Maintenance treatment of immunotherapy after microwave ablation plus drug-eluting bead bronchial arterial chemoembolization for advanced non-small cell lung cancer: a retrospective single-center cohort study.

Background: The combination therapy of immunotherapy and drug-eluting bead bronchial artery chemoembolization (DEB-BACE) or microwave ablation (MWA) has been attempted as an effective and safe approach for advanced non-small cell lung cancer (NSCLC). However, the outcomes of immunotherapy plus multiple interventional techniques for advanced NSCLC remain unclear. This retrospective study thus aimed to investigate the effectiveness and safety of the maintenance treatment of programmed cell death protein 1 (PD-1) blockade after MWA plus DEB-BACE for advanced NSCLC. Methods: This retrospective cohort study consists of 95 patients with advanced NSCLC who were treated with DEB-BACE between April 2017 and October 2022 and who were allocated to three groups: group A (MWA + DEB-BACE + PD-1 blockade; n=15), group B (MWA + DEB-BACE; n=25), and group C (DEB-BACE alone; n=55). The adverse events (AEs) were compared between the three groups. The outcomes were compared via Kaplan-Meier methods, including median progression-free survival (PFS) and overall survival (OS). Survival analyses were performed via the univariate and multivariate analyses to investigate the prognostic predictors. Results: The overall incidence of AEs in the groups A-C was 53.3% (8/15), 36.0% (9/25), and 32.7% (18/55), respectively, which did not represent a significant difference (P=0.42). No severe AEs (SAEs) occurred. Group A, compared with group B and group C, had a significantly longer estimated median PFS (33.0 vs. 7.0 vs. 3.0 months; P<0.001) and OS (33.0 vs. 13.0 vs. 6.0 months; P=0.002). PD-1 blockade (P=0.006), tumor number (P=0.01), and DEB-BACE/bronchial artery infusion (BAI) chemotherapy cycles (P=0.04) were identified as the predictors of PFS, while the predictors of OS were PD-1 blockade (P<0.001), number of metastases (P<0.001), tumor diameter (P<0.001), and DEB-BACE/BAI cycles (P=0.02). Conclusions: Compared with that of advanced NSCLC treated with MWA plus DEB-BACE or DEB-BACE alone, the maintenance treatment of immunotherapy after MWA plus DEB-BACE might provide a superior prognosis without increasing the risk of AEs.

Crotonoids A-H, Labdane-Type Diterpenoids with Anti-Inflammatory Activity from Croton sublyratus.

Croton sublyratus (Euphorbiaceae) is a traditional medicinal plant used by the Thai populace to treat helminthic infections and dermatologic conditions. In present study, eight new labdane-type diterpenoids, crotonoids A-H (1-8) and one known analogue (9) were isolated from the aerial parts of C. sublyratus. Compounds 6 and 7 belong to the rare class of 14,15-dinor-labdane diterpenoids. Compound 8 exhibited a rare 14,15,17-trinor-labdane skeleton. The structures of all these diterpenoids were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Compound 9 exhibited moderate anti-inflammatory activity via the inhibition of NO production in lipopolysaccharide-induced RAW 264.7 cells.

Promoting Oxygen Evolution Electrocatalysis by Coordination Engineering in Cobalt Phosphate.

Understanding the structure-activity correlation is an important prerequisite for the rational design of high-efficiency electrocatalysts at the atomic level. However, the effect of coordination environment on electrocatalytic oxygen evolution reaction (OER) remains enigmatic. In this work, the regulation of proton transfer involved in water oxidation by coordination engineering based on Co3(PO4)2 and CoHPO4 is reported. The HPO4 2- anion has intermediate pKa value between Co(II)-H2O and Co(III)-H2O to be served as an appealing proton-coupled electron transfer (PCET) induction group. From theoretical calculations, the pH-dependent OER properties, deuterium kinetic isotope effects, operando electrochemical impedance spectroscopy (EIS) and Raman studies, the CoHPO4 catalyst beneficially reduces the energy barrier of proton hopping and modulates the formation energy of high-valent Co species, thereby enhancing OER activity. This work demonstrates a promising strategy that involves tuning the local coordination environment to optimize PCET steps and electrocatalytic activities for electrochemical applications. In addition, the designed system offers a motif to understand the structure-efficiency relationship from those amino-acid residue with proton buffer ability in natural photosynthesis.

Interaction between catechol-O-methyltransferase Val/Met polymorphism and cognitive reserve for negative symptoms in schizophrenia.

BACKGROUND: Cognitive reserve (CR) and the catechol-O-methyltransferase (COMT) Val/Met polymorphism are reportedly linked to negative symptoms in schizophrenia. However, the regulatory effect of the COMT genotype on the relationship between CR and negative symptoms is still unexamined. AIM: To investigate whether the relationship between CR and negative symptoms could be regulated by the COMT Val/Met polymorphism. METHODS: In a cross-sectional study, 54 clinically stable patients with schizophrenia underwent assessments for the COMT genotype, CR, and negative symptoms. CR was estimated using scores in the information and similarities subtests of a short form of the Chinese version of the Wechsler Adult Intelligence Scale. RESULTS: COMT Met-carriers exhibited fewer negative symptoms than Val homozygotes. In the total sample, significant negative correlations were found between negative symptoms and information, similarities. Associations between information, similarities and negative symptoms were observed in Val homozygotes only, with information and similarities showing interaction effects with the COMT genotype in relation to negative symptoms (information, ß = -0.282, 95%CI: -0.552 to -0.011, P = 0.042; similarities, ß = -0.250, 95%CI: -0.495 to -0.004, P = 0.046). CONCLUSION: This study provides initial evidence that the association between negative symptoms and CR is under the regulation of the COMT genotype in schizophrenia.

A study on the mechanism of Beclin-1 m6A modification mediated by catalpol in protection against neuronal injury and autophagy following cerebral ischemia.

OBJECTIVE: Catalpol (CAT) has various pharmacological activities and plays a protective role in cerebral ischemia. It has been reported that CAT played a protective role in cerebral ischemia by upregulaing NRF1 expression. Bioinformatics analysis reveals that NRF1 can be used as a transcription factor to bind to the histone acetyltransferase KAT2A. However, the role of KAT2A in cerebral ischemia remains to be studied. Therefore, we aimed to investigate the role of CAT in cerebral ischemia and its related mechanism. METHODS: In vitro, a cell model of oxygen and glucose deprivation/reperfusion (OGD/R) was constructed, followed by evaluation of neuronal injury and the expression of METTL3, Beclin-1, NRF1, and KAT2A. In vivo, a MCAO rat model was prepared by means of focal cerebral ischemia, followed by assessment of neurological deficit and brain injury in MCAO rats. Neuronal autophagy was evaluated by observation of autophagosomes in neurons or brain tissues by TEM and detection of the expression of LC3 and p62. RESULTS: In vivo, CAT reduced the neurological function deficit and infarct volume, inhibited neuronal apoptosis in the cerebral cortex, and significantly improved neuronal injury and excessive autophagy in MCAO rats. In vitro, CAT restored OGD/R-inhibited cell viability, inhibited cell apoptosis, LDH release, and neuronal autophagy. Mechanistically, CAT upregulated NRF1, NRF1 activated METTL3 via KAT2A transcription, and METTL3 inhibited Beclin-1 via m6A modification. CONCLUSION: CAT activated the NRF1/KAT2A/METTL3 axis and downregulated Beclin-1 expression, thus relieving neuronal injury and excessive autophagy after cerebral ischemia.

IGF2BP3 modified GLI2 transcriptionally regulates SYVN1 and facilitates sepsis liver injury through autophagy.

Autophagy enhancement in septic liver injury can play a protective role. Nerveless, the mechanism of autophagy-mediated septic liver injury needs further investigation. Our study demonstrated that in septic condition, GLI Family Zinc Finger 2 (GLI2) was elevated, whereas peroxisome-proliferator-activated receptor α (PPARα) was downregulated. Suppressing GLI2 or synovialapoptosis inhibitor 1 (SYVN1) in LPS-exposed cells increased PPARα levels, enhanced cell viability and autophagy, while inhibiting apoptosis. LPS enhanced the GLI2-SYVN1 promoter binding. SYVN1 fostered ubiquitin-mediated degradation of PPARα. IGF2BP3 stabilized GLI2 mRNA by targeting its m6A site. Silencing IGF2BP3 led to decreased GLI2 and SYVN1 but increased PPARα levels, promoting cell survival and autophagy, while repressing apoptosis. This was counteracted by SYVN1 overexpression. In cecal ligation and puncture mice, IGF2BP3, SYVN1, or GLI2 knockdown ameliorated liver damage and augmented autophagy. In summary, IGF2BP3 enhanced GLI2 stability, overexpressed GLI2 subsequent promoted SYVN1 levels by interacting with its promoter, leading to ubiquitinated degradation of PPARα, thereby inhibiting PPARα-mediated autophagy and then exacerbating liver injury in sepsis.

Further clarification of cognitive processes of prospective memory in schizophrenia by comparing eye-tracking and ecologically-valid measurements.

The aim of this study is to compare ecologically-valid measure (the Cambridge Prospective Memory Test, CAMPROMPT) and laboratory measure (eye-tracking paradigm) in assessing prospective memory (PM) in individuals with schizophrenia spectrum disorders (SSDs). In addition, eye-tracking indices are used to examine the relationship between PM and other cognitive domains in SSDs patients. Initially, the study sample was formed by 32 SSDs patients and 32 healthy control subjects (HCs) who were matched in sociodemographic profile and the performance on CAMPROMPT. An eye-tracking paradigm was employed to examine the differences in PM accuracy and key cognitive processes (e.g., cue monitoring) between the two groups. Additional 31 patients were then recruited to investigate the relationship between PM cue monitoring, other cognitive functions, and the severity of clinical symptoms within the SSDs group. The monitoring of PM cue was reflected in total fixation time and total fixation counts for distractor words. Cognitive functions were assessed using the Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathology. SSDs patients exhibited fewer total fixation counts for distractor words and lower PM accuracy compared to HCs, even though they were priori matched on CAMPROMPT. Correlation analysis within the SSDs group (63 cases) indicated a negative correlation between PM accuracy and PANSS total score, and a positive correlation with working memory and attention/vigilance. Regression analysis within the SSDs group revealed that higher visual learning and lower PANSS total scores independently predicted more total fixation counts on distractor words. Impairment in cue monitoring is a critical factor in the PM deficits in SSDs. The eye-tracking laboratory paradigm has advantages over the ecologically-valid measurement in identifying the failure of cue detection, making it a more sensitive tool for PM deficits in patients with SSDs.

Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis.

White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.

Changes in the structure and enzyme binding of starches during in vitro enzymatic hydrolysis using mammalian mucosal enzyme mixtures.

Starches are hydrolyzed into monosaccharides by mucosal α-glucosidases in the human small intestine. However, there are few studies assessing the direct digestion of starch by these enzymes. The objective of this study was to investigate the changes in the structure and enzyme binding of starches during in vitro hydrolysis by mammalian mucosal enzymes. Waxy maize (WMS), normal maize (NMS), high-amylose maize (HAMS), waxy potato (WPS), and normal potato (NPS) starches were examined. The order of the digestion rate was different compared with other studies using a mixture of pancreatic α-amylase and amyloglucosidase. NPS was digested more than other starches. WPS was more digestible than WMS. Hydrolyzed starch from NPS, NMS, WPS, WMS, and HAMS after 24 h was 66.4, 64.2, 61.7, 58.7, and 46.2 %, respectively. Notably, a significant change in the morphology, reduced crystallinity, and a decrease in the melting enthalpy of the three starches (NPS, NMS, and WPS) after 24 h of hydrolysis were confirmed by microscopy, X-ray diffraction, and differential scanning calorimetry, respectively. The bound enzyme fraction of NPS, NMS, and WPS increased as hydrolysis progressed. In contrast, HAMS was most resistant to hydrolysis by mucosal α-glucosidases in terms of digestibility, changes in morphology, crystallinity, and thermal properties.

Paper-based fluorescence sensor array with functionalized carbon quantum dots for bacterial discrimination using a machine learning algorithm.

The rapid discrimination of bacteria is currently an emerging trend in the fields of food safety, medical detection, and environmental observation. Traditional methods often require lengthy culturing processes, specialized analytical equipment, and bacterial recognition receptors. In response to this need, we have developed a paper-based fluorescence sensor array platform for identifying different bacteria. The sensor array is based on three unique carbon quantum dots (CQDs) as sensing units, each modified with a different antibiotic (polymyxin B, ampicillin, and gentamicin). These antibiotic-modified CQDs can aggregate on the bacterial surface, triggering aggregation-induced fluorescence quenching. The sensor array exhibits varying fluorescent responses to different bacterial species. To achieve low-cost and portable detection, CQDs were formulated into fluorescent ink and used with an inkjet printer to manufacture paper-based sensor arrays. A smartphone was used to collect the responses generated by the bacteria and platform. Diverse machine learning algorithms were utilized to discriminate bacterial types. Our findings showcase the platform's remarkable capability to differentiate among five bacterial strains, within a detection range spanning from 1.0 × 103 CFU/mL to 1.0 × 107 CFU/mL. Its practicality is further validated through the accurate identification of blind bacterial samples. With its cost-effectiveness, ease of fabrication, and high degree of integration, this platform holds significant promise for on-site detection of diverse bacteria.

Value of quantitative microsurface structure analysis for evaluating the invasion depth of type 0-II early gastric cancer.

Background and Aim: The microsurface structure reflects the degree of damage to the glands, which is related to the invasion depth of early gastric cancer. To evaluate the diagnostic value of quantitative microsurface structure analysis for estimating the invasion depth of early gastric cancer. Methods: White-light imaging and narrow-band imaging (NBI) endoscopy were used to visualize the lesions of the included patients. The area ratio and depth-predicting score (DPS) of each patient were calculated; meanwhile, each lesion was examined by endoscopic ultrasonography (EUS). Results: Ninety-three patients were included between 2016 and 2019. Microsurface structure is related to the histological differentiation and progression of early gastric cancer. The receiver operating characteristic curve showed that when an area ratio of 80.3% was used as a cut-off value for distinguishing mucosal (M) and submucosal (SM) type 0-II gastric cancers, the sensitivity, specificity, and accuracy were 82.9%, 80.2%, and 91.6%, respectively. The accuracies for distinguishing M/SM differentiated and undifferentiated early gastric cancers were 87.4% and 84.8%, respectively. The accuracy of EUS for distinguishing M/SM early gastric cancer was 74.9%. DPS can only distinguish M-SM1 (SM infiltration <500 µm)/SM (SM infiltration ≥500 µm) with an accuracy of 83.8%. The accuracy of using area ratio for distinguishing 0-II early gastric cancers was better than those of using DPS and EUS (P < 0.05). Conclusion: Quantitative analysis of microsurface structure can be performed to assess M/SM type 0-II gastric cancer and is expected to be effective for judging the invasion depth of gastric cancer.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

SifiNet: a robust and accurate method to identify feature gene sets and annotate cells.

SifiNet is a robust and accurate computational pipeline for identifying distinct gene sets, extracting and annotating cellular subpopulations, and elucidating intrinsic relationships among these subpopulations. Uniquely, SifiNet bypasses the cell clustering stage, commonly integrated into other cellular annotation pipelines, thereby circumventing potential inaccuracies in clustering that may compromise subsequent analyses. Consequently, SifiNet has demonstrated superior performance in multiple experimental datasets compared with other state-of-the-art methods. SifiNet can analyze both single-cell RNA and ATAC sequencing data, thereby rendering comprehensive multi-omic cellular profiles. It is conveniently available as an open-source R package.

Precise tooth design using deep learning-based templates.

OBJECTIVES: In prosthodontic procedures, traditional computer-aided design (CAD) is often time-consuming and lacks accuracy in shape restoration. In this study, we combined implicit template and deep learning (DL) to construct a precise neural network for personalized tooth defect restoration. METHODS: Ninety models of right maxillary central incisor (80 for training, 10 for validation) were collected. A DL model named ToothDIT was trained to establish an implicit template and a neural network capable of predicting unique identifications. In the validation stage, teeth in validation set were processed into corner, incisive, and medium defects. The defective teeth were inputted into ToothDIT to predict the unique identification, which actuated the deformation of the implicit template to generate the highly customized template (DIT) for the target tooth. Morphological restorations were executed with templates from template shape library (TSL), average tooth template (ATT), and DIT in Exocad (GmbH, Germany). RMSestimate, width, length, aspect ratio, incisal edge curvature, incisive end retraction, and guiding inclination were introduced to assess the restorative accuracy. Statistical analysis was conducted using two-way ANOVA and paired t-test for overall and detailed differences. RESULTS: DIT displayed significantly smaller RMSestimate than TSL and ATT. In 2D detailed analysis, DIT exhibited significantly less deviations from the natural teeth compared to TSL and ATT. CONCLUSION: The proposed DL model successfully reconstructed the morphology of anterior teeth with various degrees of defects and achieved satisfactory accuracy. This approach provides a more reliable reference for prostheses design, resulting in enhanced accuracy in morphological restoration. CLINICAL SIGNIFICANCE: This DL model holds promise in assisting dentists and technicians in obtaining morphology templates that closely resemble the original shape of the defective teeth. These customized templates serve as a foundation for enhancing the efficiency and precision of digital restorative design for defective teeth.

Stress response of Microcystis aeruginosa to chlorine during transportation: The significance of surface-adsorbed organic matter.

The desorption of surface-adsorbed organic matter (S-AOM) without damaging algal cells was reported to be the key to destabilizing Microcystis aeruginosa (M. aeruginosa) cells while avoiding intracellular organic matter (IOM) release in our previous study. However, a temporal effect was found from spontaneous and continuous damage to algal cells even after quenching. This study aims to demonstrate the mechanism of the temporal inactivation effect and the stress response exhibited by chlorine-oxidized algal cells, and finally guide the prechlorination process for algae-laden water at water sources. Chlorine was proved to cause oxidative stress to M. aeruginosa cells, and result in a rapid increase in intracellular reactive oxygen species (ROS) levels. S-AOM appeared to have a protective effect on algal cells against oxidative damage, as evidenced by the maintenance of algal cell integrity and activated antioxidant enzymes. In addition, the activity of Caspase 3, a key protease for the execution of programmed cell death (PCD), was significantly enhanced during prechlorination. Cellular chromatin condensation and DNA fragmentation occurred in the early stages of PCD in algal cells. Therefore, the pre-treatment of algae-laden water at water sources, even with low chlorine doses, can induce a risk of significant algal cell death during the water transfer process due to activation of the PCD process, resulting in a higher health risk for drinking water. These findings indicate that both the dosage of chlorine and the duration of the transportation process should be considered during the prechlorination of algae-laden water, which can provide an important basis for avoiding increasing the risk to drinking water safety.

An investigation into the potential association between nutrition and Alzheimer's disease.

Background: Malnutrition is the most common nutritional issue in Alzheimer's disease (AD) patients, but there is still a lack of a comprehensive evaluation of the nutritional status in AD patients. This study aimed to determine the potential association of various nutritional indices with AD at different stages. Methods: Subjects, including individuals with normal cognition (NC) and patients diagnosed with AD, were consecutively enrolled in this cross-sectional study. Demographics, body composition, dietary patterns, nutritional assessment scales and nutrition-related laboratory variables were collected. Binary logistics regression analyses and receiver operating characteristic (ROC) curves were used to indicate the association between nutrition-related variables and AD at different stages. Results: Totals of 266 subjects, including 73 subjects with NC, 72 subjects with mild cognitive impairment due to AD (AD-MCI) and 121 subjects with dementia due to AD (AD-D) were included. There was no significant difference in dietary patterns, including Mediterranean diet and Mediterranean-DASH diet intervention for neurodegenerative delay (MIND) diet between the three groups. Lower BMI value, smaller hip and calf circumferences, lower Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) scores, and lower levels of total protein, albumin, globulin, and apolipoprotein A1 were associated with AD (all p < 0.05). Total protein and albumin levels had the greatest ability to distinguish AD from non-AD (AUC 0.80, 95% CI 0.74-0.84, p < 0.001), increased by combining calf circumference, MNA score and albumin level (AUC 0.83, 95% CI 0.77-0.88, p < 0.001). Albumin level had the greatest ability to distinguish NC from AD-MCI (AUC 0.75, 95% CI 0.67-0.82, p < 0.001), and MNA score greatest ability to distinguish AD-MCI from AD-D (AUC 0.72, 95% CI 0.65-0.78, p < 0.001). Conclusion: Nutritional status of AD patients is significantly compromised compared with normal controls, and tends to be worsened with AD progresses. Early identification and intervention of individuals with nutritional risk or malnutrition may be significantly beneficial for reducing the risk, development, and progression of AD.

Missense mutation of angiotensin converting enzyme gene in an Alzheimer's disease patient: a case report.

Alzheimer's disease (AD) is the most common type of cognitive impairment in the elderly. In this report, we presented a case of a 52-year-old woman with rapid disease progression within 6 months. She was diagnosed with mild dementia according to the clinical symptoms and neuropsychological assessment results. Based on the results of neuropathological proteins in cerebrospinal fluid, cranial magnetic resonance imaging, and positron emission tomography/computed tomography, the patient showed the presence of ß amyloid deposition, pathologic tau along with neurodegeneration [A+T+(N+)], indicative of AD. Whole exome sequencing revealed a heterozygous C-to-T missense mutation of nucleotide 3,755 (c.3755C > T) in exon 25 of the angiotensin converting enzyme (ACE) gene on chromosome 17q23 (rs762056936).

GTPase activity of porcine Mx1 plays a dominant role in inhibiting the N-Nsp9 interaction and thus inhibiting PRRSV replication.

Porcine Mx1 is a type of interferon-induced GTPase that inhibits the replication of certain RNA viruses. However, the antiviral effects and the underlying mechanism of porcine Mx1 for porcine reproductive and respiratory syndrome virus (PRRSV) remain unknown. In this study, we demonstrated that porcine Mx1 could significantly inhibit PRRSV replication in MARC-145 cells. By Mx1 segment analysis, it was indicated that the GTPase domain (68-341aa) was the functional area to inhibit PRRSV replication and that Mx1 interacted with the PRRSV-N protein through the GTPase domain (68-341aa) in the cytoplasm. Amino acid residues K295 and K299 in the G domain of Mx1 were the key sites for Mx1-N interaction while mutant proteins Mx1(K295A) and Mx1(K299A) still partially inhibited PRRSV replication. Furthermore, we found that the GTPase activity of Mx1 was dominant for Mx1 to inhibit PRRSV replication but was not essential for Mx1-N interaction. Finally, mechanistic studies demonstrated that the GTPase activity of Mx1 played a dominant role in inhibiting the N-Nsp9 interaction and that the interaction between Mx1 and N partially inhibited the N-Nsp9 interaction. We propose that the complete anti-PRRSV mechanism of porcine Mx1 contains a two-step process: Mx1 binds to the PRRSV-N protein and subsequently disrupts the N-Nsp9 interaction by a process requiring the GTPase activity of Mx1. Taken together, the results of our experiments describe for the first time a novel mechanism by which porcine Mx1 evolves to inhibit PRRSV replication. IMPORTANCE: Mx1 protein is a key mediator of the interferon-induced antiviral response against a wide range of viruses. How porcine Mx1 affects the replication of porcine reproductive and respiratory syndrome virus (PRRSV) and its biological function has not been studied. Here, we show that Mx1 protein inhibits PRRSV replication by interfering with N-Nsp9 interaction. Furthermore, the GTPase activity of porcine Mx1 plays a dominant role and the Mx1-N interaction plays an assistant role in this interference process. This study uncovers a novel mechanism evolved by porcine Mx1 to exert anti-PRRSV activities.

Transvenous endocardial pacing with SelectSecure™ 3830 lead in pediatric patients: case series of two infants and a literature review.

BACKGROUND: The SelectSecure™ 3830 lead is an innovative, lumenless, and thin active fixed lead with a nonretractable screw-in tip and a diameter of 4.1 Fr, making it the thinnest pacing lead available. Its high anti-extrusion properties and durability have shown favorable outcomes in cardiac pacing, especially in pediatric patients. The superfine design and easy implantation of the lead have rendered it a preferred choice in children, particularly in cases of congenital heart disease. CASE PRESENTATION: This case series presents two infant patients who underwent transvenous endocardial pacing using the SelectSecure™ 3830 lead, along with a comprehensive literature review on the topic. The study followed the patients for 5 years and 3 years, respectively, and observed stable pacing parameters, indicating a positive therapeutic outcome and safety. This article discusses the optimal age and body shape for transvenous lead implantation in infants and highlights the advantages and disadvantages of endocardial and epicardial pacing approaches. Although endocardial pacing offers several benefits such as minimal trauma, short hospital stay, and longer battery life, it may not be suitable for intracardiac shunts, and venous occlusion remains a concern. On the other hand, epicardial pacing may be considered for children with challenging endocardial access but comes with higher risk of lead failure and coronary artery compression. This study emphasizes the importance of careful follow-up in pediatric patients with pacing, as lead failure can occur in young patients owing to growth and development, leading to syncope and battery depletion. The article also underscores the significance of selecting the appropriate pacing location to minimize the impact of cardiac function, with right ventricular septal pacing emerging as a preferable option. CONCLUSIONS: The SelectSecure™ 3830 lead presents a promising solution for transvenous endocardial pacing in pediatric patients with high degree atrioventricular block and bradycardia, ensuring safe and effective pacing as they grow and develop.

DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8+ T-cell Immunity in Hepatocellular Carcinoma.

Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair antitumor immunity and thereby promote HCC progression. TGFß1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFß1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGFß1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression. SIGNIFICANCE: TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.