Repression of SMAD3 by STAT3 and c-Ski induces conventional dendritic cell differentiation.

A pleiotropic immunoregulatory cytokine, TGF-ß, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115+ common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115+ CDPs, SiglecH- pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH- pre-DCs, and CD115+ CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115+ CDP.

Induction of protective immune responses at respiratory mucosal sites.

Many pathogens enter the host through mucosal sites. Thus, interfering with pathogen entry through local neutralization at mucosal sites therefore is an effective strategy for preventing disease. Mucosally administered vaccines have the potential to induce protective immune responses at mucosal sites. This manuscript delves into some of the latest developments in mucosal vaccination, particularly focusing on advancements in adjuvant technologies and the role of these adjuvants in enhancing vaccine efficacy against respiratory pathogens. It highlights the anatomical and immunological complexities of the respiratory mucosal immune system, emphasizing the significance of mucosal secretory IgA and tissue-resident memory T cells in local immune responses. We further discuss the differences between immune responses induced through traditional parenteral vaccination approaches vs. mucosal administration strategies, and explore the protective advantages offered by immunization through mucosal routes.

Efficient multi-stage feedback attention for diverse lesion in cancer image segmentation.

In the domain of Computer-Aided Diagnosis (CAD) systems, the accurate identification of cancer lesions is paramount, given the life-threatening nature of cancer and the complexities inherent in its manifestation. This task is particularly arduous due to the often vague boundaries of cancerous regions, compounded by the presence of noise and the heterogeneity in the appearance of lesions, making precise segmentation a critical yet challenging endeavor. This study introduces an innovative, an iterative feedback mechanism tailored for the nuanced detection of cancer lesions in a variety of medical imaging modalities, offering a refining phase to adjust detection results. The core of our approach is the elimination of the need for an initial segmentation mask, a common limitation in iterative-based segmentation methods. Instead, we utilize a novel system where the feedback for refining segmentation is derived directly from the encoder-decoder architecture of our neural network model. This shift allows for more dynamic and accurate lesion identification. To further enhance the accuracy of our CAD system, we employ a multi-scale feedback attention mechanism to guide and refine predicted mask subsequent iterations. In parallel, we introduce a sophisticated weighted feedback loss function. This function synergistically combines global and iteration-specific loss considerations, thereby refining parameter estimation and improving the overall precision of the segmentation. We conducted comprehensive experiments across three distinct categories of medical imaging: colonoscopy, ultrasonography, and dermoscopic images. The experimental results demonstrate that our method not only competes favorably with but also surpasses current state-of-the-art methods in various scenarios, including both standard and challenging out-of-domain tasks. This evidences the robustness and versatility of our approach in accurately identifying cancer lesions across a spectrum of medical imaging contexts. Our source code can be found at https://github.com/dewamsa/EfficientFeedbackNetwork.

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Implementation of Head of Bed Elevation Using Adjustable Bed and Its Effects on Sleep: A Pilot Randomized Trial.

Background: Although mild head of bed elevation (HBE) is a proven method to reduce obstructive sleep apnea, there is no study to apply mild HBE in daily life using an adjustable bed. Objective: We aimed to explore the applicability of mild HBE using an adjustable bed in daily life by investigating adverse events and discomforts induced by mild HBE. This pilot randomized trial additionally investigated the objective effects of mild HBE on sleep using polysomnography (PSG). Methods: Pilot randomized controlled trial. With a two-tailed alpha of 0.05 and a power of 0.95, the minimum number of participants for each group; control group slept on flat bed and study group slept on bed with mild HBE on follow-up PSG; was calculated to be 12. Considering a 20% follow-up loss, we enrolled a total of 32 participants (16 participants for each group). Setting: Dongguk University, Ilsan hospital. Participants: A total of 37 individuals complained of subjective sleep disturbance in the Republic of Korea, 32 of whom met the inclusion criteria between September 2021 to July 2022. 23 participants completed the study and participants were randomly assigned into two groups. Intervention: A mild HBE of 7.5 degrees using an adjustable bed was implemented. PSG results and questionnaires were evaluated. Results: There was no difference in the proportion of adverse events between groups after post-intervention which was adjusting mild HBE on study group. Changes in sleep satisfaction from baseline to post-intervention showed no significant difference between groups either. However, changes in respiratory distress index (RDI) (F = 6.088, 95% CI, 17.0% to 26.4%; P = .023) and apnea-hypopnea index (AHI) (F = 5.542, 95% CI, 13.6% to 23.5%; P = .029) were significantly different. Conclusions: Mild HBE is an implementable method for changing sleep posture without definitely causing discomfort or worsening sleep satisfaction. Since an easily applicable way to implement mild HBE using an adjustable bed in daily life reduces RDI and AHI in both subjects complaining of sleep disturbance and obstructive sleep apnea, it can be an alternative treatment for obstructive sleep apnea.

Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. Conclusion: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Lignin-derived carbon quantum dot/PVA films for totally blocking UV and high-energy blue light.

Excessive exposure to UV and high-energy blue light (HEBL) can cause fatal eye and skin injuries. As a result, it is crucial to protect our bodies from UV and HEBL radiation. To achieve complete blocking of UV and HEBL, we developed a lignin-derived carbon quantum dot (L-CQD)/polyvinyl alcohol (PVA) film. L-CQD was synthesized from lignin, a waste woody biomass, and then blended with a PVA matrix to create a flexible L-CQD/PVA film. Thanks to simultaneous UV and HEBL absorption characteristics and bright color of L-CQD, the PVA film with 0.375 wt% L-CQD demonstrated outstanding blocking efficiency: 100 % in UV-C, UV-B, and UV-A, and at least 99.9 % in HEBL. It also exhibited a 44 % increase in lightness and a 12 % enhancement in transparency compared to lignin/PVA film. The film's ability to block UV and HEBL was further demonstrated by reducing >40 % UV-induced ROS formation in both cancerous and normal cell lines (Hs 294T, HeLa, CCD-986sk, and L929), as well as by blocking blue laser diode (LD) and LED. Since the L-CQD/PVA film is simple to produce, environmentally friendly, flexible, and thermally stable, it is suitable for use as a protective coating against sunlight and harmful emissions from IT devices.

Vaccine Development for Severe Fever with Thrombocytopenia Syndrome Virus in Dogs.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening viral zoonosis. The causative agent of this disease is the Dabie bandavirus, which is usually known as the SFTS virus (SFTSV). Although the role of vertebrates in SFTSV transmission to humans remains uncertain, some reports have suggested that dogs could potentially transmit SFTSV to humans. Consequently, preventive measures against SFTSV in dogs are urgently needed. In the present study, dogs were immunized three times at two-week intervals with formaldehyde-inactivated SFTSV with two types of adjuvants. SFTSV (KCD46) was injected into all dogs two weeks after the final immunization. Control dogs showed viremia from 2 to 4 days post infection (dpi), and displayed white pulp atrophy in the spleen, along with a high level of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay (TUNEL) positive area. However, the inactivated SFTSV vaccine groups exhibited rare pathological changes and significantly reduced TUNEL positive areas in the spleen. Furthermore, SFTSV viral loads were not detected at any of the tested dpi. Our results indicate that both adjuvants can be safely used in combination with an inactivated SFTSV formulation to induce strong neutralizing antibodies. Inactivated SFTSV vaccines effectively prevent pathogenicity and viremia in dogs infected with SFTSV. In conclusion, our study highlighted the potential of inactivated SFTSV vaccination for SFTSV control in dogs.

Pediatric Benign Paroxysmal Positional Vertigo: Degree of Nystagmus and Concurrent Dizziness Differs from Adult BPPV.

Background: Benign paroxysmal positional vertigo (BPPV) is characterized by brief, intense episodes of vertigo triggered by abrupt changes in head position. It is generally accepted as being most common in adults, while it is regarded as rare in children. It is necessary to compare the disease between pediatric and adult patients for a better understanding of the disease's characteristics and its natural history. This study aimed to identify the clinical characteristics of BPPV in children and compare them with those of adult BPPV patients. Methods: All children ≤ 18 years old who were diagnosed with BPPV were selected by searching the electronic database of our hospital. Clinical features were identified by medical record review. For adult patients, we collected data from patients > 19 years of age. Results: A total of 30 pediatric (13.65 ± 4.15 years old) and 264 adult patients (60.86 ± 13.74 years old) were included in the study. Among pediatric patients, the lateral canals were involved in 80% and the posterior canals in 16.67%. In adult patients, the lateral and posterior canals were involved similarly (p = 0.007). The degree of nystagmus in pediatric patients was 6.82 ± 12.09, while in adults it was 15.58 ± 20.90 (p < 0.001). The concurrent dizziness disorder was higher in the pediatric group and recurrence was higher in the adult group. In the regression analysis, it was found that adult patients had a stronger nystagmus with a value of 6.206 deg/sec, and the risk of concurrent dizziness disorder was found to be 5.413 times higher in the pediatric group (p < 0.05). Conclusions: BPPV occurs in pediatric patients with lower prevalence, but it cannot be overlooked. In the pediatric group, a relatively high proportion of patients demonstrated lateral canal involvement, weaker nystagmus, and additional dizziness disorder.

Effect of platelet-rich plasma in Achilles tendon allograft in rabbits.

BACKGROUND: Achilles tendon is composed of dense connective tissue and is one of the largest tendons in the body. In veterinary medicine, acute ruptures are associated with impact injury or sharp trauma. Healing of the ruptured tendon is challenging because of poor blood and nerve supply as well as the residual cell population. Platelet-rich plasma (PRP) contains numerous bioactive agents and growth factors and has been utilized to promote healing in bone, soft tissue, and tendons. OBJECTIVE: The purpose of this study was to evaluate the healing effect of PRP injected into the surrounding fascia of the Achilles tendon after allograft in rabbits. METHODS: Donor rabbits (n = 8) were anesthetized and 16 lateral gastrocnemius tendons were fully transected bilaterally. Transected tendons were decellularized and stored at -80°C prior to allograft. The allograft was placed on the partially transected medial gastrocnemius tendon in the left hindlimb of 16 rabbits. The allograft PRP group (n = 8) had 0.3 mL of PRP administered in the tendon and the allograft control group (n = 8) did not receive any treatment. After 8 weeks, rabbits were euthanatized and allograft tendons were transected for macroscopic, biomechanical, and histological assessment. RESULTS: The allograft PRP group exhibited superior macroscopic assessment scores, greater tensile strength, and a histologically enhanced healing process compared to those in the allograft control group. CONCLUSIONS: Our results suggest administration of PRP on an allograft tendon has a positive effect on the healing process in a ruptured Achilles tendon.

Poly(p-phenylene)-based membranes with cerium for chemically durable polymer electrolyte fuel cell membranes.

A poly(p-phenylene)-based multiblock polymer is developed with an oligomeric chain extender and cerium (CE-sPP-PPES + Ce3+) to realize better performance and durability in proton exchange membrane fuel cells. The membrane performance is evaluated in single cells at 80 °C and at 100% and 50% relative humidity (RH). The accelerated stability test is conducted 90 °C and 30% RH, during which linear sweep voltammetry and hydrogen permeation detection are monitored periodically. Results demonstrate that the proton conductivity of the pristine hydrocarbon membranes is superior to that of PFSA membranes, and the hydrogen crossover is significantly lower. In addition, a composite membrane containing cerium performs similarly to a pristine membrane, particularly at low RH levels. Adding cerium to CE-sPP-PPES + Ce3+ membranes improves their chemical durability significantly, with an open circuit voltage decay rate of only 89 µV/h for 1000 h. The hydrogen crossover is maintained across accelerated stability tests, as confirmed by hydrogen detection and crossover current density. The short-circuit resistance indicates that membrane thinning is less likely to occur. Collectively, these results demonstrate that a hydrocarbon membrane with cerium is a potential alternative for fuel cell applications.

Difference in Intraspecies Transmissibility of Severe Fever with Thrombocytopenia Syndrome Virus Depending on Abrogating Type 1 Interferon Signaling in Mice.

Severe fever with thrombocytopenia syndrome (SFTS), a tick-borne zoonotic disease, is caused by infection with SFTS virus (SFTSV). A previous study reported that human-to-human direct transmission of SFTSV can occur. However, potential animal-to-animal transmission of SFTSV without ticks has not been fully clarified. Thus, the objective of this study was to investigate potential mice-to-mice transmission of SFTSV by co-housing three groups of mice [i.e., wild-type mice (WT), mice injected with an anti-type I interferon-α receptor-blocking antibody (IFNAR Ab), and mice with knockout of type I interferon-α receptor (IFNAR KO)] as spreaders or recipients with different immune competence. As a result, co-housed IFNAR Ab and IFNAR KO mice showed body weight loss with SFTS viral antigens detected in their sera, extracorporeal secretions, and various organs. Based on histopathology, white pulp atrophy in the spleen was observed in all co-housed mice except WT mice. These results obviously show that IFNAR Ab and IFNAR KO mice, as spreaders, exhibited higher transmissibility to co-housed mice than WT mice. Moreover, IFNAR KO mice, as recipients, were more susceptible to SFTSV infection than WT mice. These findings suggest that type I interferon signaling is a pivotal factor in mice intraspecies transmissibility of SFTSV in the absence of vectors such as ticks.

Predicting Obstructive Sleep Apnea Based on Computed Tomography Scans Using Deep Learning Models.

Rationale: The incidence of clinically undiagnosed obstructive sleep apnea (OSA) is high among the general population because of limited access to polysomnography. Computed tomography (CT) of craniofacial regions obtained for other purposes can be beneficial in predicting OSA and its severity. Objectives: To predict OSA and its severity based on paranasal CT using a three-dimensional deep learning algorithm. Methods: One internal dataset (N = 798) and two external datasets (N = 135 and N = 85) were used in this study. In the internal dataset, 92 normal participants and 159 with mild, 201 with moderate, and 346 with severe OSA were enrolled to derive the deep learning model. A multimodal deep learning model was elicited from the connection between a three-dimensional convolutional neural network-based part treating unstructured data (CT images) and a multilayer perceptron-based part treating structured data (age, sex, and body mass index) to predict OSA and its severity. Measurements and Main Results: In a four-class classification for predicting the severity of OSA, the AirwayNet-MM-H model (multimodal model with airway-highlighting preprocessing algorithm) showed an average accuracy of 87.6% (95% confidence interval [CI], 86.8-88.6%) in the internal dataset and 84.0% (95% CI, 83.0-85.1%) and 86.3% (95% CI, 85.3-87.3%) in the two external datasets, respectively. In the two-class classification for predicting significant OSA (moderate to severe OSA), the area under the receiver operating characteristic curve, accuracy, sensitivity, specificity, and F1 score were 0.910 (95% CI, 0.899-0.922), 91.0% (95% CI, 90.1-91.9%), 89.9% (95% CI, 88.8-90.9%), 93.5% (95% CI, 92.7-94.3%), and 93.2% (95% CI, 92.5-93.9%), respectively, in the internal dataset. Furthermore, the diagnostic performance of the Airway Net-MM-H model outperformed that of the other six state-of-the-art deep learning models in terms of accuracy for both four- and two-class classifications and area under the receiver operating characteristic curve for two-class classification (P < 0.001). Conclusions: A novel deep learning model, including a multimodal deep learning model and an airway-highlighting preprocessing algorithm from CT images obtained for other purposes, can provide significantly precise outcomes for OSA diagnosis.

Higher mortality and longer length of stay in hospitalized patients with newly diagnosed diabetes.

AIMS: We investigated the association between diabetes status at admission and in-hospital outcomes in all hospitalized patients, regardless of the reason for admission. METHODS: All individuals aged 20 years or older who were admitted to Yongin Severance Hospital between March 2020 and February 2022 were included in study. Subjects were categorized into three groups: non-DM, known DM, and newly diagnosed DM, based on medical history, anti-diabetic medications use, and laboratory test. Hospitalization-related outcomes, including in-hospital mortality and length of hospital stay, were compared between groups. RESULTS: 33,166 participants were enrolled. At hospitalization, 6,572 (19.8 %) subjects were classified as known DM, and another 2,634 (7.9 %) subjects were classified as newly diagnosed DM. In-hospital mortality was highest in newly diagnosed DM (HR 1.89, 95% CI 1.58-2.26, p < 0.001) followed by known DM (HR 1.41, 95% CI 1.18-1.69, p < 0.001) compared to non-DM. Length of hospital stay was significantly longer in newly diagnosed DM (median [IQR] 9.0 [5.0-18.0],days) than known DM (median [IQR] 5.0 [3.0-10.0],days)(p < 0.001) and non-DM (median [IQR] 4.0 [2.0-7.0],days). After adjusting for multiple covariates, newly diagnosed diabetes was independently associated with increased in-hospital mortality (p < 0.001). CONCLUSIONS: Diabetes status at admission was closely linked to hospitalization-related outcomes. Notably, individuals with newly diagnosed diabetes demonstrated a higher risk of in-hospital mortality and a prolonged length of hospital stay.

Effect of Perioperative Prophylactic Intravenous Antibiotic Use in Immediate Implant-Based Breast Reconstruction: A Retrospective Matched Cohort Study.

Background Among breast reconstruction methods, implant-based breast reconstruction has become the mainstream. However, periprosthetic infection is still an unresolved problem. Although published articles have revealed that limited use of antibiotics is sufficient to reduce infection rates, the number of surgeons still preferring elongated usage of antibiotics is not less. The aim of our study is to validate the appropriate duration of antibiotic use to reduce infection rate after implant-based breast reconstruction. Methods A retrospective study reviewed medical record of 235 patients (274 implants for reconstruction) who underwent prepectoral direct to implant breast reconstruction using acellular dermal matrix wrapping technique. Infection rates were analyzed for the patients administered postoperative prophylactic antibiotics until drain removal and those who received only perioperative prophylactic antibiotics for 24 hours. Results Of the 274 implants, 98 who were administered prophylactic antibiotics until drain removal had an infection rate of 3.06% (three implants) and 176 who received prophylactic antibiotics no longer than 24 hours postoperatively had an infection rate of 4.49% (eight implants). A total of 11 patients diagnosed with postoperative infection clinically, 8 were salvaged by antibiotic treatment, and 3 had implant removal and replacement with autologous flap. Postoperative antibiotic prophylaxis duration had no statistically significant effects in the risk of infection ( p = 0.549). Conclusion The duration of prophylactic antibiotics after surgery was not related to infection risk. Further study with a large number of patients, randomized control study, and route of antibiotics is needed.

Elaeagnus umbellata Fruit Extract Protects Skin from Ultraviolet-Mediated Photoaging in Hairless Mice.

Photoaging refers to the accumulation of skin damage which includes wrinkle formation, loss of elasticity, and epidermal thickening due to repeated ultraviolet (UV) irradiation. The present study investigated the protective effects of Elaeagnus umbellata fruit extract (Elaea) on UV-mediated photoaged skin of SKH1 hairless mice and compared the effects of Elaea with ascorbic acid. Although there was no difference in body weight between groups during experimental period, oral administration of 50-200 mg/kg Elaea once daily for 15 weeks significantly prevented an increase in skin weight, epithelial thickening of epidermis, and apoptosis caused by UV irradiation. Skin replica and histopathological analyses revealed that Elaea dose-dependently decreased wrinkle and microfold formation. In addition, Elaea administration restored UV-mediated reduction in type I collagen and hyaluronan through the inhibition of matrix metalloproteinases and p38 mitogen-activated protein kinase expression. Moreover, Elaea suppressed UV-dependent increases in superoxide anion production, fatty acid oxidation, and protein nitration by up-regulating antioxidant system. Furthermore, Elaea alleviated infiltration of inflammatory cells in UV-irradiated skin. The preventive effects of 100 mg/kg Elaea administration against UV-induced photoaging were similar to those by 100 mg/kg ascorbic acid. Collectively, the present study suggests that the E. umbellata fruit is a promising edible candidate to prevent skin photoaging.

SERTAD1 initiates NLRP3-mediated inflammasome activation through restricting NLRP3 polyubiquitination.

We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1ß and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.

Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.

Prevalence of porcine circovirus type 2 and type 3 in slaughtered pigs and wild boars in Korea.

BACKGROUND: Porcine circovirus, a non-enveloped single-stranded DNA virus belonging to the genus Circovirus of the family Circoviridae, is a major pathogen of porcine circovirus-associated disease. Porcine circovirus 3, a novel porcine circovirus, has been identified in individuals with clinical symptoms. OBJECTIVES: The prevalence of porcine circovirus 2 and porcine circovirus 3 and the confirmation of diagnosis of this emerging viral disease have not been fully studied yet. Therefore, the objective of the present study was to investigate the prevalence of porcine circovirus 2 and porcine circovirus 3 in slaughtered pigs and wild boars in Korea between 2018 and 2019. METHODS: Lungs and hilar lymph nodes of healthy pigs slaughtered in slaughterhouses and captured wild pigs were collected, and viruses were detected by multiplex quantitative polymerase chain reaction and two staining methods (in situ hybridization and immunohistochemistry) to confirm the presence of porcine circovirus 2 and porcine circovirus 3. RESULTS: Positive rates of porcine circovirus 2 in lungs and hilar lymph nodes were 78.1% (75/96) and 89.5% (86/96) in slaughtered pigs, respectively. They were 18.0% (30/167) and 46.3% (24/55) in wild boars, respectively. Positive rates of porcine circovirus 3 in lungs and hilar lymph nodes were 30.2% (29/96) and 13.5% (13/96) in slaughtered pigs, respectively. They were 4.2% (7/167) and 5.5% (3/55) in wild boars, respectively. At the farm level, positive rates of porcine circovirus 2 and porcine circovirus 3 were 97.9% (47/48) and 54.2% (26/48), respectively. Positive rates of porcine circovirus 2 and porcine circovirus 3 decreased in spring. Immunohistochemistry and in situ hybridization confirmed the presence of porcine circovirus 2 and porcine circovirus 3 in lungs, but not porcine circovirus 3 in the hilar lymph nodes. CONCLUSION: These results suggest that the prevalence of porcine circovirus 2 and porcine circovirus 3 might vary depending on the season and the type of sample. Wild boars might play a role in the epidemiology of porcine circovirus 2 and porcine circovirus 3 in South Korea. Continuous surveillance and further study are needed for this emerging disease.

Lipid Nanoparticle Encapsulation Empowers Poly(I:C) to Activate Cytoplasmic RLRs and Thereby Increases Its Adjuvanticity.

Poly(I:C) is a synthetic analogue of dsRNA capable of activating both TLR3 and RLRs, such as MDA-5 and RIG-I, as pathogen recognition receptors. While poly(I:C) is known to provoke a robust type I IFN, type III IFN, and Th1 cytokine response, its therapeutic use as a vaccine adjuvant is limited due to its vulnerability to nucleases and poor uptake by immune cells. is encapsulated poly(I:C) into lipid nanoparticles (LNPs) containing an ionizable cationic lipid that can electrostatically interact with poly(I:C). LNP-formulated poly(I:C) triggered both lysosomal TLR3 and cytoplasmic RLRs, in vitro and in vivo, whereas poly(I:C) in an unformulated soluble form only triggered endosomal-localized TLR3. Administration of LNP-formulated poly(I:C) in mouse models led to efficient translocation to lymphoid tissue and concurrent innate immune activation following intramuscular (IM) administration, resulting in a significant increase in innate immune activation compared to unformulated soluble poly(I:C). When used as an adjuvant for recombinant full-length SARS-CoV-2 spike protein, LNP-formulated poly(I:C) elicited potent anti-spike antibody titers, surpassing those of unformulated soluble poly(I:C) by orders of magnitude and offered complete protection against a SARS-CoV-2 viral challenge in vivo, and serum from these mice are capable of significantly reducing viral infection in vitro.