Role of Gasdermin E in the Biogenesis of Apoptotic Cell-Derived Exosomes.

The gasdermins are a family of pore-forming proteins that has recently been suggested to play a central role in pyroptosis. In this study, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell-derived exosomes. In apoptotic human HeLa and HEK293 cells, GSDMA, GSDMC, GSDMD, and GSDME increased the release of apoptotic exosomes. GSDMB and DFNB59, in contrast, negatively affected the release of apoptotic exosomes. GSDME at its full-length and cleaved forms was localized in the exosomes and exosomal membrane. Full-length and cleaved forms of GSDME are suggested to increase Ca2+ influx to the cytosol through endosomal pores and thus increase the biogenesis of apoptotic exosomes. In addition, the GSDME-mediated biogenesis of apoptotic exosomes depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins, that is, annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of apoptotic exosomes begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that GSDME-bearing tumors released apoptotic exosomes to induce inflammatory responses in the in vivo mouse 4T1 orthotropic model of BALB/c breast cancer. The data indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process.

Fabrication of Versatile Janus Microparticles through Geometry and Surface Chemistry Control.

Amphiphilic Janus particles typically comprise two distinct hemispheres with spatially dispersed physicochemical properties. The anisotropic structure and physicochemical properties of Janus particles can be exploited for various applications. However, their preparation typically requires complex and sophisticated processes and expensive equipment to control the formation of different structures and chemical compositions. Herein, a simple synthetic approach for the facile fabrication of versatile Janus particles with efficient control of the Janus ratio and wettability based on particle fixation at a three-phase interface and photopolymerization is reported. Agarose gel and surfactant are used to control the surface-coated boundaries of the Janus particles through the equilibrium of a floating microparticle at the fluid interface. poly(propylene glycol) diacrylate or poly(N-isopropylacrylamide) coating on polystyrene-based microparticles allows easy control of the chemical functionality of the particle surfaces. Depending on the particle morphology and wettability, the interfacial behavior between two immiscible liquids can be adjusted, which allows the stabilization of Pickering emulsions that encapsulate independent oil droplets in water or vice versa. This facile approach has the potential to enable more efficient mass production of Janus particles and their use in various applications, such as biomedical and environmental engineering.

Itch and Janus Kinase Inhibitors.

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for pruritus in atopic dermatitis, psoriasis, and other diseases, such as prurigo nodularis and lichen planus, with rapid itch relief compared with conventional treatments. The most common adverse effects reported include nasopharyngitis, acne, and elevated blood creatine phosphokinase levels. Janus kinase inhibitors are currently prescribed with warnings about a potential increase in malignancies and cardiovascular diseases and usage in people of older ages. This review aims to provide knowledge about itch and the Janus kinase and signal transducer and activator of transcription pathway and to analyse the current evidence for itch relief by Janus kinase inhibitors.

Molecular Characteristics of Catalytic Nitrogen Removal from Coal Tar Pitch over γ-Alumina-Supported NiMo and CoMo Catalysts.

The removal of nitrogen from coal tar pitch (CTP) through the hydrodenitrogenation (HDN) of CTP and its molecular behavior were evaluated in the presence of NiMo/γ-alumina and CoMo/γ-alumina catalysts. Fourier transform ion cyclotron resonance mass spectrometry with atmospheric pressure photoionization was used to analyze the complicated chemical classes and species of CTP and the treated products at the molecular level. Nitrogen species were qualitatively analyzed before and after hydrotreatment. A single-stage hydrotreatment with an HDN catalyst resulted in a high sulfur removal performance (85.6-94.7%) but a low nitrogen removal performance (26.8-29.2%). Based on relative abundance analyses of nitrogen and binary nitrogen species, CcHh-NnSs was the most challenging species to remove during HDN treatment. Furthermore, prior hydrodesulfurization was combined with HDN treatment, and the dual hydrotreatments yielded a significantly improved nitrogen removal performance (46.4-48.7%).

RADIOGRAPHIC MEASUREMENT OF VERTEBRAL HEART SCALE IN KOREAN WILD RACCOON DOGS (NYCTEREUTES PROCYONOIDES KOREENSIS).

Raccoon dogs (Nyctereutes procyonoides koreensis), which belong to the Canidae family, are the second most injured wildlife animals rescued by the Gangwon Wildlife Medical Rescue Center. Various imaging evaluation methods including echocardiography have been developed, but thoracic radiography remains essential for the diagnosis and management of heart disease in dogs. In particular, vertebral heart scale (VHS) measurement is usually used to evaluate the dimensions of the heart silhouette on thoracic radiographs and can measure cardiomegaly more objectively. The VHS of 50 raccoon dogs without cardiac diseases were measured using thoracic radiography in right lateral (RL) and ventrodorsal (VD) recumbent positions. The VHS in the RL view of 50 raccoon dogs was 9.03 ± 0.52 vertebrae (v), which was slightly smaller than the VHS measured in the VD view of 46 raccoon dogs (9.79 ± 0.84 v). In addition, the thoracic morphology of raccoon dogs was determined to be intermediate (thoracic depth-to-width ratio, 0.75-1.25), and thoracic morphology, gender, and weight were not significantly correlated with VHS. The VHS of raccoon dogs in this study will help veterinarians diagnose potential cardiac diseases in raccoon dogs.

Analysis of clinical features and prognostic factors in patients with hepatic hydrothorax: a single-center study from China.

BACKGROUND: The clinical features and factors affecting the prognostic survival of hepatic hydrothorax (HH) are currently unknown. METHODS: We conducted a retrospective cohort study of 131 patients with HH using the Kaplan-Meier method and Cox proportional hazards regression analysis to assess factors influencing the prognosis of HH. RESULTS: A total of 131 patients were enrolled: the male to female ratio was 80:51 (1.59:1), and the mean age was 52.76 ± 11.88 years. Hepatitis B cirrhosis was the main cause of HH, and abdominal distention and dyspnea were the most common clinical signs. Ascites was present in varying amounts in all patients and was the most common decompensated complication, with pleural effusions mostly seen on the right side (107/131; 82%), followed by the left side (16/131; 12%) and bilateral effusions (8/131; 6%). For overall survival without transplantation, the estimated median survival time was 21 (95% confidence interval [CI]:18-25) months, and survival rates at 6 months, 1 year, and 2 years were 77.2%, 62.4%, and 29.7%, respectively. After controlling for covariates that were associated with liver-related mortality in the univariate analysis, males (hazard ratio [HR]: 1.721, 95% CI: 1.114-2.658, P = 0.005) and combined hepatic encephalopathy (HR: 2.016, 95% CI: 1.101-3.693, P = 0.001) were found to be associated with an increase in liver-related mortality. CONCLUSIONS: In this cohort of HH patients without liver transplantation, male sex and hepatic encephalopathy were associated with a higher risk of liver-related death.

Update on Extracellular Vesicle-Based Vaccines and Therapeutics to Combat COVID-19.

The COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future.

Epidemiology of Congenital Bleeding Disorders: a Nationwide Population-based Korean Study.

BACKGROUND: Except for data in the Korea Hemophilia Foundation Registry, little is known of the epidemiology of congenital bleeding disorders in Korea. METHODS: Data were obtained from the Korean Health Insurance Review and Assessment Service (HIRA) database. RESULTS: From 2010 to 2015, there were 2,029 patients with congenital bleeding disorders in the Korean HIRA database: 38% (n = 775) of these patients had hemophilia A (HA), 25% (n = 517) had von Willebrand disease (vWD), 7% (n = 132) had hemophilia B (HB), and 25% (n = 513) had less common factor deficiencies. The estimated age-standardized incidence rate (ASR) of HA and HB was 1.78-3.15/100,000 and 0.31-0.51/100,000, respectively. That of vWD was 1.38-1.95/100,000. The estimated ASR of HA showed increase over time though the number of new patients did not increase. Most patients with congenital bleeding disorders were younger than 19 years old (47.8%), and most were registered in Gyeonggi (22.1%) and Seoul (19.2%). CONCLUSION: This is the first nationwide population-based study of congenital bleeding disorders in Korea. This study provides data that will enable more accurate estimations of patients with vWD. This information will help advance the comprehensive care of congenital bleeding disorders. We need to continue to obtain more detailed information on patients to improve the management of these diseases.

Utilization of bioelectrical impedance analysis for detection of lymphedema in breast Cancer survivors: a prospective cross sectional study.

BACKGROUND: Breast cancer survivors are at risk of developing breast cancer-related lymphedema (BCRL) after surgical treatment, which may have a negative effect on quality of life. The purpose of this study was to investigate the clinical role of bioelectrical impedance analysis (BIA) and the relationship between the development of BCRL in breast cancer survivors who have undergone axillary surgery. METHODS: A total of 228 patients with breast cancer were enrolled in the study between May 2016 and January 2017. BCRL was assessed by measuring the circumference of both arms at 15 cm below the acromion process and the olecranon process. Patients were classified as BCRL (n = 22) and non-BCRL (n = 206) based on the difference of the arm circumference of 2 cm. Data including lymphedema, anthropometry, BIA measurements, food frequency questionnaire, type of surgery, total number of dissected lymph nodes, and post-operative treatment were collected. RESULTS: Of the breast cancer survivors, 10.4% had BCRL by the definition. The BCRL group contained 22 patients, while the non-BCRL group contained 206 patients. Compared to the non-BCRL group, the BCRL group had a higher body mass index, a larger percentage of ideal body weight, more dissected lymph nodes, and higher single frequency BIA (SFBIA) ratio (P = 0.027, P = 0.031, P < 0.001, and P < 0.001, respectively). The SFBIA ratio provided 63.64% sensitivity and 95.15% specificity in estimating the risk of BCRL. CONCLUSION: Our data provides evidence to support that the use of SFBIA ratio can serve as an alternative method to monitor and/or diagnose BCRL. TRIAL REGISTRATION: This trial was retrospectively registered at Clinicaltrials.gov identifier ( NCT03391206 ) on the 5 January 2018.

A bloodstream infection by Ruminococcus gnavus in a patient with a gall bladder perforation.

Ruminococcus gnavus is frequently found among human gut microbiome. However, human bloodstream infections by R. gnavus have been reported only three times. Clinical details were lacking for one case; the other two cases with concurrent bacteremia in patients with diverticulitis. We report a case of R. gnavus bloodstream infection in a patient with a gall bladder perforation suggesting its association with damage to the gastrointestinal tract. R. gnavus was misidentified using biochemical test but 16S rRNA sequencing and Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were useful for correct identification. With the advancement of identification method in clinical laboratory, more frequent identification of R. gnavus from clinical specimens is expected.

Enhanced theta synchronization correlates with the successful retrieval of trace fear memory.

Mechanisms underlying delay fear conditioning in which conditioned stimuli (CS) are paired and co-terminated with unconditioned stimuli (US), have been extensively characterized, thus expanding knowledge concerning learning and memory. However, trace fear conditioning in which CS and US are separated by trace interval periods, has received much less attention though it involves cognitive processes including timing and working memories. Various brain regions including the hippocampus are known to play an important role in memory acquisition and/or retrieval of trace fear conditioning. However, neural correlates, which are specific for the discrete steps in trace fear conditioning, have not been characterized thoroughly. Here, we investigated the network activities between the dorsal and ventral hippocampi at different stages of memory processing after trace fear conditioning. When fear memory was retrieved successfully, theta synchronization between the two regions was enhanced relative to preconditioning levels. The enhancement in theta synchronization was observed only during the trace interval period but not during CS presentation or after the trace interval period. Thus, the enhanced theta synchronization between the dorsal and ventral hippocampi may underlie a cognitive process associated with the trace interval period when fear memory is retrieved successfully.

Delayed escape behavior requires claustral activity.

Animals are known to exhibit innate and learned forms of defensive behaviors, but it is unclear whether animals can escape through methods other than these forms. In this study, we develop the delayed escape task, in which male rats temporarily hold the information required for future escape, and we demonstrate that this task, in which the subject extrapolates from past experience without direct experience of its behavioral outcome, does not fall into either of the two forms of behavior. During the holding period, a subset of neurons in the rostral-to-striatum claustrum (rsCla), only when pooled together, sustain enhanced population activity without ongoing sensory stimuli. Transient inhibition of rsCla neurons during the initial part of the holding period produces prolonged inhibition of the enhanced activity. The transient inhibition also attenuates the delayed escape behavior. Our data suggest that the rsCla activity bridges escape-inducing stimuli to the delayed onset of escape.

Enhancement of Bone Tissue Regeneration with Multi-Functional Nanoparticles by Coordination of Immune, Osteogenic, and Angiogenic Responses.

Inorganic nanoparticles are promising materials for bone tissue engineering due to their chemical resemblance to the native bone structure. However, most studies are unable to capture the entirety of the defective environment, providing limited bone regenerative abilities. Hence, this study aims to develop a multifunctional nanoparticle to collectively control the defective bone niche, including immune, angiogenic, and osteogenic systems. The nanoparticles, self-assembled by biomimetic mineralization and tannic acid (TA)-mediated metal-polyphenol network (MPN), are released sustainably after the incorporation within a gelatin cryogel. The released nanoparticles display a reduction in M1 macrophages by means of reactive oxygen species (ROS) elimination. Consequently, osteoclast maturation is also reduced, which is observed by the minimal formation of multinucleated cells (0.4%). Furthermore, the proportion of M2 macrophages, osteogenic differentiation, and angiogenic potential are consistently increased by the effects of magnesium from the nanoparticles. This orchestrated control of multiple systems influences the in vivo vascularized bone regeneration in which 80% of the critical-sized bone defect is regenerated with new bones with mature lamellar structure and arteriole-scale micro-vessels. Altogether, this study emphasizes the importance of the coordinated modulation of immune, osteogenic, and angiogenic systems at the bone defect site for robust bone regeneration.

Potential Migration and Health Risks of Heavy Metals and Metalloids in Take-Out Food Containers in South Korea.

The consumption of take-out food has increased worldwide; consequently, people are increasingly being exposed to chemicals from food containers. However, research on the migration of metals from containers to food is limited, and therefore, information required to determine the health risks is lacking. Herein, the amount of transfer of nine metals and metalloids (Pb, Sb, Cd, Ge, Co, Mn, Sn, As, and Hg) from food containers to food in South Korea was assessed from take-out food containers classified into paper and plastic container groups. The sample containers were eluted over time by either warming with 4% acetic acid at 70 °C or cooling with 4% acetic acid at 100 °C /deionized water at 25 °C. It was analyzed using an inductively coupled plasma mass spectrometer and a direct mercury analyzer. The reliability of the quantitative results was verified by calculating the linearity, limit of detection, and limit of quantification. We found that the amount of metals and metalloids (Pb, Sb, Cd, and Co) eluting over time was highly significant in the plastic group. Regardless of the food simulant and elution time, the amount of Sb transferred from the food containers to food was substantially higher in the plastic (average concentration: 0.488-1.194 µg/L) than in the paper group (average concentration: 0.001-0.03 µg/L). Fortunately, all food containers were distributed at levels safe for human health (hazard index: 0.000-64.756%). However, caution is needed when warm food is added to food containers. Overall, our results provide baseline data for the management and use of take-out containers.

Cell-homing and immunomodulatory composite hydrogels for effective wound healing with neovascularization.

Wound healing in cases of excessive inflammation poses a significant challenge due to compromised neovascularization. Here, we propose a multi-functional composite hydrogel engineered to overcome such conditions through recruitment and activation of macrophages with adapted degradation of the hydrogel. The composite hydrogel (G-TSrP) is created by combining gelatin methacryloyl (GelMA) and nanoparticles (TSrP) composed of tannic acid (TA) and Sr2+. These nanoparticles are prepared using a one-step mineralization process assisted by metal-phenolic network formation. G-TSrP exhibits the ability to eliminate reactive oxygen species and direct polarization of macrophages toward M2 phenotype. It has been observed that the liberation of TA and Sr2+ from G-TSrP actively facilitate the recruitment and up-regulation of the expression of extracellular matrix remodeling genes of macrophages, and thereby, coordinate in vivo adapted degradation of the G-TSrP. Most significantly, G-TSrP accelerates angiogenesis despite the TA's inhibitory properties, which are counteracted by the released Sr2+. Moreover, G-TSrP enhances wound closure under inflammation and promotes normal tissue formation with strong vessel growth. Genetic analysis confirms macrophage-mediated wound healing by the composite hydrogel. Collectively, these findings pave the way for the development of biomaterials that promote wound healing by creating regenerative environment.

Formulating Electron Beam-Induced Covalent Linkages for Stable and High-Energy-Density Silicon Microparticle Anode.

High-capacity silicon (Si) materials hold a position at the forefront of advanced lithium-ion batteries. The inherent potential offers considerable advantages for substantially increasing the energy density in batteries, capable of maximizing the benefit by changing the paradigm from nano- to micron-sized Si particles. Nevertheless, intrinsic structural instability remains a significant barrier to its practical application, especially for larger Si particles. Here, a covalently interconnected system is reported employing Si microparticles (5 µm) and a highly elastic gel polymer electrolyte (GPE) through electron beam irradiation. The integrated system mitigates the substantial volumetric expansion of pure Si, enhancing overall stability, while accelerating charge carrier kinetics due to the high ionic conductivity. Through the cost-effective but practical approach of electron beam technology, the resulting 500 mAh-pouch cell showed exceptional stability and high gravimetric/volumetric energy densities of 413 Wh kg-1, 1022 Wh L-1, highlighting the feasibility even in current battery production lines.

Cross-sectional and skeletal anatomy of long-tailed gorals (Naemorhedus caudatus) using imaging evaluations.

BACKGROUND: Accurate diagnosis of diseases in animals is crucial for their treatment, and imaging evaluations such as radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) are important tools for this purpose. However, a cross-sectional anatomical atlas of normal skeletal and internal organs of long-tailed gorals (Naemorhedus caudatus) has not yet been prepared for diagnosing their diseases. OBJECTIVES: The objective of this study was to create an anatomical atlas of gorals using CT and MRI, which are imaging techniques that have not been extensively studied in this type of wild animal in Korea. METHODS: The researchers used CT and MRI to create an anatomical atlas of gorals, and selected 37 cross-sections from the head, thoracic, lumbar, and sacrum parts of gorals to produce an average cross-sectional anatomy atlas. RESULTS: This study successfully created an anatomical atlas of gorals using CT and MRI. CONCLUSIONS: The atlas provides valuable information for the diagnosis of diseases in gorals, which can improve their treatment and welfare. The study highlights the importance of developing cross-sectional anatomical atlases of gorals to diagnose and treat their diseases effectively.

TR score: A noninvasive model to predict histological stages in patients with primary biliary cholangitis.

Introduction: The aim of this study was to develop a noninvasive prediction model for histological stages in PBC that is simple, easy to implement, and highly accurate. Methods: A total of 114 patients with PBC were included in this study. Demographic, laboratory data and histological assessments were collected. The independent predictors of histological stages were selected to establish a noninvasive serological model. The scores of 22 noninvasive models were calculated and compared with the established model. Results: This study included 99 females (86.8%) and 15 males (13.2%). The number of patients in Scheuer's stage 1, 2, 3 and 4 was 33 (29.0%), 34 (29.8%), 16 (14.0%), and 31 (27.2%), respectively. TBA and RDW are independent predictors of PBC histological stages. The above indexes were used to establish a noninvasive model-TR score. When predicting early histological change (S1) or liver fibrosis and cirrhosis (S3-S4), the AUROC of TR score were 0.887 (95% CI, 0.809-0.965) and 0.893 (95% CI, 0.816-0.969), higher than all of the other 22 models included in this study. When predicting cirrhosis (S4), its AUROC is still as high as 0.921 (95% CI, 0.837-1.000). Conclusion: TR score is an easy, cheap and stable noninvasive model, without complex calculation formulas and tools, and shows good accuracy in diagnosing the histological stages of PBC.

Design and Optimization of Composite Cathodes for Solid-State Batteries Using Hybrid Carbon Networks with Facile Electronic and Ionic Percolation Pathways.

Solid-state batteries (SSBs) have emerged as a promising alternative to conventional liquid electrolyte batteries due to their potential for higher energy density and improved safety. However, achieving high performance in SSBs is difficult because of inadequate contact and interfacial reactions that generate high interfacial resistance, as well as inadequate solid-solid contact between electrodes. These chronic issues are associated with inhomogeneous ion and electron transport networks owing to imperfect solid-solid interfacial contact. This study developed an optimal interfacial engineering strategy to facilitate an ion-electron transport network by designing an active material (NCM622) uniformly filled with a thin layer of a solid electrolyte (garnet-type Li6.25Ga0.25La3Zr2O12) and conductive additives. The optimal composite electrode architecture enhanced the high capacity, high rate capability, and long-term cycle stability, even at room temperature, owing to the percolating network for facile ionic conduction that assured a homogeneous reaction. In addition to mitigating the mechanical degradation of the cathode electrode, it also reduced the crosstalk effects on the anode-solid electrolyte interface. Effectively optimizing the selection and use of conductive additives in composite electrodes offers a promising approach to addressing key performance-limiting factors in SSBs, including interfacial resistance and solid-solid contact issues. This study underscores the critical importance of cathode architecture design for achieving high-performance SSBs by ensuring that the interfaces are intact with solid electrolytes at both the cathode and anode interfaces while promoting uniform reactions. This study provides valuable insights into the development of SSBs with improved performance, which could have significant implications for a wide range of applications.