendon rupture were included in this study. We analyzed 6 sonographic features: discontinuity of the tendon, pseudomass formation, decreased echogenicity of the tendon, retraction of the ruptured tendon, fluid collection within the tendon sheath, and the motion of the tendon. We compared the sonographic features of ruptured extensor pollicis longus tendons with the other ruptured finger tendons. RESULTS:Discontinuity of the tendon was the most common sonographic findings and retraction of the ruptured tendon was the second most common findings. Fourteen of 16 cases with a dynamic study on sonography showed loss of normal motion of the tendon. Pseudomass formation was the second most common feature in ruptured extensor pollicis longus tendons, in contrast to the other ruptured finger tendons (p < 0.05). CONCLUSION:Using ultrasonography, detection of discontinuity of the tendon, retraction of the ruptured tendon, and limitation of tendon motion could be very helpful for diagnosing a tendon rupture in hand and wrist trauma. Pseudomass formation could be more specific for diagnosing extensor pollicis longus tendon ruptures compared with other finger tendons.

The thickness effects of SiOx which was deposited as an intermediate layer between aluminum and silicon were studied on Aluminum-induced crystallization (AIC). The SiOx layer thickness varied from 2 nm to 20 nm and affected the crystallization process of the AIC. In the case of the thin SiOx layer, crystallized silicon morphology showed kinetic-limited aggregation. On the other hand, crystallized silicon processed with the thick SiOx layer showed diffusion-limited aggregation due to slow silicon diffusion velocity. Kinetic-limited aggregation showed large grain. The schematic crystallization model was used to describe the relationship between crystallization and grain size in this paper.

Developing a better method for the metallization of silicon solar cells is integral part of realizing superior efficiency. Currently, contact realization using screen printing is the leading technology in the silicon based photovoltaic industry, as it is simple and fast. However, the problem with metallization of this kind is that it has a lower aspect ratio and higher contact resistance, which limits solar cell efficiency. The mounting cost of silver pastes and decreasing silicon wafer thicknesses encourages silicon solar cell manufacturers to develop fresh metallization techniques involving a lower quantity of silver usage and not relying pressing process of screen printing. In recent times nickel/copper (Ni/Cu) based metal plating has emerged as a metallization method that may solve these issues. This paper offers a detailed review and understanding of a Ni/Cu based plating technique for silicon solar cells. The formation of a Ni seed layer by adopting various deposition techniques and a Cu conducting layer using a light induced plating (LIP) process are appraised. Unlike screen-printed metallization, a step involving patterning is crucial for opening the masking layer. Consequently, experimental procedures involving patterning methods are also explicated. Lastly, the issues of adhesion, back ground plating, process complexity and reliability for industrial applications are also addressed.

Abstract Background Lymph node (LN) metastasis is an established prognostic factor for patients with surgically resected ampulla of Vater (AoV) cancer. The standard procedure for radical resection, including removal of regional LNs, is pancreaticoduodenectomy (PD); however, local excision has been considered as an alternative option for patients in the early stage cancer with significant comorbidities. In the present study, we elucidated the preoperative factors associated with LN metastasis to determine the appropriate surgical extent for T1 AoV cancer. Methods We included patients who underwent surgery for T1 AoV cancer at Samsung Medical Center and Severance Hospital between 2000 and 2019. Risk factors were analyzed to identify the preoperative parameters associated with LN metastasis or regional LN recurrence during follow-up. Finally, using the identified risk factors, a prediction model was constructed. Results Among 342 patients, 311 patients underwent PD, whereas 31 patients underwent transduodenal ampullectomy. Fourty-eight patients had LN metastasis according to pathology report, and two patients presented with regional LN recurrence. Age, carbohydrate antigen 19 − 9 (CA 19 − 9), and tumor differentiation were identified as factors associated with the increased risk of LN metastasis or regional LN recurrence. The area under the curve of the prediction model with these three factors was 0.728. Conclusion Our newly developed prediction model using age, CA 19 − 9, and tumor differentiation can help select patients who require PD over local excision. Nevertheless, additional in-depth analysis is warranted to select appropriate surgical extent for patients with presumed T1 AoV cancer.

Cellular reprogramming technologies have been developed with different physicochemical factors to improve the reprogramming efficiencies of induced pluripotent stem cells (iPSCs). Ultrasound is a clinically applied noncontact biophysical factor known for regulating various cellular behaviors but remains uninvestigated for cellular reprogramming. Here, we present a new reprogramming strategy using low-intensity ultrasound (LIUS) to improve cellular reprogramming of iPSCs in vitro and in vivo. Under 3D microenvironment conditions, increased LIUS stimulation shows enhanced cellular reprogramming of the iPSCs. The cellular reprogramming process facilitated by LIUS is accompanied by increased mesenchymal to epithelial transition and histone modification. LIUS stimulation transiently modulates the cytoskeletal rearrangement, along with increased membrane fluidity and mobility to increase HA/CD44 interactions. Furthermore, LIUS stimulation with HA hydrogel can be utilized in application of both human cells and in vivo environment, for enhanced reprogrammed cells into iPSCs. Thus, LIUS stimulation with a combinatorial 3D microenvironment system can improve cellular reprogramming in vitro and in vivo environments, which can be applied in various biomedical fields.

Abstract Background Silica nanoparticles (SNPs) have immense potential in biomedical research, particularly in drug delivery and imaging applications, owing to their stability and minimal interactions with biological entities such as tissues or cells. Results With synthesized and characterized cyanine-dye-doped fluorescent SNPs (CSNPs) using cyanine 3.5, 5.5, and 7 (Cy3.5, Cy5.5, and Cy7). Through systematic analysis, we discerned variations in the surface charge and fluorescence properties of the nanoparticles contingent on the encapsulated dye-(3-aminopropyl)triethoxysilane conjugate, while their size and shape remained constant. The fluorescence emission spectra exhibited a redshift correlated with increasing dye concentration, which was attributed to cascade energy transfer and self-quenching effects. Additionally, the fluorescence signal intensity showed a linear relationship with the particle concentration, particularly at lower dye equivalents, indicating a robust performance suitable for imaging applications. In vitro assessments revealed negligible cytotoxicity and efficient cellular uptake of the nanoparticles, enabling long-term tracking and imaging. Validation through in vivo imaging in mice underscored the versatility and efficacy of CSNPs, showing single-switching imaging capabilities and linear signal enhancement within subcutaneous tissue environment. Conclusions This study provides valuable insights for designing fluorescence imaging and optimizing nanoparticle-based applications in biomedical research, with potential implications for targeted drug delivery and in vivo imaging of tissue structures and organs. Graphical Abstract

Although lying (bear false witness) is explicitly prohibited in the Decalogue and a focus of interest in philosophy and theology, more recently the behavioral and neural mechanisms of deception are gaining increasing attention from diverse fields especially economics, psychology and neuroscience. Despite the considerable role of heredity in explaining individual differences in deceptive behavior, few studies have investigated which specific genes contribute to the heterogeneity of lying behavior across individuals. Also, little is known concerning which specific neurotransmitter pathways underlie deception. Towards addressing these two key questions, we implemented a neurogenetic strategy and modeled deception by an incentivized die-under-cup task in a laboratory setting. The results of this exploratory study provide provisional evidence that SNP variants across the tryptophan hydroxylase 2 (TPH2) gene, that encodes the rate-limiting enzyme in the biosynthesis of brain serotonin, contribute to individual differences in deceptive behavior.

On a large sample of 2288 Han Chinese undergraduates, we investigated how religion and DRD4 are related to human altruistic giving behavior as measured with the Andreoni-Miller Dictator Game. This game enables us to clearly specify (non-)selfishness, efficiency, and fairness motives for sharing. Participants were further classified into religious categories (Christian, Buddhist-Tao, and No Religion) based on self-reports, and genotyped for the dopamine D4 receptor (DRD4) gene exon III VNTR. Our analysis revealed a significant interaction between religion and DRD4 correlated with giving behavior solely among males: Whereas no significant association between religion and sharing decisions was observed in the majority 4R/4R genotype group, a significant difference in giving behavior between Christian and non-Christian males was seen in the non-4R/4R group, with Christian men being overall more altruistic (less selfish and fairer) than non-Christian men. These results support the vantage sensitivity hypothesis regarding DRD4 that the non-4R/4R ‘susceptibility’ genotype is more responsive to a positive environment provided by some religions.

Abstract Background Remimazolam is safe and effective for moderate sedation during flexible bronchoscopy, but its safety and efficacy during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) remains undetermined. The REST trial (NCT06275594) will be a prospective randomized study of remimazolam in patients undergoing EBUS-TBNA with conscious sedation. The primary aim is to evaluate whether remimazolam is safe and effective for moderate sedation during EBUS-TBNA compared to real-world midazolam and on-label midazolam. Methods The REST trial will recruit 330 patients from four university hospitals with mediastinal lesions suspected of being lung cancer who are eligible for EBUS-TBNA under moderate sedation. The participants will be randomized into groups using remimazolam, real-world midazolam, and on-label midazolam (US prescribing information dosage) to perform EBUS-TBNA for procedural sedation. The primary endpoint will be procedural success using composite measures. Discussion The REST trial will prospectively evaluate the efficacy and safety of remimazolam during EBUS-TBNA under moderate sedation. It will provide information for optimizing sedation modalities and contribute to practical benefits in patients undergoing EBUS-TBNA. Trial registration ClinicalTrials.gov (NCT06275594). Prospectively registered on 15 February 2024.

Abstract Objectives Since the enactment of the School Nutrition Act in 1981, school lunch programs in South Korea have grown quantitatively and qualitatively with a current student participation rate of 99.8%. Nonetheless, educational materials are needed to reduce misunderstanding and ignorance about school lunch programs. This study aimed to develop 3 educational videos that help students of various ages (kindergarteners/lower-grade elementary, upper-grade elementary, and secondary school, respectively), understand the school lunch program. Methods A scenario was created, was made, and the opinions on the scenario from experts in foodservice sectors were collected. A survey was conducted to students and parents to determine topics they wanted to know about school foodservice. The final videos were produced using this information and the expert opinions. The data were analyzed using SPSS 27.0 for Mac (IBM Corp., Armonk, NY, USA); a P-value of < 0.05 was considered significant. Results Three videos on school foodservice were developed for various age levels of students: kindergarten/lower-grade elementary, upper-grade elementary, and secondary school. Additionally, English subtitles were included for the multicultural student population. These videos, each lasting about 7 minutes, cover topics such as nutrition, hygiene, and the cultural significance of the school lunch program. The survey results showed that parents and students wanted to know the following topics about the school lunch program: “nutritionally balanced diet” (11.9%), “purchasing safe food ingredients” (10.9%), and “healthy eating habits” (9.9%). Conclusions The developed videos will serve as valuable educational resources on school foodservice, foster a deeper understanding of the school lunch program in parents and students, and potentially address their inquiries regarding production processes, nutrition, hygiene, cultural heritage, and health.

Abstract Although previous studies have examined the signaling pathway involved in melanogenesis through which ultraviolet (UV) or α-melanocyte-stimulating hormones (α-MSH) stimuli act as key inducers to produce melanin at the stratum basal layer of the epidermis, the signaling pathway regulating melanogenesis is still controversial. This study reports that α-MSH, not UVA and UVB, acted as a major stimulus of melanogenesis in B16F10 melanoma cells. Signaling pathway analysis using gene knockdown technology and chemical inhibitors, the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 2 (RSK2) played an important role in melanogenesis. Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis. Chemical inhibition of the MEKs/ERKs/RSK2 signaling pathway using U0126 or BI-D1870 suppressed melanogenesis by stimulation of UVA or α-MSH stimulation, or both. In particular, the genetic depletion of RSK2 or constitutive active (CA)-RSK2 overexpression showed that RSK2 plays a key role in melanogenesis. Interestingly, forkhead box protein O4 (FOXO4) was phosphorylated by RSK2, resulting in the increase of FOXO4’s transactivation activity. Notably, the FOXO4 mutant harboring serine-to-alanine replacement at the phosphorylation sites totally abrogated the transactivation activity and reduced melanin production, indicating that RSK2-mediated FOXO4 activity plays a key role in melanogenesis. Furthermore, kaempferol, a flavonoid inhibiting the RSK2 activity, suppressed melanogenesis. In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis.

Abstract Background Pancreatic neuroendocrine tumors (PNETs) represent 1–2% of pancreatic tumors, with recent guidelines recommending active surveillance for non-functioning PNETs (NF-PNETs) smaller than 2 cm. However, the management of multiple NF-PNETs, as well as the influence of tumor number on prognosis, remains under-researched. Methods This retrospective study analyzed NF-PNET patients who underwent pancreatic resection at Severance Hospital between February 1993 and August 2023, comparing the characteristics of patients diagnosed with multifocal tumors and those with unifocal tumors. A subgroup analysis of overall survival (OS) and recurrence-free survival (RFS) was performed based on multifocality employing the Kaplan-Meier method and the log-rank test. Results Of 187 patients, 169 (90.4%) had unifocal and 18 (9.6%) had multifocal tumors. Multifocal tumors were more likely to be diffusely spread, necessitating more total pancreatectomies (diffuse tumor location: 4.7% in unifocal vs. 38.9% in multifocal cases, p

Abstract Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis.

Abstract Limited information is available regarding the association between preoperative lung function and postoperative pulmonary complications (PPCs) in patients with esophageal cancer who undergo esophagectomy. This is a retrospective cohort study. Patients were classified into low and high lung function groups by the cutoff of the lowest fifth quintile of forced expiratory volume in 1 s (FEV1) %predicted (%pred) and diffusing capacity of the carbon monoxide (DLco) %pred. The PPCs compromised of atelectasis requiring bronchoscopic intervention, pneumonia, and acute lung injury/acute respiratory distress syndrome. Modified multivariable-adjusted Poisson regression model using robust error variances and inverse probability treatment weighting (IPTW) were used to assess the relative risk (RR) for the PPCs. A joint effect model considered FEV1%pred and DLco %pred together for the estimation of RR for the PPCs. Of 810 patients with esophageal cancer who underwent esophagectomy, 159 (19.6%) developed PPCs. The adjusted RR for PPCs in the low FEV1 group relative to high FEV1 group was 1.48 (95% confidence interval [CI] = 1.09–2.00) and 1.98 (95% CI = 1.46–2.68) in the low DLco group relative to the high DLco group. A joint effect model showed adjusted RR of PPCs was highest in patients with low DLco and low FEV1 followed by low DLco and high FEV1, high DLco and low FEV1, and high DLco and high FEV1 (Reference). Results were consistent with the IPTW. Reduced preoperative lung function (FEV1 and DLco) is associated with post-esophagectomy PPCs. The risk was further strengthened when both values decreased together.

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

Abstract Recently, extracellular vesicles (EVs) have been developed as therapeutic targets for various diseases. Biodistribution is crucial for EVs intended for therapeutic purposes because it can determine the degree of on‐ and off‐target effects. This study aimed to explore techniques to evaluate the biodistribution of unmodified EVs. We devised a novel quantitative polymerase chain reaction (qPCR)‐based assay to detect unmodified EVs by targeting mitochondrial deoxyribonucleic acid (mtDNA), a constituent of EVs. We focused on specific mtDNA regions that exhibited homologous variations distinct from their rodent mtDNA counterparts to establish this analytical approach. Herein, we successfully designed primers and probes targeting human and rodent mtDNA sequences and developed a highly specific and sensitive qPCR method. Furthermore, the quantification range of EVs isolated from various cells differed based on the manufacturer and cell source. IRDye 800CW‐labelled Expi293F EV mimetics were administered to the animals via the tail vein to compare the imaging test and mtDNA‐qPCR results. The results obtained from imaging tests and mtDNA‐qPCR to investigate EV biodistribution patterns revealed differences. The results revealed that our newly developed method effectively determined the biodistribution of unmodified EVs with high sensitivity and reproducibility.

Since the Global Financial Crisis of 2008-2009, the importance of non-bank financial institutions in macroprudential management has increased significantly. Consequently, major countries and international financial institutions have been actively discussing and implementing macroprudential supervision and regulation for non-bank financial institutions (NBFI). In this context, this paper analyzes the systemic risk of both banks and non-bank sectors (securities firms and insurance companies) in South Korea over different time periods. Using the widely recognized ΔCoVaR methodology for measuring systemic risk, the analysis reveals that systemic risk increased substantially across all three sectors (banks, securities firms, and insurance companies) during the Global Financial Crisis, the European Sovereign Debt Crisis, and the COVID-19 pandemic. Although the banking sector exhibited relatively high systemic risk compared to the securities and insurance sectors, the relative differences in systemic risk varied across the different crisis periods. Notably, during the margin call crisis in March of 2020, the gap in systemic risk between the banking and securities sectors decreased significantly compared to that during both the Global Financial Crisis and the European Sovereign Debt Crisis, indicating that securities firms had a more substantial impact on risk in the overall financial system during this period. Furthermore, I analyze the impact of the issuance of equity-linked securities (ELS) by financial institutions on systemic risk, as measured by ΔCoVaR, finding that an increase in the outstanding balance of ELS issuance by financial institutions had an impact on increasing ΔCoVaR during the three crisis periods. These findings underscore the growing importance of non-bank financial institutions in relation to South Korea’s macroprudential management and supervision. To address this evolving landscape, enhanced monitoring and regulatory measures focusing on non-bank systemic risk are essential components of maintaining financial stability in the country.

Human beings are an extraordinarily altruistic species often willing to help strangers at a considerable cost (sometimes life itself) to themselves. But as Darwin noted …he who was ready to sacrifice his life, as many a savage has been, rather than betray his comrades, would often leave no offspring to inherit his noble nature. Hence, this is the paradox of altruism. Twin studies have shown that altruism and other prosocial behavior show considerable heritability and more recently a number of candidate genes have been identified with this phenotype. Among these first provisional findings are genes encoding elements of dopaminergic transmission. In this article we will review the evidence for the involvement of one of these, the dopamine D4 receptor (DRD4) gene, in shaping human prosocial behavior and consider the methodologies employed in measuring this trait, specific molecular genetic findings and finally, evidence from several Gene x Environment (GxE) studies that imply differential susceptibility of this gene to environmental influences.

The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.

The p-type crystalline silicon wafers have occupied most of the solar cell market today. However, modules made with n-type crystalline silicon wafers are actually the most efficient modules up to date. This is because the material properties offered by n-type crystalline silicon substrates are suitable for higher efficiencies. Properties such as the absence of boron-oxygen related defects and a greater tolerance to key metal impurities by n-type crystalline silicon substrates are major factors that underline the efficiency of n-type crystalline silicon wafer modules. The bi-facial design of n-type cells with good rear-side electronic and optical properties on an industrial scale can be shaped as well. Furthermore, the development in the industrialization of solar cell designs based on n-type crystalline silicon substrates also highlights its boost in the contributions to the photovoltaic industry. In this paper, a review of various solar cell structures that can be realized on n-type crystalline silicon substrates will be given. Moreover, the current standing of solar cell technology based on n-type substrates and its contribution in photovoltaic industry will also be discussed.

Epidemiological evidence suggests that fruit and vegetable intake significantly positively affects cardiovascular health. Since vegetable juice is more accessible than raw vegetables, it attracts attention as a health functional food for circulatory diseases. Therefore, this study measured blood lipids, antioxidants, blood circulation indicators, and changes in the microbiome to confirm the effect of organic vegetable mixed juice (OVJ) on improving blood circulation. This 4-week, randomized, double-blinded, placebo-controlled study involved adult men and women with borderline total cholesterol (TC) and low-density lipoprotein (LDL) levels. As a result, blood lipid profile indicators, such as TC, triglycerides, LDL cholesterol, and apolipoprotein B, decreased (p < 0.05) in the OVJ group compared with those in the placebo group. Additionally, the antioxidant biomarker superoxide dismutase increased (p < 0.05). In contrast, systolic and diastolic blood viscosities, as blood circulation-related biomarkers, decreased (p < 0.05) in the OVJ group compared with those in the placebo group. After the intervention, a fecal microbiome analysis confirmed differences due to changes in the intestinal microbiome composition between the OVJ and placebo groups. In conclusion, our research results confirmed that consuming OVJ improves blood circulation by affecting the blood lipid profile, antioxidant enzymes, and microbiome changes.

Trust underpins much of social and economic exchanges across human societies. In experimental economics, the Trust Game has served as the workhorse for the study of trust in a controlled incentivized setting. Recent evidence using intranasal drug administration, aka 'sniffing', suggests that oxytocin (OT) can function as a social hormone facilitating trust and other affiliative behaviors. Here we hypothesized that baseline plasma OT is a biomarker that partially predicts the degree of trust and trustworthiness observed in the trust game. Using a large sample of 1,158 participants, we observed a significant U-shaped relationship between plasma OT with the level of trust, and marginally with the level of trustworthiness, especially among males. Specifically, subjects with more extreme levels of plasma OT were more likely to be trusting as well as trustworthy than those with moderate levels of plasma OT. Our results contribute to a deeper understanding of the biological basis of human trust and underscore the usefulness of peripheral plasma OT measures in characterizing human social behavior.

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making.

Decision making often entails longshot risks involving a small chance of receiving a substantial outcome. People tend to be risk preferring (averse) when facing longshot risks involving significant gains (losses). This differentiation towards longshot risks underpins the markets for lottery as well as for insurance. Both lottery and insurance have emerged since ancient times and continue to play a useful role in the modern economy. In this study, we observe subjects' incentivized choices in a controlled laboratory setting, and investigate their association with a widely studied, promoter-region repeat functional polymorphism in monoamine oxidase A gene (MAOA). We find that subjects with the high activity (4-repeat) allele are characterized by a preference for the longshot lottery and also less insurance purchasing than subjects with the low activity (3-repeat) allele. This is the first result to link attitude towards longshot risks to a specific gene. It complements recent findings on the neurobiological basis of economic risk taking.