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Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have been reported to exhibit immature embryonic or fetal cardiomyocyte-like phenotypes. To enhance the maturation of hESC-CMs, we identified a natural steroidal alkaloid, tomatidine, as a new substance that stimulates the maturation of hESC-CMs. Treatment of human embryonic stem cells with tomatidine during cardiomyocyte differentiation stimulated the expression of several cardiomyocyte-specific markers and increased the density of T-tubules. Furthermore, tomatidine treatment augmented the number and size of mitochondria and enhanced the formation of mitochondrial lamellar cristae. Tomatidine treatment stimulated mitochondrial functions, including mitochondrial membrane potential, oxidative phosphorylation, and ATP production, in hESC-CMs. Tomatidine-treated hESC-CMs were more sensitive to doxorubicin-induced cardiotoxicity than the control cells. In conclusion, the present study suggests that tomatidine promotes the differentiation of stem cells to adult cardiomyocytes by accelerating mitochondrial biogenesis and maturation and that tomatidine-treated mature hESC-CMs can be used for cardiotoxicity screening and cardiac disease modeling.

Although it has been more than ten years since its first introduction, single-incision distal gastrectomy (SIDG) still lacks solid evidence and there are also no reports on patient quality of life (QOL). This study evaluates the postoperative outcomes and patient QOL of SIDG compared to multiport laparoscopic distal gastrectomy (MLDG).This study was designed as a prospective phase II randomized controlled study. Patients diagnosed with early gastric cancer in the distal 2/3rd of the stomach were randomized to either multiport or single-port group. Primary endpoint was pain using the visual analogue scale on postoperative day (POD) 1. Other outcomes include operative data, complications, and patient QOL using the EORTC C30 and STO22 modules.A total of 43 patients in the SIDG group and 40 patients in the MLDG group were enrolled from September 2017 to February 2020. Mean operation time was 154.3 ± 53.3 min in the MLDG group and 148.9 ± 50.1 min in the SIDG group (p = 0.631). There was no difference in POD1 pain scores between the two groups (MLDG = 4.0 ± 1.3, SIDG = 4.3 ± 1.3, p = 0.372). Mean hospital stay was 5.5 (range 4-12) days in the MLDG group and 5 (range 4-17) days in the SIDG group (p = 0.993). There was no statistical significance in postoperative QOL scores.Unlike previous reports, there was no difference in POD1 pain scores between SIDG and MLDG. Nevertheless, SIDG did not increase short-term morbidity compared to MLDG and had similar outcomes in QOL.

Hypermucoviscous strains of Klebsiella pneumoniae (KP) are associated with invasive liver abscess syndrome. However, little is known about the characteristics of this phenotype in non-hepatobiliary infections. In this study, we investigated the clinical characteristics of patients with hypermucoviscous Kp (hmvKp) bacteremia from non-hepatobiliary tract infection.This retrospective cohort study was implemented at Samsung Changwon Hospital. From March 2018 to December 2019, adult patients (≥ 18 years) with KP bacteremia of the extra-hepatobiliary system were enrolled. Hypermucoviscosity was defined by the string test. Clinical characteristics and 30-day all-cause mortality between patients with hmvKp and non-hmvKp bacteremia were compared.Among 179 cases of non-hepatobiliary KP bacteremia, 67 (37.4%) and 112 (62.6%) isolates were classified as hmvKp and non-hmvKp, respectively. In the hmvKp group, metastatic infection (9.0 vs. 1.8%, P = 0.054) and purulent or necrotizing infection (31.3 vs. 9.8%, P 0.001) were more frequently observed. Additionally, non-hmvKp had more frequent resistance to cefotaxime (11.9 vs. 38.4%, P 0.001). Thirty-day all-cause mortality was similar in the hmvKp (41.8%) and non-hmvKp (39.3%) groups (P = 0.643). In multivariable analysis, septic shock (adjusted hazard ratio [aHR] = 3.05, 95% confidence interval [CI]: 1.22-7.63) and Pitt bacteremia score (aHR = 1.23 per 1 point, 95% CI 1.14-1.33) were associated with increased mortality in patients with Kp bacteremia, while urinary-tract infection (aHR = 0.38, 95% CI 0.18-0.76) was associated with decreased mortality.hmvKp was associated with less frequent drug resistance and metastatic-purulent presentation in non-hepatobiliary infection like in hepatobiliary infection. However, hmvKp was not associated with clinical outcomes.

A novel bacterium designated RR4-40

Previous genomewide association studies (GWASs), single nucleotide polymorphisms (SNPs) on cyclin-dependent kinase inhibitor 2 A (CDKN2A), cyclin-dependent kinase inhibitor 2B (CDKN2B), and cyclin-dependent kinase inhibitor 2B antisense RNA1 (CDKN2B-AS1) were reported as risk loci for glioma, a subgroup of the brain tumor. To further characterize this association with the risk of brain tumors in a Korean population, we performed a fine-mapping association study of CDKN2A, CDKN2B, and CDKN2B-AS1.A total of 17 SNPs were selected and genotyped in 1,439 subjects which were comprised of 959 patients (pituitary adenoma 335; glioma 324; meningioma 300) and 480 population controls (PCs). We discovered that a 3'untranslated region (3'UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA.Although further studies are needed to verify the impact of this variant on PA susceptibility, our results may help to understand CDKN2B polymorphism and the risk of PA.

In this retrospective study, the effectiveness of short-term teriparatide with denosumab in reducing fragility fracture risk was determined in comparison with denosumab monotherapy. Administration of sequential teriparatide with denosumab showed excellent outcomes in suppressing the risk for fragility fractures compared with denosumab monotherapy.To determine the effectiveness of short-term teriparatide with denosumab in reducing the risk of fragility fractures in comparison to denosumab monotherapy.The data of postmenopausal patients treated with denosumab for 2 years between August 2015 and October 2020 were retrospectively analyzed. One hundred sixty four postmenopausal women of a total 615 were excluded, since they did not undergo 2 bone mineral density (BMD) tests, were lost to follow-up, or received long-term teriparatide therapy. Total 320 patients received denosumab monotherapy and 131 patients received teriparatide for ≥ 3 months followed by denosumab. The number of osteoporotic fractures, presence of back pain before and after treatment, and annual BMD during treatment were comparatively assessed using t-test, Chi-square test, and linear mixed model analysis.Before treatment, the denosumab monotherapy group had fewer osteoporotic fractures (mean ± standard deviation; 0.459 ± 0.689) than the sequential therapy group had (1.037 ± 0.871; p 0.001). After treatment, the sequential therapy group had fewer osteoporotic fractures than the denosumab monotherapy group had (0.119 ± 0.348 versus 0.144 ± 0.385; p 0.001). At 1 and 2 years after treatment, the increase in lumbar spine BMD was greater in the sequential therapy group than in the denosumab monotherapy group (p = 0.08, group × time). The difference between post and pre-treatment back pain visual analog scale score was significantly lower in the sequential therapy group than in the monotherapy group (3.246 ± 3.426 versus 1.734 ± 3.049; p 0.001).Short-term teriparatide use before denosumab showed excellent outcomes in suppressing the risk of fragility fractures compared with denosumab monotherapy.

In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment strategies for gastric cancer patients receiving neoadjuvant chemotherapy.A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed.The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (P 0.01). PFS and OS were also different according to the ypStage (P 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (P 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively.Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage.

The use of zinc oxide (ZnO) and titanium oxide (TiO2) nanoparticles in ultraviolet (UV) filters can cause serious health issues due to their genotoxicity and cytotoxicity effect. Recent research on cerium oxide (CeO2) nanoparticles has demonstrated their biocompatible nature, excellent antioxidant and ultraviolet–visible (UV–Vis) absorption properties. CeO2-based nanocomposite materials or nano-architectures can offer uniform absorptive properties, therapeutic skin effect and easy skin application. In this study, cerium oxide-polyethylene glycol (CeO2-PEG) nano-architecture was prepared by hydrothermal processing with the aim to improve stability, antioxidant properties, and enhance UV absorption for UV filtering applications. The morphology study of the developed nanocomposite revealed the formation of polymer bands with well-dispersed CeO2 nanoparticles. The nanocomposite structure has exhibited excellent UV absorption in the UV range 200–400 nm due to decrease in optical band gap in comparison to the naked CeO2 NPs. The evaluation of the photocatalytic activity (PCA) of the nanocomposite structure against P25 photocatalyst and ZnO nanoparticles showed no dye (crystal violet) degradation on UV irradiation. Hence, PCA assay verified the absence of ROS generation and increased stability of the nanostructure under UV irradiation. The investigation of antioxidant properties of the Ce-PEG nanocomposite by a dichlorofluorescein (DCF)-based assay revealed sufficient intracellular ROS scavenging in comparison to N-acetylcysteine (NAC) and H2O2 only assays. In vitro toxicity evaluation of Ce-PEG nanocomposite towards non-malignant human keratinocyte cell line (HaCaT) revealed a non-significant cell mortality ~ 10% of control at a dosage of 50 mg L−1. The nanocomposite structure also exhibited excellent UV protection for HaCaT cells under UV irradiation conditions compared to P25. Our findings suggest that the developed nanocomposite combined the antioxidant and UV absorption properties of CeO2 and skin emollient role of (PEG), and hence offered a novel biocompatible and multifunctional structure for sunscreens and therapeutic skin product. Graphical abstract

Air pollution remains a major threat to cardiovascular health and most acute myocardial infarction (AMI) deaths occur at home. However, currently established knowledge on the deleterious effect of air pollution on AMI has been limited to routinely monitored air pollutants and overlooked the place of death. In this study, we examined the association between short-term residential exposure to China’s routinely monitored and unmonitored air pollutants and the risk of AMI deaths at home. A time-stratified case-crossover analysis was undertaken to associate short-term residential exposure to air pollution with 0.1 million AMI deaths at home in Jiangsu Province (China) during 2016–2019. Individual-level residential exposure to five unmonitored and monitored air pollutants including PM1 (particulate matter with an aerodynamic diameter ≤ 1 μm) and PM2.5 (particulate matter with an aerodynamic diameter ≤ 2.5 μm), SO2 (sulfur dioxide), NO2 (nitrogen dioxide), and O3 (ozone) was estimated from satellite remote sensing and machine learning technique. We found that exposure to five air pollutants, even below the recently released stricter air quality standards of the World Health Organization (WHO), was all associated with increased odds of AMI deaths at home. The odds of AMI deaths increased by 20% (95% confidence interval: 8 to 33%), 22% (12 to 33%), 14% (2 to 27%), 13% (3 to 25%), and 7% (3 to 12%) for an interquartile range increase in PM1, PM2.5, SO2, NO2, and O3, respectively. A greater magnitude of association between NO2 or O3 and AMI deaths was observed in females and in the warm season. The greatest association between PM1 and AMI deaths was found in individuals aged ≤ 64 years. This study for the first time suggests that residential exposure to routinely monitored and unmonitored air pollutants, even below the newest WHO air quality standards, is still associated with higher odds of AMI deaths at home. Future studies are warranted to understand the biological mechanisms behind the triggering of AMI deaths by air pollution exposure, to develop intervention strategies to reduce AMI deaths triggered by air pollution exposure, and to evaluate the cost-effectiveness, accessibility, and sustainability of these intervention strategies. Graphical abstract

Early allograft dysfunction (EAD) and acute kidney injury (AKI) are common and clinically important complications after liver transplantation. Serum lactate level at the end of surgery could predict EAD and neutrophil gelatinase-associated lipocalin (NGAL) is known as a biomarker for AKI after liver transplantation. The authors investigated whether the combination of these two laboratory tests could be used as an early predictor of these two complications of EAD and AKI. We reviewed cases undergoing living donor liver transplantation (n = 353). Lactate-adjusted NGAL level, a combination of these two predictors, was calculated as the sum of each value multiplied by the odds ratio for EAD or AKI. We evaluated whether this combined predictor at the end of surgery is significantly associated with both postoperative AKI or EAD. We compared the area under the receiver operating characteristic curve (AUC) between our multivariable regression models with and without NGAL, lactate, or lactate-adjusted NGAL. NGAL, lactate and lactate-adjusted NGAL are significant predictors for EAD and AKI. The regression model for EAD or AKI including lactate-adjusted NGAL showed a greater AUC (for EAD: odds ratio [OR] 0.88, 95% confidence interval [CI] 0.84–0.91; for AKI: OR 0.89, 95% CI 0.85–0.92) compared to the AUC of the models including lactate (for EAD: OR 0.84, 95% CI 0.81–0.88; for AKI: OR 0.79, 95% CI 0.74–0.83) or NGAL alone (for EAD: OR 0.82, 95% CI 0.77–0.86; for AKI: OR 0.84, 95% CI 0.80–0.88) or the model without lactate or NGAL (for EAD: OR 0.64, 95% CI 0.58–0.69, for AKI: OR 0.75, 95% CI 0.70–0.79). In conclusion, lactate-adjusted NGAL level at the end of surgery could be a reliable combined laboratory predictor for postoperative EAD or AKI after liver transplantation with a greater discriminative ability than lactate or NGAL alone.

Background Claudin-4 (CLDN4), a tight junction protein, is overexpressed in several types of cancer, and is considered a biomarker for cancer-targeted treatment. CLDN4 is not exposed in normal cells, but becomes accessible in cancer cells, in which tight junctions are weakened. Notably, surface-exposed CLDN4 has recently been found to act as a receptor for Clostridium perfringens enterotoxin (CPE) and fragment of CPE (CPE17) that binds to the second domain of CLDN4. Methods Here, we sought to develop a CPE17-containing liposome that targets pancreatic cancers through binding to exposed CLDN4. Results Doxorubicin (Dox)-loaded, CPE17-conjugated liposomes (D@C-LPs) preferentially targeted CLDN4-expressing cell lines, as evidenced by greater uptake and cytotoxicity compared with CLDN4-negative cell lines, whereas uptake and cytotoxicity of Dox-loaded liposomes lacking CPE17 (D@LPs) was similar for both CLDN4-positive and negative cell lines. Notably, D@C-LPs showed greater accumulation in targeted pancreatic tumor tissues compared with normal pancreas tissue; in contrast, Dox-loaded liposomes lacking CPE17 (D@LPs) showed little accumulation in pancreatic tumor tissues. Consistent with this, D@C-LPs showed greater anticancer efficacy compared with other liposome formulations and significantly extended survival. Conclusions We expect our findings will aid in the prevention and treatment of pancreatic cancer and provide a framework for identifying cancer-specific strategies that target exposed receptors. Graphical Abstract

The development of memory devices with functions that simultaneously process and store data is required for efficient computation. To achieve this, artificial synaptic devices have been proposed because they can construct hybrid networks with biological neurons and perform neuromorphic computation. However, irreversible aging of these electrical devices causes unavoidable performance degradation. Although several photonic approaches to controlling currents have been suggested, suppression of current levels and switching of analog conductance in a simple photonic manner remain challenging. Here, we demonstrated a nanograin network memory using reconfigurable percolation paths in a single Si nanowire with solid core/porous shell and pure solid core segments. The electrical and photonic control of current percolation paths enabled the analog and reversible adjustment of the persistent current level, exhibiting memory behavior and current suppression in this single nanowire device. In addition, the synaptic behaviors of memory and erasure were demonstrated through potentiation and habituation processes. Photonic habituation was achieved using laser illumination on the porous nanowire shell, with a linear decrease in the postsynaptic current. Furthermore, synaptic elimination was emulated using two adjacent devices interconnected on a single nanowire. Therefore, electrical and photonic reconfiguration of the conductive paths in Si nanograin networks will pave the way for next-generation nanodevice technologies.

We prove the conjecture of Pollack and Weston on the quantitative analysis of the level lowering congruence \`{a} la Ribet for modular forms of higher weight. It was formulated and studied in the context of the integral Jacquet-Langlands correspondence and anticyclotomic Iwasawa theory for modular forms of weight two and square-free level for the first time. We use a completely different method based on the $R=\mathbb{T}$ theorem established by Diamond-Flach-Guo and Dimitrov and an explicit comparison of adjoint $L$-values. We briefly discuss arithmetic applications of our main result at the end., Comment: To appear in Research in the Mathematical Sciences