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Genistein, an isoflavone found in soybeans, exhibits antioxidant, anti-inflammatory, and anticancer properties. This study explored the molecular mechanisms behind genistein’s anticancer effects in prostate cancer DU145 cells. In this study, genistein decreased cell viability, increased annexin V-PE(+) cells, and enhanced the sub-G0/G1 peak by flow cytometric analysis. Increased reactive oxygen species increased mitochondrial depolarization indicating mitochondrial dysfunction and inhibition of ATP formation were also observed in genistein-treated DU145 cells. Genistein upregulated p53 at the mRNA and protein levels and increased caspase-3/7 activity along with the cleavage of Bax, procaspase-3, and PARP. With the increasing genistein concentrations, the percentage of cells in the sub-G0/G1 peak and G2/M phase increased, which was inhibited by treatment with the pan-caspase inhibitor Z-VAD together with 100 μM genistein, which had little toxicity to normal prostate epithelial HPrEC cells. Genistein treatment simultaneously inhibited the activation of STAT3 and other closely related oncogenic kinases such as AKT and ERK and p38 and decreased VEGF expression. Taken together, these results suggest that genistein inhibits the growth of DU145 cells and induces apoptosis by inhibiting STAT3, AKT, ERK, and p38 which provides a molecular basis for the anticancer activity of genistein and suggests its potential as a valuable therapeutic candidate for prostate cancer.

Objectives In this study, Machine Learning (ML) algorithms were evaluated to predict the concentration of particulate matter (PM10 and PM2.5) using air quality and meteorological data in small/medium-sized city. Methods ML models, including Multiple Linear Regression (MLR), Decision Tree Regression (DTR), Random Forest (RF), Extreme Gradient Boosting (XGB), Light Gradient Boosting Machine (LGB), were used to predict PM10 and PM2.5 concentrations. Five air quality variables, including NO2, SO2, CO, PM10 and PM2.5, and seven meteorological variables, including temperature, humidity, vapor pressure, wind speed, precipitation, local atmospheric pressure, and sea-level atmosphere pressure, were collected from three air quality monitoring stations and one meteorological observatory from 2017 to 2022. A total of 52,583 sets of data were used for ML. The prediction accuracies of the applied ML models were evaluated using the Root Mean Squared Error (RMSE), Mean Absolute Error (MAE), and Coefficient of determination (R2). Results and Discussion Higher ML performance was obtained when using the data including PM10 and PM2.5 compared to the data excluding these variables. Among five different ML models, the XGB model showed the highest accuracy in predicting PM10 and PM2.5 one hour in the future. However, poorer performance was obtained as the predicted period increased from one hour to 72 hours. Conclusion The application of ML algorithms for the short-term prediction of PM10 and PM2.5 was successful in this study. However, more input variables and deep learning algorithms are needed for long-term prediction of PM10 and PM2.5.

Immune checkpoint inhibition shows promise for cancer treatment, but only a minority of patients respond. Combination strategies have been explored to overcome this resistance. Combining immunogenic clearance using immunogenic cell death inducers with a rho kinase inhibitor enhances phagocytosis of immunogenically dying cancer cells by antigen-presenting cells, stimulating tumor-specific immune responses by activating CD8+ T cells via dendritic cell-mediated priming. This approach increases the responsiveness of immune checkpoint blockade (ICB)-resistant cancer to ICB. However, the precise mechanisms remain unclear. This study elucidates cellular mechanisms of immunogenic clearance enhancing ICB response. Using single-cell RNA sequencing, we observed an increase in effector memory-like CD8+ T cells within the tumor microenvironment with combined treatment. We propose this cell cluster may originate from proliferating CD8+ T cells elevated by immunogenic clearance. Notably, abundant effector memory-like CD8+ T cells in ICB-responsive patients suggest their antitumor effect. Thus, increasing this cell population through enhanced T cell priming may improve the response of ICB-resistant tumors.

Abstract mRNA vaccines against SARS-CoV-2 have revolutionized vaccine development, but their immunological mechanisms are not fully understood. Here, we investigate injection site responses of mRNA vaccines by generating a comprehensive single-cell transcriptome profile upon lipid nanoparticle (LNP) or LNP-mRNA challenge in female BALB/c mice. We show that LNP-induced stromal pro-inflammatory responses and mRNA-elicited type I interferon responses dominate the initial injection site responses. By tracking the fate of delivered mRNA, we discover that injection site fibroblasts are highly enriched with the delivered mRNA and that they express IFN-β specifically in response to the mRNA component, not to the LNP component of mRNA vaccines. Moreover, the mRNA-LNP, but not LNP alone, induces migratory dendritic cells highly expressing IFN-stimulated genes (mDC_ISGs) at the injection site and draining lymph nodes. When co-injected with LNP-subunit vaccine, IFN-β induces mDC_ISGs at the injection site, and importantly, it substantially enhances antigen-specific cellular immune responses. Furthermore, blocking IFN-β signaling at the injection site significantly decreases mRNA vaccine-induced cellular immune responses. Collectively, these data highlight the importance of injection site fibroblasts and IFN-β signaling during early immune responses against the mRNA vaccine and provide detailed information on the initial chain of immune reactions elicited by mRNA vaccine injection.

Background Continuous kidney replacement therapy (CKRT) is crucial in the management of acute kidney injury in intensive care units (ICUs). Nonetheless, the optimal anticoagulation strategy for patients with bleeding tendencies remains debated. This study aimed to evaluate patient outcomes and safety of nafamostat mesylate (NM) compared with no anticoagulation (NA) in critically ill patients with bleeding tendencies who were undergoing CKRT. Methods This retrospective study enrolled 2,313 patients who underwent CKRT between March 2013 and December 2022 at the third affiliated hospital in South Korea. After applying the exclusion criteria, 490 patients were included in the final analysis, with 245 patients in the NM and NA groups each, following 1:1 propensity score matching. Subsequently, in-hospital mortality, incidence of bleeding complications, agranulocytosis, hyperkalemia, and length of hospital stay were assessed. Results No significant differences were observed between the groups regarding the lengths of hospital and ICU stays or the incidence of agranulocytosis and hyperkalemia. The NM group showed a smaller decrease in hemoglobin levels during CKRT (–1.90 g/dL vs. –2.39 g/dL) and less need for blood product transfusions than the NA group. Furthermore, the NM group exhibited a survival benefit in patients who required transfusion of all three blood products. Conclusion NM is an effective and safe anticoagulant for CKRT in critically ill patients, especially those requiring transfusion of all three blood products. Although these findings are promising, further multicenter studies are needed to validate them and explore the mechanisms underlying the observed benefits.

Background Though acute kidney injury (AKI) is a prevalent complication in critically ill patients, knowledge on the epidemiological differences and clinical characteristics of patients with AKI admitted to medical and surgical intensive care units (ICUs) remains limited. Methods Electronic medical records of patients in ICUs in Pusan National University Hospital and Pusan National University Hospital Yangsan, from January 2011 to December 2020, were retrospectively analyzed. Different characteristics of AKI between patients were analyzed. The contribution of AKI to the in-hospital mortality rate was assessed using a Cox proportional hazards model. Results A total of 7,150 patients were included in this study. AKI was more frequent in medical (48.7%) than in surgical patients (19.7%), with the severity of AKI higher in medical patients. In surgical patients, hospital-acquired AKI was more frequent (51.0% vs. 49.0%), whereas community-acquired AKI was more common in medical patients (58.5% vs. 41.5%). 16.9% and 5.9% of medical and surgical patients died in the hospital, respectively. AKI affected patient groups to different degrees. In surgical patients, AKI patients had 4.778 folds higher risk of mortality (95% confidence interval [CI], 3.577–6.382; p < 0.001) than non-AKI patients; whereas in medical AKI patients, it was 1.239 (95% CI, 1.051–1.461; p = 0.01). Conclusion While the prevalence of AKI itself is higher in medical patients, the impact of AKI on mortality was stronger in surgical patients compared to medical patients. This suggests that more attention is needed for perioperative patients to prevent and manage AKI.

Abstract Background As the number of COVID-19 patients rises, there has been a notable increase in the workload for nurses. However, medium-sized hospitals lacked standardized protocols or consistent approaches to address the specific working conditions of nurses. Furthermore, concerns about patient care have heightened as the issue of nursing shortages coincides with the expansion of the comprehensive nursing care services project. Purpose This study aimed to investigate the factors that influence patient safety management activities, such as calling, organizational commitment, job stress, and nursing work environment, among comprehensive nursing care service unit nurses during the COVID-19 pandemic. Methods A conceptual framework based on the Job Demand-Resource model and literature review of patient safety management activities was used to develop structured questionnaires that were distributed to 206 participants working in 7 comprehensive nursing care service units of small and medium-sized hospitals with at least 300 beds in the S and K provinces. Data analysis was conducted using descriptive statistics, chi-squared tests, t-tests, ANOVA, and hierarchical regression with the SPSS/WIN 23.0 program. Results The results showed that calling (β =.383, p

Abstract Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor‐specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use. This study introduces a novel approach to repurpose TEVs as potent personalized cancer vaccines. The study shows that inhibition of both YAP and autophagy not only diminishes the malignancy‐associated traits of TEVs but also enhances their immunogenic attributes by enriching their load of tumor antigens and adjuvants. These revamped TEVs, termed attenuated yet immunogenically potentiated TEVs (AI‐TEVs), showcase potential in inhibiting tumor growth, both as a preventive measure and a possible treatment for recurrent cancers. They prompt a tumor‐specific and enduring immune memory. In addition, by showing that AI‐TEVs can counteract cancer growth in a personalized vaccine approach, a potential strategy is presented for developing postoperative cancer immunotherapy that's enduring and tailored to individual patients.

Background Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear.Methods We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses.Results Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction.Conclusions This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX’s immunomodulatory role in TNBC but also underscore the potential of targeting TAMs’ antigen presentation capabilities in immunotherapy approaches.

Abstract O2-type lithium-rich layered oxides, known for mitigating irreversible transition metal migration and voltage decay, provide suitable framework for exploring the inherent properties of oxygen redox. Here, we present a series of O2-type lithium-rich layered oxides exhibiting minimal structural disordering and stable voltage retention even with high anionic redox participation based on the nominal composition. Notably, we observe a distinct asymmetric lattice breathing phenomenon within the layered framework driven by excessive oxygen redox, which includes substantial particle-level mechanical stress and the microcracks formation during cycling. This chemo-mechanical degradation can be effectively mitigated by balancing the anionic and cationic redox capabilities, securing both high discharge voltage (~ 3.43 V vs. Li/Li+) and capacity (~ 200 mAh g−1) over extended cycles. The observed correlation between the oxygen redox capability and the structural evolution of the layered framework suggests the distinct intrinsic capacity fading mechanism that differs from the previously proposed voltage fading mode.

Abstract Several studies have utilized a lipid nanoparticle delivery system to enhance the effectiveness of mRNA therapeutics and vaccines. However, these nanoparticles are recognized as foreign materials by the body and stimulate innate immunity, which in turn impacts adaptive immunity. Therefore, it is crucial to understand the specific type of innate immune response triggered by lipid nanoparticles. This article provides an overview of the immunological response in the body, explores how lipid nanoparticles activate the innate immune system, and examines the adverse effects and immunogenicity-related development pathways associated with these nanoparticles. Finally, we highlight and explore strategies for regulating the immunogenicity of lipid nanoparticles.

Abstract Regulatory T cells (Treg) are CD4+ T cells with immune-suppressive function, which is defined by Foxp3 expression. However, the molecular determinants defining the suppressive population of T cells have yet to be discovered. Here we report that the cell surface protein Lrig1 is enriched in suppressive T cells and controls their suppressive behaviors. Within CD4+ T cells, Treg cells express the highest levels of Lrig1, and the expression level is further increasing with activation. The Lrig1+ subpopulation from T helper (Th) 17 cells showed higher suppressive activity than the Lrig1- subpopulation. Lrig1-deficiency impairs the suppressive function of Treg cells, while Lrig1-deficient naïve T cells normally differentiate into other T cell subsets. Adoptive transfer of CD4+Lrig1+ T cells alleviates autoimmune symptoms in colitis and lupus nephritis mouse models. A monoclonal anti-Lrig1 antibody significantly improves the symptoms of experimental autoimmune encephalomyelitis. In conclusion, Lrig1 is an important regulator of suppressive T cell function and an exploitable target for treating autoimmune conditions.

This study screened two probiotic preparations and comprehensively evaluated for anti-obesity efficacy in high-fat diet-induced obese mice. Obese mice were orally administered with low, medium, and high doses of AB-Kefir (ABK) or Lactiplantibacillus plantarum TWK10 (TWK), respectively. After 8 weeks of administration, medium doses and above of ABK and TWK significantly reduced body weight, white adipose tissue weight, serum glucose, and lipid levels and attenuated hepatic steatosis and adipocyte hypertrophy in obese mice without affecting appetite. ABK and TWK also decreased serum adipokine levels and increased the adiponectin/leptin ratio to ameliorate obesity-induced adipose tissue dysfunction and chronic inflammation. Moreover, ABK and TWK reduced adipogenesis/lipogenesis-related transcription factors and enzymes in adipose tissue and improved energy metabolism by activating the AMPK pathway. In particular, TWK showed superior anti-obesity activity compared to ABK. The outcomes of this study will help explore potential anti-obesity probiotic functional foods.

The tumor microenvironment consists of diverse, complex etiological factors. The matrix component of pancreatic ductal adenocarcinoma (PDAC) plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness. Although significant efforts have been made to model desmoplastic PDAC, existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC. Here, two major components in desmoplastic pancreatic matrices, hyaluronic acid- and gelatin-based hydrogels, are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts (CAF). Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation. Higher expression levels of markers associated with proliferation, epithelial to mesenchymal transition, mechanotransduction, and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels, while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1 (TGF-β1). The proposed multicellular pancreatic tumor model, in combination with proper mechanical properties and TGF-β1 supplement, makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors, which could be potentially applicable for realizing personalized medicine and drug testing applications.

Recent therapeutic strategies for hemophilia include long-term therapeutic gene expression using adeno-associated virus (AAV) and rebalancing therapy via the downregulation of anticoagulant pathways. However, these approaches have limitations in immune responses or insufficiency to control acute bleeding. Thus, we developed a therapeutic strategy for hemophilia B by a combined rebalancing and human factor 9 (hF9) gene knockin (KI) using a lipid nanoparticle (LNP) and AAV. Antithrombin (AT; Serpin Family C Member 1 [Serpinc1]) was selected as the target anticoagulation pathway for the gene KI. First, the combined use of LNP-clustered regularly interspaced short palindromic repeats (CRISPR) and AAV donor resulted in 20% insertions or deletions (indels) in Serpinc1 and 67% reduction of blood mouse AT concentration. Second, hF9 coding sequences were integrated into approximately 3% of the target locus. hF9 KI yielded approximately 1,000 ng/mL human factor IX (hFIX) and restored coagulation activity to a normal level. LNP-CRISPR injection caused sustained AT downregulation and hFIX production up to 63 weeks. AT inhibition and hFIX protein-production ability could be maintained by the proliferation of genetically edited hepatocytes in the case of partial hepatectomy. The co-administration of AAV and LNP showed no severe side effects except random integrations. Our results demonstrate hemophilia B therapy by a combination of rebalancing and hF9 KI using LNP and AAV.

Abstract Background Alzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD. Methods We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models. Results Gene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34. Conclusions These findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.

Gene therapy and rebalancing therapy have emerged as promising approaches for treating hemophilia A, but there are limitations, such as temporary efficacy due to individual differences. Genome editing for hemophilia has shown long-term therapeutic potential in preclinical trials. However, a cautious approach is necessary because genome editing is irreversible. Therefore, we attempted to induce low-level human factor 8 (hF8) gene knockin (KI) using 244-cis lipid nanoparticles and low-dose adeno-associated virus to minimize side effects and achieve a therapeutic threshold in hemophilia A mice. We selected the serpin family C member 1, SerpinC1, locus as a target to enable a combined rebalancing strategy with hF8 KI to augment efficacy. This strategy improved blood coagulation activity and reduced hemophilic complications without adverse effects. Furthermore, hemophilic mice with genome editing exhibit enhanced survival for 40 weeks. Here, we demonstrate an effective, safe, and sustainable treatment for hemophilia A. This study provides valuable information to establish safe and long-term genome-editing-mediated treatment strategies for treating hemophilia and other protein-deficient genetic diseases.

Self-assembly generates three-dimensional architectures through the non-covalent interactions of building blocks of various sizes, ranging from nanometers to micrometers, and the assembled structures may have new functions that the building blocks do not have. Cell self-assembly has attracted considerable attention in cancer treatment because it can overcome the side effects of conventional chemotherapy and the low therapeutic effect on drug-resistant cells. In addition, the trigger in the building block reacts with the specific environment of the cancer, such as pH, ions, redox reactions, enzymes, or receptors, facilitating cancer-targeted therapy. However, the precise control of self-assembly for the construction of nanostructures is difficult in harsh intracellular environments. To overcome this challenge, various researchers have investigated intracellular self-assembly. In particular, the self-assembly in cellular organelles is of great interest. Compared with self-assembly in the cytoplasm of cells, organelle-targeting self-assembly has the advantage of being able to self-assemble without side effects under more stable conditions with a relatively low concentration of building blocks. In this mini-review, we discuss the latest research on self-assembly inside or near organelles for cancer treatment.

Abstract mRNA‐based protein replacement therapy has received much attention as a novel intervention in clinical disease treatment. Lipid nanoparticles (LNPs) are widely used for their therapeutic potential to efficiently deliver mRNA. However, clinical translation has been hampered by the immunogenicity of LNPs that may aggravate underlying disease states. Here, we report a novel ionizable LNP with enhanced potency and safety. The piperazine‐based biodegradable ionizable lipid (244cis) was developed for LNP formulation and its level of protein expression and immunogenicity in the target tissue was evaluated. It was found that 244cis LNP enabled substantial expression of the target protein (human erythropoietin), while it minimally induced the secretion of monocyte chemoattractant protein 1 (MCP‐1) as compared to other conventional LNPs. Selective lung targeting of 244cis LNP was further investigated in tdTomato transgenic mice with bleomycin‐induced pulmonary fibrosis (PF). The repeated administration of 244cis LNP with Cre recombinase mRNA achieved complete transfection of lung endothelial cells (~80%) and over 40% transfection of Sca‐1‐positive fibroblasts. It was shown that 244cis LNP allows the repeated dose of mRNA without the loss of activity due to its low immunogenicity. Our results demonstrate that 244cis LNP has great potential for the treatment of chronic diseases in the lungs with improved potency and safety.

Recently, as global climate change and local disturbances such as wildfires continue, long- and short-term changes in the high-latitude vegetation systems have been observed in various studies. Although remote sensing technology using optical satellites has been widely used in understanding vegetation dynamics in high-latitude areas, there has been limited understanding of various landscape changes at different spatiotemporal scales, their mutual relationships, and overall long-term landscape changes. The objective of this study is to devise a change monitoring strategy that can effectively observe landscape changes at different spatiotemporal scales in the boreal ecosystems from temporally sparse time series remote sensing data. We presented a new post-classification-based change analysis scheme and applied it to time series Landsat data for the central Yakutian study area. Spectral variability between time series data has been a major problem in the analysis of changes that make it difficult to distinguish long- and short-term land cover changes from seasonal growth activities. To address this issue effectively, two ideas in the time series classification, such as the stepwise classification and the lateral stacking strategies were implemented in the classification process. The proposed classification results showed consistently higher overall accuracies of more than 90% obtained in all classes throughout the study period. The temporal classification results revealed the distinct spatial and temporal patterns of the land cover changes in central Yakutia. The spatiotemporal distribution of the short-term class illustrated that the ecosystem disturbance caused by fire could be affected by local thermal and hydrological conditions of the active layer as well as climatic conditions. On the other hand, the long-term class changes revealed land cover trajectories that could not be explained by monotonic increase or decrease. To characterize the long-term land cover change patterns, we applied a piecewise linear model with two line segments to areal class changes. During the former half of the study period, which corresponds to the 2000s, the areal expansion of lakes on the eastern Lena River terrace was the dominant feature of the land cover change. On the other hand, the land cover changes in the latter half of the study period, which corresponds to the 2010s, exhibited that lake area decreased, particularly in the thermokarst lowlands close to the Lena and Aldan rivers. In this area, significant forest decline can also be identified during the 2010s.

Small Extracellular Vesicles (sEVs) are typically 30–150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of functions or differentiation of target cells. Owing to these properties, sEVs have recently gained attention as potential carriers for functional molecules and drug delivery tools. However, their use as a therapeutic platform faces limitations, such as challenges in mass production, purity issues, and the absence of established protocols and characterization methods. To overcome these, researchers are exploring the characterization and engineering of sEVs for various applications. This review discusses the origins of sEVs and their engineering for therapeutic effects, proposing areas needing intensive study. It covers the use of cell-derived sEVs in their natural state and in engineered forms for specific purposes. Additionally, the review details the sources of sEVs and their subsequent purification methods. It also outlines the potential of therapeutic sEVs and the requirements for successful clinical trials, including methods for large-scale production and purification. Finally, we discuss the progress of ongoing clinical trials and the implications for future healthcare, offering a comprehensive overview of the latest research in sEV applications.

With the continuous development of front-end-of-line (FEOL) technology, the development of interconnection processes at nanoscale process nodes is becoming important. We conducted a post-layout circuit simulation to consider the effect of parasitic R and C components of middle-of-Line (MOL) and back-end-of-line (BEOL) on the circuit performance. We constructed a process design kit (PDK) for path-finding to analyze the circuit layout in a 3nm technology node based on gate-all-around FET (GAA-FET). It consists of the spice model library that satisfies the 3nm power performance area (PPA) target, and the layout versus schematic (LVS), parasitic extraction (PEX) model that checks whether the layout and schematic match, extracts the RC values in the FEOL MOL and BEOL areas. Subsequently, the effect of the interconnection on complex logic circuits (RO, full adder) was confirmed using PDK. As a result of quantifying the effects of FEOL, MOL, and BEOL on the circuit, circuit degradation due to the RC of MOL and BEOL accounts for more than 60%. Furthermore, we introduced the air spacer process as a way to improve the circuit performance by reducing the CMOL owing to the reduction in the dielectric constant of the spacer. When an air spacer is introduced, based on 9-stages FO1 INV RO with k = 7 at VDD = 0.7V, under iso-speed condition, the active power decreases by 30%, 35% when k is 3.3, 1.65, respectively. Under iso-power condition, frequency increases by 9%, 11% when k is 3.3, 1.65, respectively. And based on full adder with k = 7 at VDD = 0.7V, Under iso-speed conditions, the active power decreases by 47%, 58% when k is 3.3, 1.65, respectively. Under iso-power conditions, the delay decreases by 14%, 20% when k is 3.3, 1.65, respectively. PDP decreases by 22%, 32% when k is 3.3, 1.65, respectively. EDP decreases by 31%, 44% when k is 3.3, 1.65, respectively. In conclusion, in this work, we provide a guide for determining the BEOL load and developing an improved wiring process.

Abstract Background To evaluate the current status of emotional exhaustion and peritraumatic distress of healthcare workers (HCWs) in the COVID-19 pandemic, and identify factors associated with their mental health status. Methods An online survey involving 1068 of consented HCWs that included nurses, physicians, and public health officers was conducted in May 2020. Descriptive statistics and multivariate regression analyses were performed on the collected data. Results Although no significant difference in peritraumatic distress was observed among the surveyed HCWs, the workers’ experience of emotional exhaustion varied according to work characteristics. Respondents who were female, older, living with a spouse, and/or full-time workers reported higher levels of emotional exhaustion. Public health officers and other medical personnel who did not have direct contact with confirmed patients and full-time workers had a higher level of peritraumatic distress. Forced involvement in work related to COVID-19, worry about stigma, worry about becoming infected, and perceived sufficiency of organizational support negatively predict emotional exhaustion and peritraumatic distress. Conclusions Job-related and emotional stress of HCWs should not be neglected. Evidence-based interventions and supports are required to protect HCWs from mental illness and to promote mental health of those involved in the response to the COVID-19 pandemic.

Background Ibuprofen, a well-known analgesic, is commonly used as a component of a multimodal analgesic approach for postoperative pain. This systematic review and meta-analysis aimed to investigate whether a single-dose preoperative intravenous ibuprofen can reduce postoperative pain and opioid consumption. Methods PubMed/MEDLINE, Embase, Cochrane Library (CENTRAL), and Web of Science databases were searched to identify relevant studies published up to May 2020. Randomized controlled trials comparing preoperative single-dose intravenous ibuprofen effect with the control group on postoperative pain and opioid consumption after surgery under general anesthesia were included. Results Six studies involving 366 participants were included. Single-dose administration of intravenous ibuprofen preoperatively significantly reduced postoperative pain score on a scale of 0-10 at 1 h (MD: -1.64, 95% CI [-2.56, -0.72], P < 0.001, I2 = 95%), at 4-6 h (MD: -1.17, 95% CI [-2.09, -0.26], P < 0.001, I2 = 94%), and 24 h (MD: -0.58, 95% CI [-0.99, -0.18], P < 0.001, I2 = 90%). Cumulative opioid consumption, presented as fentanyl equivalents, was also reduced significantly in the ibuprofen group compared to placebo group until postoperative 4-6 h (MD: -56.35 μg, 95% CI [-101.10, -11.60], P < 0.001, I2 = 91%) and 24 h (MD: -131.39 μg, 95% CI [-224.56, -38.21], P < 0.001, I2 = 95%). Conclusions Preoperative single-dose intravenous ibuprofen can reduce postoperative pain and opioid consumption until 24 h postoperatively. Considering the high heterogeneity and small number of studies included, care should be taken when generalizing these findings.

Abstract Photocatalytic N2 reduction has emerged as one of the most attractive routes to produce NH3 as a useful commodity for chemicals used in industries and as a carbon-free energy source. Recently, significant progress has been made in understanding, exploring, and designing efficient photocatalyst. In this review, we outline the important mechanistic and experimental procedures for photocatalytic NH3 production. In addition, we review effective strategies on development of photocatalysts. Finally, our analyses on the characteristics and modifications of photocatalysts have been summarized, based on which we discuss the possible future research directions, particularly on preparing more efficient catalysts. Overall, this review provides insights on improving photocatalytic NH3 production and designing solar-driven chemical conversions.

The miniaturization of biocompatible microsystems that enable self-sufficiency and autarkic operations is ever increasing. Here, the authors demonstrate a robust integratable nano-biosupercapacitor with enhanced performance in complex biological fluids, thus enabling autarkic sensor operation in blood.

This paper proposed an efficient and adaptive frequency sampling algorithm for frequency response analysis using dynamic condensation-based reduced-order modeling. For the degree of freedom-based model reduction method, the reduced-order basis becomes a frequency-dependent matrix since the relationship between master and slave degrees of freedom stems from partial equations of a second-order dynamical system. Such frequency-dependency makes the analysis inefficient for investigating the frequency response of the system. Considering that the coverage of a local reduced-order basis at a single frequency varies depending on the frequency, a new frequency sampling algorithm was proposed with a strategy of constructing multiple local reduced-order models (ROMs) at sample frequencies. For adaptive sampling, the frequency range of a local ROM was evaluated, and a new sample was added if there was a gap between two adjacent ROMs. As a result, the accuracy of the local ROM can be estimated, and the efficiency in the online stage was greatly enhanced. The proposed method was verified by performing frequency response analysis with several numerical examples, including a large-scale structural and dynamic system.

[2 + 2] cycloaddition of alkynes with alkenes would normally require UV light irradiation. Here, the authors report an alkyne–alkene [2 + 2] cycloaddition based on visible light energy transfer photocatalysis, both inter- and intramolecularly, to afford cyclobutenes and 1,3-dienes.

Obesity produces many health problems, including systemic oxidative stress. This study comprehensively investigated the effects of Sanguisorba officinalis L. extract (SO) as an antioxidant on abnormal lipid accumulation and oxidative stress in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice (n = 48). We evaluated the anti-adipogenic and antioxidant effects of SO on 3T3-L1 by cell viability, Oil red O staining, and NBT assays. The ameliorative effects of SO in HFD-induced C57BL/6J mice were investigated by measuring body weight, serum lipids, adipocyte size, hepatic steatosis, AMPK pathway-related proteins, and thermogenic factors. In addition, the effect of SO on oxidative stress in obese mice was evaluated by the activity of antioxidant enzymes and the production of lipid peroxidation products and ROS production in adipose tissue. We found that SO dose-dependently decreased lipid accumulation and ROS production in 3T3-L1 adipocytes. In C57BL/6J obese mice, SO (above 200 mg/kg) attenuated the HFD-induced gain in body weight and white adipose tissue (WAT) weight without affecting appetite. SO also decreased serum glucose, lipid, and leptin levels and attenuated adipocyte hypertrophy and hepatic steatosis. Furthermore, SO increased the expression of SOD1 and SOD2 in WAT, decreased ROS and lipid peroxides, and activated the AMPK pathway and thermogenic factors. In summary, SO reduces oxidative stress in adipose tissue by increasing antioxidant enzyme activity and improves obesity symptoms through AMPK-pathway-regulated energy metabolism and mitochondrial respiratory thermogenesis.

Objectives Young adulthood represents a critical developmental period during which the use of tobacco may begin or cease. Furthermore, differences in smoking behaviors between younger (aged 18-24 years) and older (aged 25-34 years) young adults may exist. This study aimed to characterize patterns related to current smoking in younger and older young adults. Methods This study used data acquired from the Sixth Korea National Health and Nutrition Examination Survey conducted from 2013 to 2014. A total of 2069 subjects were categorized as younger (712 subjects) and older (1357 subjects) young adults. The chi-square test was used to assess the relationships between smoking status and socio-demographic, health-related, and smoking-related factors. Multivariable logistic regression models were constructed to assess the factors affecting current smoking in these age groups. Results The current smoking prevalence was 18.3% among the younger young adults and 26.0% among the older young adults. Sex, education level, occupation, perceived health status, alcohol consumption, and electronic cigarette use were related to current smoking in both age groups. Secondhand smoke exposure at home and stress levels showed significant relationships with smoking in younger and older young adults, respectively. Conclusions Strong correlations were found between the observed variables and smoking behaviors among young adults. Determining the factors affecting smoking and designing interventions based on these factors are essential for smoking cessation in young adults.

To increase the accuracy of photovoltaic (PV) power prediction, meteorological data measured at a plant’s target location are widely used. If observation data are missing, public data such as automated synoptic observing systems (ASOS) and automatic weather stations (AWS) operated by the government can be effectively utilized. However, if the public weather station is located far from the target location, uncertainty in the prediction is expected to increase owing to the difference in distance. To solve this problem, we propose a power output prediction process based on inverse distance weighting interpolation (IDW), a spatial statistical technique that can estimate the values of unsampled locations. By demonstrating the proposed process, we tried to improve the prediction of photovoltaic power in random locations without data. The forecasting accuracy depends on the power generation forecasting model and proven case, but when forecasting is based on IDW, it is up to 1.4 times more accurate than when using ASOS data. Therefore, if measured data at the target location are not available, it was confirmed that it is more advantageous to use data predicted by IDW as substitute data than public data such as ASOS.

Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.

Summary: MYC activates different metabolic programs in a cell-type- and cell-status-dependent manner. However, the role of MYC in inflammatory macrophages has not yet been determined. Metabolic and molecular analyses reveal that MYC, but not hypoxia inducible factor 1 (HIF1), is involved in enhancing early glycolytic flux during inflammatory macrophage polarization. Ablation of MYC decreases lactate production by regulating lactate dehydrogenase (LDH) activity and causes increased inflammatory cytokines by regulating interferon regulatory factor 4 (IRF4) in response to lipopolysaccharide. Moreover, myeloid-specific deletion of MYC and pharmacological inhibition of the MYC/LDH axis enhance inflammation and the bacterial clearance in vivo. These results elucidate the potential role of the MYC/LDH/IRF4 axis in inflammatory macrophages by connecting early glycolysis with inflammatory responses and suggest that modulating early glycolytic flux mediated by the MYC/LDH axis can be used to open avenues for the therapeutic modulation of macrophage polarization to fight against bacterial infection.

The objectives of this study were to investigate the melanogenetic potential of the psoralen derivatives 5-hydroxypsoralen, 5-methoxypsoralen, 8-hydroxypsoralen, 8-methoxypsoralen, and 5,8-dimethoxypsoralen in B16F10 melanoma cells. The results indicated that melanin production is significantly stimulated in B16F10 melanoma cells with 5-methoxypsoralen, 8-methoxypsoralen, and 5,8-dimethoxypsoralen, especially for 5-methoxypsoralen (bergapten), as reported previously. In addition, Western blot results showed that the protein levels of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2) increase after bergapten treatment for the first time. The results also showed that bergapten promotes the phosphorylation of Akt at Ser 473 and glycogen synthase kinase-3β at Ser 9. Moreover, bergapten increased the content of β-catenin in the cell cytoplasm and nucleus by reducing the phosphorylated β-catenin (p-β-catenin) content. The results also indicated that bergapten regulates melanogenesis by upregulating the phosphorylation of p38 and JNK-mitogen-activated protein kinase. Taken together, these findings suggest that the regulation of melanogenesis by bergapten may be mediated by the β-catenin and MAPK signaling pathways and that bergapten might provide new insights into the pathogenesis of pigmented diseases.

BackgroundThe tobacco industry has aggressively introduced new and diverse products in the market, including electronic cigarettes (e-cigarettes) and heat-not-burn (HNB) tobacco products, to which adolescents are readily susceptible. Conventional cigarettes have a well-established relationship with adolescent risky behaviors such as alcohol and drug use; however, no studies exist on the association between alcohol consumption and use of e-cigarettes or HNB tobacco products among Korean adolescents. This study evaluated alcohol-related behaviors and drug use in relation to whether a Korean nationally representative adolescent sample had ever used e-cigarettes and HNB tobacco products.MethodsData from the 2018 Korean Youth Risk Behavior Web-based Survey were analyzed. The final study sample comprised 60,040 adolescents. Chi-square and logistic regression were used to examine whether the ever having used e-cigarettes and HNB tobacco products was associated with alcohol-related behaviors and drug use. P-values for trends were calculated to examine the dose-response relationship for each variable.ResultsRespondents with higher drinking frequency, drinking quantity, alcohol intoxication, alcohol availability, and drug use were more likely to report having used e-cigarettes and HNB tobacco products, thus implying a significant relationship between substance use and novel tobacco product (P < .001).ConclusionsOur findings suggest that at-risk adolescents who are engaged in other forms of risk-taking behaviors are prone to attract the experimentation with e-cigarettes or HNB tobacco products. Thus, smoking cessation programs related to substance use should be implemented, and there is an urgent need to monitor and regulate these products effectively.